GIP/GLP1 CO-AGONIST COMPOUNDS

Abstract

The present invention relates to compounds having activity at both the human glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) receptors. The present invention also relates to compounds having an extended duration of action at each of these receptors. Furthermore, the present invention relates to compounds that may be administered orally. Compounds may be useful in the treatment of type 2 diabetes mellitus (“T2DM”). Also, the compounds may be useful in the treatment of obesity.

Claims

1. (canceled)

2. (canceled)

3. (canceled)

4. (canceled)

5. (canceled)

6. (canceled)

7. (canceled)

8. (canceled)

9. (canceled)

10. (canceled)

11. (canceled)

12. (canceled)

13. (canceled)

14. (canceled)

15. (canceled)

16. (canceled)

17. (canceled)

18. (canceled)

19. (canceled)

20. (canceled)

21. (canceled)

22. (canceled)

23. (canceled)

24. (canceled)

25. (canceled)

26. (canceled)

27. (canceled)

28. (canceled)

29. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

34. (canceled)

35. (canceled)

36. (canceled)

37. (canceled)

38. (canceled)

39. (canceled)

40. (canceled)

41. (canceled)

42. (canceled)

43. (canceled)

44. (canceled)

45. (canceled)

46. (canceled)

47. (canceled)

48. (canceled)

49. (canceled)

50. (canceled)

51. (canceled)

52. (canceled)

53. (canceled)

54. (canceled)

55. A compound, or a pharmaceutically acceptable salt thereof, of the formula: R.sub.1X.sub.1X.sub.2X.sub.3GTX.sub.6TSDX.sub.10X.sub.11X.sub.12X.sub.13X.sub.14DX.sub.16X.sub.17AX.sub.19X.sub.20X.sub.21X.sub.22X.sub.23X.sub.24X.sub.25X.sub.26X.sub.27X.sub.28X.sub.29X.sub.30X.sub.31 (SEQ ID NO:3) wherein: R.sub.1 is a modification of the N-terminal amino group wherein the modification is selected from the group consisting of Ac and absent; X.sub.1 is selected from the group consisting of Y, H, D-Tyr, F, desH, and desY; X.sub.2 is selected from the group consisting of Aib, αMeP, A, P, and D-Ala; or X.sub.1 and X.sub.2 combine to form desH-ψ[NHCO]-Aib; X.sub.3 is selected from the group consisting of E, N, Aad, and cTA; X.sub.6 is F; X.sub.10 is selected from the group consisting of A, L, H, 3l Pal, 4Pal, V, Y, E, αMeF, αMeF(2F), I, αMeY, Q, D-His, D-Tyr, cTA, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.11 is selected from the group consisting of S, αMeS, and D-Ser; X.sub.12 is selected from the group consisting of I, S, D-Ile, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.13 is selected from the group consisting of Aib, L, αMeL; X.sub.14 is selected from the group consisting of L and K, wherein K is conjugated to a C.sub.16-C.sub.22 fatty acid wherein said fatty acid is optionally conjugated to said K via a linker; X.sub.16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, R, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.17 is selected from the group consisting of K, Q, I, and an amino acid conjugated to a C.sub.16-C.sub.22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; X.sub.19 is selected from the group consisting of Q, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.20 is selected from the group consisting of Aib, Q, H, R, K, αMeK, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.21 is selected from the group consisting of H, Aad, D, Aib, T, A, E, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.22 is selected from the group consisting of F and αMeF; X.sub.23 is selected from the group consisting of I, L, A, G, F, H, E, V, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.24 is selected from the group consisting of S, Aad, D-Glu, E, Aib, H, V, A, Q, D, P, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.25 is selected from the group consisting of Y and αMeY; X.sub.26 is selected from the group consisting of L, αMeL, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.27 is selected from the group consisting of L, I, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.28 is selected from the group consisting of E, A, S, D-Glu, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.29 is selected from the group consisting of Aib, G, A, and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2)qCO.sub.2H; X.sub.30 is selected from the group consisting of C, G, G-R.sub.2 and K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H; X.sub.31 is absent or is selected from the group consisting of PX.sub.32X.sub.33X.sub.34-R.sub.2 (SEQ ID NO:4), PX.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39-R.sub.2 (SEQ ID NO:5), PX.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39X.sub.40-R.sub.2 (SEQ ID NO:6), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H] X.sub.32X.sub.33X.sub.34-R.sub.2 (SEQ ID NO:7), K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H] X.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39-R.sub.2 (SEQ ID NO:8), and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H] X.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39X.sub.40-R.sub.2 (SEQ ID NO:9); wherein: X.sub.32 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; X.sub.33 is S or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; X.sub.34 is selected from the group consisting of G, C, and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; X.sub.35 is A or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; X.sub.36 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; X.sub.37 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; X.sub.38 is P or K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; X.sub.39 is selected from the group consisting of C, S, and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; X.sub.40 is selected from the group consisting of C and K[(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H]; q is selected from the group consisting of 14, 15, 16, 17, 18, 19, and 20; and R.sub.2 is a modification of the C-terminal group, wherein the modification is NH.sub.2 or absent; or a pharmaceutically acceptable salt thereof; wherein if X.sub.30 is G-R.sub.2, then X.sub.31 is absent; wherein no more than one of X.sub.10, X.sub.12, X.sub.13, X.sub.14, X.sub.16, X.sub.17, X.sub.19, X.sub.20, X.sub.21, X.sub.23, X.sub.24, X.sub.26, X.sub.27, X.sub.28, X.sub.29, X.sub.30, X.sub.31, X.sub.32, X.sub.33, X.sub.34, X.sub.35, X.sub.36, X.sub.37, X.sub.38, X.sub.39, and X.sub.40 may be a substituent that contains a fatty acid; and wherein no more than one of X.sub.30, X.sub.34, X.sub.39, and X.sub.40 may be C; and wherein if one of X.sub.30, X.sub.34, X.sub.39, and X.sub.40 is C, then none of X.sub.10, X.sub.12, X.sub.13, X.sub.14, X.sub.16, X.sub.17, X.sub.19, X.sub.20, X.sub.21, X.sub.23, X.sub.24, X.sub.26, X.sub.27, X.sub.28, X.sub.29, X.sub.30, X.sub.31, X.sub.32, X.sub.33, X.sub.34, X.sub.35, X.sub.36, X.sub.37, X.sub.38, X.sub.39, and X.sub.40 is a substituent that contains a fatty acid.

56. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 55 wherein R.sub.1 is absent; X.sub.2 is Aib; X.sub.3 is E; X.sub.10 is Y; X.sub.11 is S; X.sub.12 is I; X.sub.14 is L; X.sub.16 is selected from the group consisting of K, E, Orn, Dab, Dap, S, T, H, Aib, αMeK, and R X.sub.17 is an amino acid conjugated to a C.sub.16-C.sub.22 fatty acid wherein said fatty acid is optionally conjugated to said amino acid via a linker; X.sub.19 is Q; X.sub.20 is selected from the group consisting of Aib, Q, H, and K; X.sub.21 is selected from the group consisting of H, D, T, A, and E; X.sub.22 is F; X.sub.23 is I; X.sub.24 is selected from the group consisting of D-Glu and E; X.sub.26 is L; X.sub.27 is I; X.sub.28 is selected from the group consisting of E, A, S, and D-Glu; X.sub.29 is selected from the group consisting of Aib, G, and A; X.sub.30 is selected from the group consisting of C, G, and G-R.sub.2; X.sub.31 is absent or is selected from the group consisting of PX.sub.32X.sub.33X.sub.34-R.sub.2 (SEQ ID NO:4), PX.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39-R.sub.2 (SEQ ID NO:5), and PX.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39X.sub.40-R.sub.2 (SEQ ID NO:6); wherein: X.sub.32 is S; X.sub.33 is S; X.sub.34 is selected from the group consisting of G and C; X.sub.35 is A; X.sub.36 is P; X.sub.37 is P; X.sub.38 is P; X.sub.39 is selected from the group consisting of C and S; and X.sub.40 is C.

57. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 56 wherein X.sub.17 is K(2-[2-(2-amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO—(CH.sub.2).sub.q—CO.sub.2H.

58. A compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 57 wherein PX.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39-R.sub.2 is selected from the group consisting of PSSGAPPPS (SEQ ID NO:301) and PSSGAPPPS-NH.sub.2 (SEQ ID NO:302).

59. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 57 wherein X.sub.28 is A; X.sub.29 G; X.sub.30 is G; X.sub.31 is PX.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39-R.sub.2 (SEQ ID NO:5) X.sub.34 is G; and X.sub.39 is S.

60. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 55 wherein X.sub.1 is selected from the group consisting of Y and D-Tyr; and X.sub.13 is αMeL.

61. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 55 wherein q is 16.

62. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 55 wherein q is 18.

63. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 55 wherein the compound is selected from the group consisting of SEQ ID NO:303, SEQ ID NO:304, SEQ ID NO:305, SEQ ID NO:306, SEQ ID NO:307, SEQ NO:308, and SEQ ID NO:392.

64. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 63 wherein the compound is SEQ ID NO:305.

65. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 63 wherein the compound is SEQ NO:307.

66. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 63 wherein the compound is SEQ ID NO:308.

67. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 63 wherein the compound is SEQ ID NO:392.

68. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 55 wherein the compound is a partial agonist on the GIP-1R.

69. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 68 wherein the compound stimulates GLP-1R induced activation of Gα.sub.s in the GIPR and GLP-1R HEK293 Cell Membrane Guanosine 5′-(gamma-thio) Triphosphate-[.sup.35S](GTPγS) Binding Assay.

70. A compound, or pharmaceutically acceptable salt thereof, as claimed by claim 69 wherein the compound is a partial agonist on the GLP-1R with respect to the β-arrestin-2 recruitment assay.

71. A method for treating a condition selected from the group consisting of type 2 diabetes mellitus, obesity, NAFLD, nonalcoholic steatohepatitis, dyslipidemia, and metabolic syndrome, comprising administering to a patient in need thereof, an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 55.

72. A method for treating obesity, comprising administering to a patient in need thereof, an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 55.

73. A method for providing therapeutic weight loss, comprising administering to a subject in need thereof, an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 55.

74. A method for treating type 2 diabetes mellitus comprising administering to a subject in need thereof, an effective amount of the compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 55.

75. A pharmaceutical composition comprising the compound, or a pharmaceutically acceptable salt thereof, as claimed by claim 55 and at least one pharmaceutically acceptable carrier, diluent, or excipient.

76. A pharmaceutical composition as claimed by claim 75 wherein the composition is administered as a subcutaneous injection.

77. A pharmaceutical composition as claimed by claim 75 wherein the composition is administered orally.

78. A pharmaceutical composition as claimed by claim 77 wherein the composition comprises a permeation enhancer and at least one pharmaceutically acceptable carrier, diluent, or excipient.

79. A pharmaceutical composition as claimed by claim 78 wherein the permeation enhancer is selected from the group consisting of sodium decanoate (“C10”), sodium taurodeoxycholate (“NaTDC”), lauroyl carnitine (“LC”), dodecyl maltoside (“C12-maltoside”), dodecyl phosphatidylcholine (“DPC”), sodium taurodeoxycholate (“NaTDC”), and a Rhamnolipid.

80. A pharmaceutical composition as claimed by claim 79 wherein the permeation enhancer is selected from the group consisting of C10 and LC.

81. A pharmaceutical composition as claimed by claim 80 wherein the permeation enhancer is C10.

82. A pharmaceutical composition as claimed by claim 81 wherein the composition comprises a permeation enhancer and a protease inhibitor, and at least one pharmaceutically acceptable carrier, diluent, or excipient.

83. A pharmaceutical composition as claimed by claim 82 wherein the protease inhibitor is selected from the group consisting of soybean trypsin inhibitor (“SBTI”), soybean trypsin-chymotrypsin inhibitor (“SBTCI”), ecotin, sunflower trypsin inhibitor (“SFTI”), leupeptin, citric acid, ethylenediaminetetraacetic acid (“EDTA”), sodium glycocholate and 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride (“AEBSF”).

84. A pharmaceutical composition a claimed by claim 83 wherein the protease inhibitor is selected from the group consisting of SBTI, SBTICI, and SFTI.

85. A pharmaceutical composition as claimed by claim 84 wherein the protease inhibitor is SBTI.

86. A pharmaceutical composition as claimed by claim 78 wherein the composition is a monolithic formulation.

87. A pharmaceutical composition as claimed by claim 78 wherein the composition is a multiparticulate formulation.

88. A pharmaceutical composition as claimed by claim 78 wherein the composition is a capsule or tablet.

89. A pharmaceutical composition as claimed by claim 86 wherein the composition is an enteric capsule or tablet.

90. (canceled)

91. (canceled)

92. (canceled)

93. (canceled)

94. (canceled)

95. (canceled)

Description

PEPTIDE SYNTHESIS

Example 1

[0271]

TABLE-US-00002 (SEQ ID NO: 10) Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ- Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2.

[0272] The structure of SEQ ID NO:10 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, αMeL13, K17, Aib20, D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:

##STR00006##

[0273] The peptide backbone of Example 1 is synthesized using Fluorenylmethyloxycarbonyl (Fmoc)/tert-Butyl (t-Bu) chemistry on a Symphony X peptide synthesizer (Gyros Protein Technologies. Tucson, Ariz.).

[0274] The resin consists of 1% DVB cross-linked polystyrene (Fmoc-Rink-MBHA Low Loading resin. 100-200 mesh, EMI) Millipore) at a substitution of 0.3-0.4 meq/g. Standard side-chain protecting groups were used. Fmoc-Lys(Mtt)-OH is used for the lysine at position 17 and Boc-Tyr(tBu)-OH) was used for the tyrosine at position 1. Fmoc groups are removed prior to each coupling step (2×7 minutes) using 20? piperidine in DMF. All standard amino acid couplings are performed for 1 hour to a primary amine and 3 hour to a secondary amine, using an equal molar ratio of Fmoc amino acid (0.3 mM), diisopropylcarbodiimide (0.9 mM) and Oxyma (0.9 mM), at a 9-fold molar excess over the theoretical peptide loading, Exceptions are couplings to C α-methylated amino acids, which are coupled for 3 hours. After completion of the synthesis of the peptide backbone, the resin is thoroughly washed with DCM for 6 times to remove residual DMF. The Mtt protecting group on the lysine at position 17 is selectively removed from the peptide resin using two treatments of 30% hexafluoroisopropanol (Oakwood Chemicals) in DCM (2×40-minute treatment),

[0275] Subsequent attachment of the fatty acid-linker moiety is accomplished by coupling of 2-[2-(2-Fmoc-amino-ethoxy)-ethoxy]-acetic acid (Fmoc-AEEA-OH, ChemPep, Inc.), Fmoc-glutamic acid α-t-butyl ester (Fmoc-Glu-OtBu, Ark Pharm, mono-OtBu-eicosanedioic acid (WuXi AppTec, Shanghai, China). 3-Fold excess of reagents (AA:PyAOP:DIPEA=1:1:1 mol/mol) are used for each coupling that is 1-hour long.

[0276] After the synthesis is complete, the peptide resin is washed with DCM, and then thoroughly air-dried. The dry resin is treated with 10 mL of cleavage cocktail (trifluoroacetic acid:water:triisopropylsilane, 95:2.5:2.5 v/v) for 2 hours at room temperature. The resin is filtered off, washed twice each with 2 mL of neat T′FA, and the combined filtrates are treated with 5-fold excess volume of cold diethyl ether (−20° C.) to precipitate the crude peptide. The peptide/ether suspension is then centrifuged at 3500 rpm for 2 min to form a solid pellet, the supernatant is decanted, and the solid pellet is triturated with ether two additional times and dried in vacuo. The crude peptide is solubilized in 20% acetonitrile/20% Acetic acid/60% water and purified by RP-HPLC on a Luna 5 μm Phenyl-Hexyl preparative column (21×250 mm, Phenomenex) with linear gradients of 100% acetonitrile and 0.1% TFA/water buffer system (30-50% acetonitrile in 60 min). The purity of peptide is assessed using analytical RP-HPLC and pooling criteria is >95%. The main pool purity of compound 1 is found to be 98.0%. Subsequent lyophilization of the final main product pool yielded the lyophilized peptide TFA salt. The molecular weight is determined by LC-MS (obsd: M+3=1657.2; Calc M+3=1657.0).

Example 2

[0277]

TABLE-US-00003 (SEQ ID NO: 11) Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ- Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2

[0278] The structure of SEQ ID NO:11 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, αMeL13, Orn16, K17, Aib20 D-Glu24, and Ser39 where the structures of these amino acid residues have been expanded:

##STR00007##

The compound according to SEQ ID NO:11 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1642.6; Calc M+3=1642.8).

Example 3

[0279] Example 3 is a compound represented by the following description:

TABLE-US-00004 (SEQ ID NO: 12) Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD-Orn-K((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-GLu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2

[0280] The structure of SEQ ID NO:12 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, αMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00008##

[0281] The compound according to SEQ ID NO:12 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1651.8; Calc M+3=1652.2).

Example 4

[0282]

TABLE-US-00005 (SEQ ID NO: 13) Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF-LD-Orn-K((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-C.sub.O2H)AQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPS-NH.sub.2

[0283] The structure of SEQ ID NO:13 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, 4Pal10, αMeL13, Orn16, K17, Aib20, D-Glu24 αMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00009##

The compound according to SEQ ID NO:13 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1642.5; Calc M+3=1642.1).

Example 5

[0284]

TABLE-US-00006 (SEQ ID NO: 14) Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeF-LD-Orn-K((2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPS-NH.sub.2

[0285] The structure of SEQ ID NO:14 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeF(2F)6, αMeL13, Orn16, K17, Aib20, D-Glu24,αMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00010##

[0286] The compound according to SEQ ID NO:14 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1626.1; Calc M+3=1626.1).

Example 6 Through Example 287

[0287] The compounds according to Examples 6 (SEQ ID NO:15) through Example 287 (SEQ ID NO:296) are prepared substantially as described by the procedures of Example 1.

TABLE-US-00007 Calculated Found SEQ MW MW Example Compound Name ID NO (average) (average) 6 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 15 4863.5 4862.1 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLLEGGPSSGAPPPS-NH.sub.2 7 Y-Aib-EGTFTSDYSILLDSK((2-[2-(2- 16 4822.4 4821.3 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLLEGGPSSGAPPPS-NH.sub.2 8 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 17 4863.5 4863.2 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 9 Y-Aib-EGTFTSDYSILLDSK((2-[2-(2- 18 4822.4 4820.7 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 10 Y-Aib-EGTFTSDYSILLDSIAQ-Aib- 19 4776.5 4775.4 AFIK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)YLLA- Aib-GPSSGAPPPS-NH.sub.2 11 Y-Aib-EGTFTSDYSILLDSIAQ-Aib- 20 4834.5 4834.8 AFIEYLLK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)- Aib-GPSSGAPPPS-NH.sub.2 12 Y-Aib-EGTFTSDYSILLDKIAQK((2-[2-(2- 21 4891.6 4890.0 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)-AFIEYLIEGGPSSGAPPPS- NH.sub.2 13 Y-Aib-EGTFTSDYSILLD-Aib-IAQK((2-[2- 22 4848.5 4846.8 (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)- AFIEYLIEGGPSSGAPPPS-NH.sub.2 14 Y-Aib-EGTFTSDYSILLDKIAQK((2-[2-(2- 23 4976.7 4975.5 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)EFIQYLLE-Aib- GPSSGAPPPS-NH.sub.2 15 H-Aib-EGTFTSDYSILLDKK((2-[2-(2- 24 4865.5 4863.9 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLLE-Aib- GPSSGAPPPS-NH.sub.2 16 H-Aib-EGTFTSDYSILLDKK((2-[2-(2- 25 4865.5 4863.9 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLIE-Aib- GPSSGAPPPS-NH.sub.2 17 H-Aib-EGTFTSDYSILLDKIAQK((2-[2-(2- 26 4444.1 4442.7 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AFIEYLLE-Aib-GPSSG-NH.sub.2 18 H-Aib-EGTFTSDYSI-αMeF-LDKK(Dab-(2- 27 4979.8 4978.8 [2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Dab-(2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-αMeK-AFIQYLLA-Aib- GPSSGAPKPS-NH.sub.2 19 H-Aib-EGTFTSDYSI-αMeF-LDKK(Dab-(2- 28 4948.8 4947.2 [2-(2-Amino-ethoxy)-ethoxy]-acetyl)-Dab-(2- [2-(2-Amino-ethoxy)-ethoxy]-acetyl)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-αMeK-AFIQYLLA-Aib- GPSSGAPPPS-NH.sub.2 20 Y-Aib-EGTFTSDYSI-αMeF-LDKK((2-[2- 29 4877.5 4875.9 (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 21 Y-Aib-EGTFTSDYSI-αMeF-LDEK((2[2- 30 4935.6 4934.1 (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-αMeK- AFIEYLLEGGPSSGAPPPS-NH.sub.2 22 Y-Aib-EGTFTSDYSI-αMeF-LDEK((2[2- 31 4963.6 4962.0 (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-αMeK-AFIEYLLE- Aib-GPSSGAPPPS-NH.sub.2 23 Y-Aib-EGTFTSDK((2-[2-(2-Amino-ethoxy)- 32 4813.5 4812.9 ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)SILLDKIAQ-Aib- AFIEYLIEGGPSSGAPPPS-NH2 24 Y-Aib-EGTFTSDYK((2-[2-(2-Amino- 33 4889.6 4888.6 ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)ILLDKIAQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 25 Y-Aib-EGTFTSDYSK((2-[2-(2-Amino- 34 4863.5 4862.5 ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)LLDKIAQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 26 Y-Aib-EGTFTSDYSIK((2-[2-(2-Amino- 35 4863.5 N/I ethoxy)-ethoxy]-acetyl).sub.2-[γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)LDKIAQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 27 Y-Aib-EGTFTSDYSILK((2-[2-(2-Amino- 36 4863.5 N/I ethoxy)-ethoxy]-acetyl).sub.2-[γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)DKIAQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 28 Y-Aib-EGTFTSDYSILLK((2-[2-(2-Amino- 37 4861.6 N/I ethoxy)-ethoxy]-acetyl).sub.2-[γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)KIAQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 29 Y-Aib-EGTFTSDYSILLDK((2-[2-(2-Amino- 38 4848.5 N/I ethoxy)-ethoxy]-acetyl).sub.2-[γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)IAQ-Aib-AFIEYLIEGGPSSGAPPPS- NH.sub.2 30 Y-Aib-EGTFTSDYSILLDKIK((2-[2-(2- 39 4905.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)Q-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 31 Y-Aib-EGTFTSDYSILLDKIAK((2-[2-(2- 40 4848.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 32 Y-Aib-EGTFTSDYSILLDKIAQ-Aib-K((2- 41 4905.6 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)FIEYLIEGGPSSGAPPPS-NH.sub.2 33 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 42 4863.5 N/I AFK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-[γ-Glu)-CO-(CH.sub.2).sub.18- CO2H)EYLIEGGPSSGAPPPS-NH.sub.2 34 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 43 4847.6 N/I AFIK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)24γ-Glu)-CO-(CH2)18- CO2H)YLIEGGPSSGAPPPS-NH2 35 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 44 4863.5 N/I AFIEYK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)IEGGPSSGAPPPS-NH.sub.2 36 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 45 4863.5 N/I AFIEYLK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)EGGPSSGAPPPS-NH.sub.2 37 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 46 4847.6 N/I AFIEYLIK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)GGPSSGAPPPS-NH.sub.2 38 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 47 4919.6 N/I AFIEYLIEK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)GPSSGAPPPS-NH.sub.2 39 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 48 4919.6 N/I AFIEYLIEGK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)PSSGAPPPS-NH.sub.2 40 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 49 4879.5 N/I AFIEYLIEGGK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)SSGAPPPS-NH.sub.2 41 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 50 4889.6 N/I AFIEYLIEGGPK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)SGAPPPS-NH.sub.2 42 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 51 4889.6 N/I AFIEYLIEGGPSK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)GAPPPS-NH.sub.2 43 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 52 4919.6 N/I AFIEYLIEGGPSSK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)APPPS-NH.sub.2 44 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 53 4905.6 N/I AFIEYLIEGGPSSGK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)PPPS-NH.sub.2 45 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 54 4879.5 N/I AFIEYLIEGGPSSGAK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)PPS-NH.sub.2 46 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 55 4879.5 N/I AFIEYLIEGGPSSGAPK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)PS-NH.sub.2 47 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 56 4879.5 N/I AFIEYLIEGGPSSGAPPK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)S-NH.sub.2 48 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 57 4889.6 N/I AFIEYLIEGGPSSGAPPPK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)-NH.sub.2 49 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 58 4976.7 N/I AFIEYLIEGGPSSGAPPPSK((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)-NH.sub.2 50 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 59 4414.0 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-C.sub.O2H)AQ-Aib-AFIEYLIEGGPSSG- NH.sub.2 51 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 60 4085.7 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLIEGG-NH.sub.2 52 Y-Aib-EGTFTSDYSI-αMeF-LDSK((2-[2-(2- 61 4836.4 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 53 H-Aib-EGTFTSDYSI-αMeF-LDKK((2-[2- 62 4851.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 54 H-Aib-EGTFTSDYSI-αMeF-LDKK((2[2- 63 4903.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18- CO.sub.2H)AQHAFIEYLIEGGPSSGAPPPS-NH.sub.2 55 H-Aib-EGTFTSDYSI-αMeF-LDEK((2[2- 64 4904.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18- CO.sub.2H)AQHAFIEYLIEGGPSSGAPPPS-NH.sub.2 56 Y-Aib-EGTFTSDYSI-αMeF-LDEK((2[2- 65 4930.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18- CO.sub.2H)AQHAFIEYLIEGGPSSGAPPPS-NH.sub.2 57 Y-Aib-EGT-αMeF-TSDYSILLDKK((2[2- 66 4877.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 58 Y-Aib-EGTFTSDYSSLLDKK((2-[2-(2- 67 4837.4 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 59 Y-Aib-EGTFTSDYSI-αMeF-LDEK((2[2- 68 4878.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 60 Y-Aib-EGTFTSDYSI-αMeF-LD-Aib-K((2- 69 4834.5 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 61 Y-Aib-EGTFTSDYSI-αMeF-LDSK((2-[2-(2- 70 4836.4 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLLEGGPSSGAPPPS-NH.sub.2 62 Y-Aib-EGTFTSDYSI-αMeF-LDKK((2[2- 71 4099.7 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLIEGG- NH.sub.2 63 Y-Aib-EGTFTSDYSI-αMeF-LDEK((2[2- 72 4100.6 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLIEGG- NH.sub.2 64 Y-Aib-EGTFTSDYSI-αMeF-LDSK((2-[2-(2- 73 4058.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLIEGG-NH.sub.2 65 Y-Aib-EGTFTSDYSI-αMeF-LDTK((2-[2- 74 4072.6 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLIEGG- NH.sub.2 66 Y-Aib-EGTFTSDYSI-αMeF-LDEK((2[2- 75 4878.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLLEGGPSSGAPPPS-NH.sub.2 67 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 76 4877.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-A-αMeF- IEYLIEGGPSSGAPPPS-NH.sub.2 68 Y-Aib-EGTFTSDY-αMeS-ILLDKK((2[2- 77 4877.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 69 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 78 4891.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 70 Y-Aib-EGTFTSDK((2-[2-(2-Amino-ethoxy)- 79 4035.7 N/I ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)SILLDKIAQ-Aib-AFIEYLIEGG-NH.sub.2 71 Y-Aib-EGTFTSDYSILK((2-[2-(2-Amino- 80 4085.7 N/I ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)DKIAQ-Aib-AFIEYLIEGG-NH.sub.2 72 Y-Aib-EGTFTSDYSILLDKIAQ-Aib-K((2- 81 4127.8 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)FIEYLIEGG-NH.sub.2 73 Y-Aib-EGTFTSDYSILLDKIAQ-Aib- 82 4069.7 N/I AFIEYLIK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)GG-NH.sub.2 74 Y-Aib-EGTFTSDYSI-αMeF-LDKK((2[2- 83 4891.6 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-A-αMeF- IEYLIEGGPSSGAPPPS-NH.sub.2 75 Y-Aib-EGTFTSDYSI-αMeF-LDKK((2[2- 84 4891.6 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEY-αMeF- IEGGPSSGAPPPS-NH.sub.2 76 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 85 4905.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- A-αMeF-IEYLIEGGPSSGAPPPS-NH.sub.2 77 Y-Aib-EGTFTSDYSILLKIAQ-Aib- 86 4764.5 N/I AFIEYLIEGGPSSGAPPK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)S-NH.sub.2 78 (D-Tyr)-Aib-EGTFTSDYSILLDKK((2-[2-(2- 87 4863.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 79 Ac-(D-Tyr)-AEGTFTSDYSILLDKK((2-[2- 88 4891.5 (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 80 Y-(D-Ala)-EGTFTSDYSILLDKK((2-[2-(2- 89 4849.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 81 Y-Aib-EGTFTSDY-(D-Ser)-ILLDKK((2-[2- 90 4863.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 82 Y-Aib-EGTFTSDYS-(D-Ile)-LLDKK((2-[2- 91 4863.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 83 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 92 4863.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLI-(D-Glu)- GGPSSGAPPPS-NH.sub.2 84 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 93 4863.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 85 Y-Aib-EGTFTSDASILLDKK((2-[2-(2- 94 4771.4 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 86 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 95 4877.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEAGPSSGAPPPS-NH.sub.2 87 Y-αMePro-EGTFTSDYSILLDKK((2-[2-(2- 96 4889.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 88 Y-Pro-EGTFTSDYSILLDKK((2-[2-(2- 97 4875.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 89 Y-Aib-Aad-GTFTSDYSILLDKK((2-[2-(2- 98 4877.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 90 Y-Aib-NGTFTSDYSILLDKK((2-[2-(2- 99 4848.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 91 Y-Aib-(γ-Glu)-GTFTSDYSILLDKK((2-[2- 100 4863.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 92 Y-Aib-EGT-αMeF-TSDK((2-[2-(2-Amino- 101 4049.7 N/I ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)SILLDKIAQ-Aib-AFIEYLIEGG-NH.sub.2 93 Y-Aib-EGT-αMeF-TSDYSILK((2-[2-(2- 102 4099.7 N/I Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO- (CH2)18-CO2H)DKIAQ-Aib-AFIEYLIEGG- NH2 94 Y-Aib-EGT-αMeF-TSDYSILLDKIAQ-Aib- 103 4141.8 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)2- (γ-Glu)-CO-(CH2)18-CO2H)FIEYLIEGG-NH2 95 Y-Aib-EGT-αMeF-TSDYSILLDKIAQ-Aib- 104 4083.7 N/I AFIEYLIK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)GG-NH.sub.2 96 Y-Aib-EGTFTSDK((2-[2-(2-Amino-ethoxy)- 105 4049.7 N/I ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)SI-αMeF-LDKIAQ-Aib- AFIEYLIEGG-NH.sub.2 97 Y-Aib-EGTFTSDYSI-αMeF-LDKIAQ-Aib- 106 4083.7 N/I AFIEYLIK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)GG-NH.sub.2 98 Y-Aib-EGT-αMeF-TSDYSILLDKK((2[2- 107 4099.7 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLIEGG- NH.sub.2 99 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 108 4113.7 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGG-NH.sub.2 100 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 109 4114.7 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGG-NH.sub.2 101 Y-Aib-EGT-αMeF(2F)-TSDYSI-Aib- 110 4090.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGG-NH.sub.2 102 Y-Aib-EGT-αMeF-TSDYSI-Aib-LDEK((2- 111 4072.6 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGG-NH.sub.2 103 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 112 4190.7 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGG-NH.sub.2 104 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 113 4162.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFIEYLIEGG-NH.sub.2 105 DesHis-ψ[NHCO]-Aib- 114 4822.5 N/I EGTFTSDYSILLDKK((2-[2-(2-Amino- ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-AFIEYLIEGGPSSGAPPPS- NH.sub.2 106 DesHis-Aib-EGTFTSDYSILLDKK((2-[2-(2- 115 4822.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 107 DesTyr-Aib-EGTFTSDYSILLDKK((2-[2-(2- 116 4848.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 108 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 117 4859.6 N/I Amino-ethoxy)-ethoxy]-acetyl)-AOC-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 109 Y-Aib-EGTFTSDYSILLDKK(AOC-(2-[2-(2- 118 4859.6 N/I Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 110 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 119 N/I Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)- (Trx)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 111 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 120 N/I Amino-ethoxy)-ethoxy]-acetyl)-(Trx)-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 112 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 121 4846.5 N/I Amino-ethoxy)-ethoxy]-acetyl)-(ϵK)-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 113 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 122 4862.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(ϵK)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 114 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 123 4845.6 N/I Amino-ethoxy)-ethoxy]-acetyl)-(ϵK)-(ϵK)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 115 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 124 4892.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 116 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 125 4950.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 117 Y-Aib-EGT-αMeF-TSDYSI-Aib-LDEK((2- 126 4850.4 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 118 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 127 4968.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 119 F-Aib-EGT-αMeF-TSDYSI-αMeF- 128 4876.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 120 Y-Aib-cTA-GT-αMeF-TSDYSI-αMeF- 129 4902.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 121 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 130 4935.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQQAFIEYLIEGGPSSGAPPPS-NH.sub.2 122 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 131 4963.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQQAFIEYLIE-Aib-GPSSGAPPPS- NH.sub.2 123 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 132 4500.1 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSG-NH.sub.2 124 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 133 4501.0 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSG-NH.sub.2 125 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 134 5020.7 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu).sub.2-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 126 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 135 4905.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEAGPSSGAPPPS-NH.sub.2 127 Y-Aib-EGT-αMeF-TSDISILLDKK((2-[2-(2- 136 4827.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 128 Y-Aib-EGT-αMeF-TSDHSILLDKK((2[2- 137 4851.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 129 Y-Aib-EGT-αMeF-TSDLSILLDKK((2[2- 138 4827.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 130 Y-Aib-EGT-αMeF-TSDESILLDKK((2[2- 139 4843.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 131 Y-Aib-EGT-αMeF-TSD-αMeF- 140 4875.6 N/I SILLDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 132 Y-Aib-EGT-αMeF-TSD-3Pal-SILLDKK((2- 141 4862.5 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(y- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 133 DesTyr-Aib-EGT-αMeF-TSDYSI-Aib- 142 4835.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 134 DesTyr-Aib-EGT-αMeF(2F)-TSDYSI- 143 4953.5 N/I αMeF-LDEK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-EFIEYLIEGGPSSGAPPPS- NH.sub.2 135 H-Aib-NGTFTSDYSILLDKK((2-[2-(2- 144 4822.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 136 Y-Aib-EGTFTSDASILLDKK((2-[2-(2- 145 4785.4 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEAGPSSGAPPPS-NH.sub.2 137 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 146 4963.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- Aad-FIEYLIEGGPSSGAPPPS-NH.sub.2 138 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 147 4907.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- SFIEYLIEGGPSSGAPPPS-NH.sub.2 139 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 148 4921.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFIEYLIEGGPSSGAPPPS-NH.sub.2 140 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 149 4935.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- DFIEYLIEGGPSSGAPPPS-NH.sub.2 141 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 150 4933.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- IFIEYLIEGGPSSGAPPPS-NH.sub.2 142 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 151 4957.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- HFIEYLIEGGPSSGAPPPS-NH.sub.2 143 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 152 4905.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- Aib-FIEYLIEGGPSSGAPPPS-NH.sub.2 144 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 153 4957.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQH- Aib-FIEYLIEGGPSSGAPPPS-NH.sub.2 145 Y-Aib-EGT-αMeF-TSDASI-αMeF- 154 4799.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 146 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 155 4967.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIQYLIEGGPSSGAPPPS-NH.sub.2 147 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 156 4982.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-Aad-YLIEGGPSSGAPPPS-NH.sub.2 148 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 157 4910.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIAYLIEGGPSSGAPPPS-NH.sub.2 149 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 158 4938.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIVYLIEGGPSSGAPPPS-NH.sub.2 150 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 159 4926.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFISYLIEGGPSSGAPPPS-NH.sub.2 151 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 160 4936.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIPYLIEGGPSSGAPPPS-NH.sub.2 152 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 161 4924.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-Aib-YLIEGGPSSGAPPPS-NH.sub.2 153 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 162 4976.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIHYLIEGGPSSGAPPPS-NH.sub.2 154 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 163 4942.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 155 Y-Aib-EGT-αMeF(2F)-TSD-cTA-SI-αMeF- 164 4944.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 156 Y-Aib-EGT-αMeF(2F)-TSD-2Pal-SI-αMeF- 165 4953.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 157 Y-Aib-EGT-αMeF(2F)-TSD-3Pal-SI-αMeF- 166 4953.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 158 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 167 4953.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 159 Y-Aib-EGT-αMeF(2F)-TSD-αMeF-SI- 168 4938.5 N/I αMeF-LDEK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-EFIEYLIEGGPSSGAPPPS- NH.sub.2 160 Y-Aib-EGT-αMeF(2F)-TSD-Aib-SI-αMeF- 169 4862.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 161 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 170 4594.1 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu).sub.2-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSG-NH.sub.2 162 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 171 4568.1 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu).sub.2-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-HLIEGGPSSG-NH.sub.2 163 H-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 172 4942.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 164 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 173 4914.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLI-(D-Glu)-GGPSSGAPPPS- NH.sub.2 165 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 174 4912.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-αMeF-LI-(D-Glu)- GGPSSGAPPPS-NH.sub.2 166 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 175 4136.7 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGG-NH.sub.2 167 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 176 4465.0 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSG-NH.sub.2 168 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 177 4914.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 169 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 178 4886.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 170 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 179 4858.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.14-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 171 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF-LD- 180 4899.5 N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 172 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF-LD- 181 4885.5 N/I Dab-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 173 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF-LD- 182 4871.5 N/I Dap-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 174 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 183 4785.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-TFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 175 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 184 4913.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(ϵK)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 176 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 185 4885.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(ϵK)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 177 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 186 4922.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- HFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 178 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 187 4894.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.14-CO.sub.2H)AQ-Aib- HFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 179 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 188 4473.0 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- HFI-(D-Glu)-YLIEGGPSSG-NH.sub.2 180 Y-Aib-EGT-αMeF(2F)-TSDHSI-αMeF- 189 4144.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- HFI-(D-Glu)-YLIEGG-NH.sub.2 181 Y-Aib-EGT-αMeF(2F)-TSD-3Pal-SI-αMeF- 190 4953.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH2 182 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 191 4953.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 183 Y-Aib-EGT-αMeF(2F)-TSDLSI-αMeF- 192 4918.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 184 Y-Aib-EGT-αMeF(2F)-TSD-(D-Tyr)-SI- 193 4968.5 N/I αMeF-LDEK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 185 Y-Aib-EGT-αMeF(2F)-TSD-(D-His)-SI- 194 4942.5 N/I αMeF-LDEK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 186 Y-Aib-EGT-αMeF(2F)-TSD-αMeY-SI- 195 4982.6 N/I αMeF-LDEK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 187 Y-Aib-EGT-αMeF(2F)-TSDQSI-αMeF- 196 4933.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 188 Y-Aib-EGT-αMeF(2F)-TSD-3Pal-SI-αMeF- 197 4909.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-Aib-YLIEGGPSSGAPPPS-NH.sub.2 189 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 198 4909.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-Aib-YLIEGGPSSGAPPPS-NH.sub.2 190 H-Aib-EGT-αMeF(2F)-TSD-3Pal-SI-αMeF- 199 4927.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 191 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeF- 200 4904.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 192 Y-Aib-EGT-αMeF(2F)-TSDASI-αMeF- 201 4876.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 193 Y-αMePro-EGTFTSDYSILLDEK((2-[2-(2- 202 4933.5 N/I Amino-ethoxy)-ethoxy]-acetyl)2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQQAFIEYLIEGGPSSGAPPPS-NH.sub.2 194 Y-αMePro-EGTFTSDYSILLDEK((2-[2-(2- 203 4942.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQHAFIEYLIEGGPSSGAPPPS-NH.sub.2 195 Y-αMePro-EGTFTSDYSILLDRK((2-[2-(2- 204 4960.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQQAFIEYLIEGGPSSGAPPPS-NH.sub.2 196 Y-αMePro-EGTFTSDYSILLDRK((2-[2-(2- 205 4969.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQHAFIEYLIEGGPSSGAPPPS-NH.sub.2 197 Y-αMePro-EGTFTSDYSILLDEK((2-[2-(2- 206 4456.0 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQQAFIEYLIEGGPSSG- NH.sub.2 198 (D-Tyr)-αMePro-EGTFTSDYSILLDEK((2- 207 4456.0 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.16- CO.sub.2H)AQQAFIEYLIEGGPSSG-NH.sub.2 199 DesTyr-Aib-EGTFTSDYSILLDEK((2-[2-(2- 208 4892.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQQAFIEYLIEGGPSSGAPPPS-NH.sub.2 200 DesTyr-AEGTFTSDYSILLDEK((2-[2-(2- 209 4878.4 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQQAFIEYLIEGGPSSGAPPPS-NH.sub.2 201 DesHis-αMePro-EGTFTSDYSILLDEK((2- 210 4892.5 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQQAFIEYLIEGGPSSGAPPPS-NH.sub.2 202 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 211 4938.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)-(γ-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 203 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 212 4952.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 204 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 213 4924.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 205 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 214 4795.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 206 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 215 4823.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 207 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 216 4923.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(6K)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 208 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 217 4912.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.14-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 209 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 218 4911.4 N/I Dab-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 210 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 219 4897.5 N/I Dap-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 211 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 220 4953.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)-(γ-Glu)-(2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 212 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 221 4967.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 213 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 222 4922.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 214 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 223 4811.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 215 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 224 4839.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 216 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 225 4967.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(ϵK)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 217 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 226 4939.5 N/I Dab-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 218 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 227 4925.5 N/I Dap-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 219 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 228 4491.0 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSG-NH.sub.2 220 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 229 4162.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGG-NH.sub.2 221 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 230 4940.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 222 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 231 4982.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 223 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 232 4982.6 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIE-αMeY-LIEGGPSSGAPPPS-NH.sub.2 224 Y-Aib-EGT-αMeF(2F)-TSDYSI-Aib- 233 4926.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 225 Y-Aib-EGT-αMeF-TSDYSI-Aib-LDEK((2- 234 4908.5 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 226 Y-Aib-EGT-αMeF(2F)-TSDYSILLDEK((2- 235 4954.5 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 227 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 236 4950.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 228 Y-Aib-EGT-αMeF-TSDYSI-αMeF- 237 4500.1 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSG-NH.sub.2 229 Y-Aib-EGT-αMeF(2F)-TSDYS-αMeF- 238 4855.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 230 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 239 4976.6 N/I LDHK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 231 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 240 4939.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 232 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 241 4910.5 N/I LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 233 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 242 4896.5 N/I LD-Dab-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 234 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SILLD- 243 4882.4 N/I Dab-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 235 Y-Aib-EGT-αMeF-TSD-4Pal-SI-αMeF-LD- 244 4878.5 N/I Dab-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 236 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 245 4939.5 N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 237 Y-Aib-EGT-αMeF(2F)-TSDASI-αMeF-LD- 246 4847.4 N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(C.sub.H2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 238 Y-Aib-EGT-αMeF(2F)-TSDLSI-αMeF-LD- 247 4889.5 N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 239 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 248 4896.5 N/I LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 240 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 249 4866.5 N/I LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 241 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeF-LD- 250 N/I N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 242 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeF-LD- 251 N/I N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 243 Y-Aib-EGT-αMeF(2F)-TSDLSI-αMeF-LD- 252 N/I N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 244 Y-Aib-EGT-αMeF(2F)-TSDLSI-αMeF-LD- 253 N/I N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH2).sub.16-CO.sub.2H)AQ-Aib- AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 245 Y-Aib-EGT-αMeF(2F)-TSDASI-αMeF-LD- 254 N/I N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- TFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 246 Y-Aib-EGT-αMeF(2F)-TSDASI-αMeF-LD- 255 N/I N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 247 Y-Aib-EGT-αMeF(2F)-TSDYSI-Aib-LD- 256 4883.4 N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 248 Y-Aib-EGT-αMeF(2F)-TSDYSILLD-Orn- 257 4911.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 249 Y-Aib-EGT-αMeF(2F)-TSDYSI-Nle-LD- 258 4911.5 N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 250 Y-Aib-EGT-αMeF(2F)-TSDYSI-Aib-LD- 259 4911.5 N/I Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 251 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 260 4893.6 N/I LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(ϵK)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 252 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 261 4835.6 N/I LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(ϵK)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFI-(D-Glu)-αMeY-LIAGGPSSGAPPP5- NH.sub.2 253 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 262 4849.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQAAFIEYLIEGGPSSGAPPPS-NH.sub.2 254 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 263 4906.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQQAFIEYLIEGGPSSGAPPPS-NH.sub.2 255 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 264 4915.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQHAFIEYLIEGGPSSGAPPPS-NH.sub.2 256 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 265 4906.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQKAFIEYLIEGGPSSGAPPPS-NH.sub.2 257 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 266 4934.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQRAFIEYLIEGGPSSGAPPPS-NH.sub.2 258 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 267 4907.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQKAFIEYLIEGGPSSGAPPPS-NH.sub.2 259 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 268 4864.4 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 260 Y-Aib-EGTFTSDHSILLDKK((2-[2-(2- 269 4837.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 261 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 270 4907.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQEAFIEYLIEGGPSSGAPPPS-NH.sub.2 262 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 271 4879.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQTAFIEYLIEGGPSSGAPPPS-NH.sub.2 263 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 272 4865.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18- CO.sub.2H)AQSAFIEYLIEGGPSSGAPPPS-NH.sub.2 264 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 273 4475.0 N/I LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGGPSSG-NH.sub.2 265 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 274 4146.7 N/I LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGG-NH.sub.2 266 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 275 4385.94 4386.6 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFIEYLIEGGPSSG- NH.sub.2 267 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 276 4057.62 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFIEYLIEGG-NH.sub.2 268 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 277 4386.88 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFIEYLIEGGPSSG- NH.sub.2 269 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 278 4058.56 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFIEYLIEGG-NH.sub.2 270 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 279 4443.98 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-C.sub.O2H)AQ-Aib-EFIEYLIEGGPSSG- NH.sub.2 271 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 280 4115.66 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-EFIEYLIEGG-NH.sub.2 272 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 281 4327.91 4327.8 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFIEYLIAGGPSSG- NH.sub.2 273 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 282 3999.58 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFIEYLIAGG-NH.sub.2 274 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- 283 4397.95 N/I (CH.sub.2).sub.16-CO.sub.2H)AQPAFIEYLIEGGPSSG- NH.sub.2 275 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 284 4069.63 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQPAFIEYLIEGG-NH.sub.2 276 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 285 4224.59 N/I LDEKAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 277 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 286 4224.55 N/I LDEQAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 278 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 287 4327.74 N/I LDEKAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPSC-NH.sub.2 279 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF- 288 4327.69 N/I LDEQAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPSC-NH.sub.2 280 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 289 4210.61 N/I Orn-KAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 281 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 290 4209.58 N/I Orn-QAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 282 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 291 4312.77 N/I Orn-KAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPSC-NH.sub.2 283 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeF-LD- 292 4312.73 N/I Orn-QAQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPSC-NH.sub.2 284 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 293 4208.64 N/I LD-Orn-KAQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPS-NH.sub.2 285 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 294 4208.6 N/I LD-Orn-QAQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPS-NH.sub.2 286 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 295 4311.78 N/I LD-Orn-KAQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPSC-NH.sub.2 287 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeF- 296 4311.74 N/I LD-Orn-QAQ-Aib-EFI-(D-Glu)-αMeY- LIEGGPSSGAPPPSC-NH.sub.2 N/I means Not Included

Example 288

[0288]

TABLE-US-00008 (SEQ ID NO: 303) Y-Aib-EGTFTSDYSILLDKK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ- Aib-AFIEYLIAGGPSSGAPPPS-NH.sub.2

[0289] The structure of SEQ ID NO:303 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00011##

[0290] The compound according to SEQ ID NO:303 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1602.5; Calc M+3=1602.8).

Example 289

[0291]

TABLE-US-00009 (SEQ ID NO: 304) Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2-Amino- ethoxy)-ethoxy]-acety1).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH.sub.2

[0292] The structure of SEQ ID NO:304 is depicted below using the standard single letter amino acid codes with the exception of residues Aib2, αMeL13, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00012##

[0293] The compound according to SEQ ID NO:304 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1626.8; Calc M+3=1626.8).

Example 290

[0294]

TABLE-US-00010 (SEQ ID NO: 305) (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- (2-Amino-ethoxy)-ethoxy]-acety1).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFIEYLIAGGPSSGAPPPS-NH.sub.2

[0295] The structure of SEQ ID NO:305 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyr1, Aib2, αMeL13, K17, Aib20, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00013##

The compound according to SEQ ID NO:305 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1626.6; Calc M+3=1626.8).

Example 291

[0296]

TABLE-US-00011 (SEQ ID NO: 306) (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- K((2-[2-(2-Amino-ethoxy)-ethoxy]-acety1).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFI- (D-Glu)-YLIAGGPSSGAPPPS-NH.sub.2

[0297] The structure of SEQ ID NO:306 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyr1, Aib2, αMeL13, Orn16, K17, Aib20, D-Glu24, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00014##

The compound according to SEQ ID NO:306 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1602.4; Calc M+3=1602.8).

Example 292

[0298]

TABLE-US-00012 (SEQ ID NO: 307) (D-Tyr)-Aib-EGTFTSDYSI-αMeL- LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H) AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH.sub.2

[0299] The structure of SEQ ID NO:307 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyr1, Aib2, αMeL13, K17, Aib20, αMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00015##

The compound according to SEQ ID NO:307 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1631.3; Calc M+3=1631.5).

Example 293

[0300]

TABLE-US-00013 (SEQ ID NO: 308) (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- K((2-[2-(2-Amino-ethoxy)-ethoxy]- acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H) AQ-Aib-EFIE-αMeY-LIAGGPSSGAPPPS-NH.sub.2

[0301] The structure of SEQ ID NO:308 is depicted below using the standard single letter amino acid codes with the exception of residues D-Tyr1, Aib2, αMeL13, Orn16, K17, Aib20, αMeY25, and Ser39, where the structures of these amino acid residues have been expanded:

##STR00016##

The compound according to SEQ ID NO:308 is prepared substantially as described by the procedures of Example 1. The molecular weight is determined by LC-MS (obsd: M+3=1626.5; Calc M+3=1626.8).

Example 294 Through Example 381

[0302] The compounds according to Examples 294 (SEQ ID NO:309) through Example 381 (SEQ ID NO:396) are prepared substantially as described by the procedures of Example 1.

TABLE-US-00014 SEQ Calculated Found ID MW MW Example Compound Name NO (average) (average) 294 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 309 4100.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQQAFIEYLIEGG-NH.sub.2 295 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 310 4109.7 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQHAFIEYLIEGG-NH.sub.2 296 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 311 4429.0 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQKAFIEYLIEGGPSSG- NH.sub.2 297 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 312 4057.6 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-EFIEYLIAGG-NH.sub.2 298 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 313 4313.9 N/I Amino-ethoxy)-ethoxy]-acety1).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFVEYLIEGGPSSG-NH.sub.2 299 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 314 4385.9 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFLEYLIEGGPSSG-NH.sub.2 300 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 315 4400.0 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSG-NH.sub.2 301 Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 316 4400.0 4399.2 (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSG-NH.sub.2 302 Y-Aib-EGT-αMeF(2F)-TSDYSILLDKK((2- 317 4418.0 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSG-NH.sub.2 303 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 318 4400.9 4400.7 (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSG-NH.sub.2 304 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 319 4458.0 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSG-NH.sub.2 305 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 320 4341.9 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFLEYLIAGGPSSG-NH.sub.2 306 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 321 4400.0 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSG-NH.sub.2 307 Y-Aib-EGT-αMeF-TSDYSILLDEK((2-[2- 322 4400.9 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSG-NH.sub.2 308 Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 323 4458.0 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSG-NH.sub.2 309 Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 324 4341.9 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSG-NH.sub.2 310 Y-Aib-EGT-αMeF-TSDYSILLDKK((2-[2- 325 4400.0 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSG-NH.sub.2 311 Y-Aib-EGT-αMeF(2F)-TSDYSILLDEK((2- 326 4418.9 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSG-NH.sub.2 312 Y-Aib-EGT-αMeF(2F)-TSDYSILLDKK((2- 327 4476.0 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- efieylieggpssg-NH.sub.2 313 Y-Aib-EGT-αMeF(2F)-TSDYSILLDKK((2- 328 4359.9 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSG-NH.sub.2 314 Y-Aib-EGT-αMeF(2F)-TSDYSILLDKK((2- 329 4418.0 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSG-NH.sub.2 315 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 330 4835.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 316 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 331 4777.4 4777.2 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 317 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 332 4356.0 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIEYLIAGGPSSG- NH.sub.2 318 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 333 4414.0 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFlEYLIAGGPSSG- NH.sub.2 319 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 334 4863.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 320 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 335 4430.0 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-DFIEYLIEGGPSSG- NH.sub.2 321 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 336 4416.0 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-TFIEYLIEGGPSSG- NH.sub.2 322 Y-Aib-EGTFTSDYSILLDKK((2-[2-(2- 337 4452.0 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-HFIEYLIEGGPSSG- NH.sub.2 323 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 338 4850.4 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 324 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 339 4819.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2)1s-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 325 Y-Aib-EGT-αMeF(2F)-TSDYSILLDKK((2- 340 4895.5 N/I [2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ- Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 326 F-Aib-EGTFTSDYSILLDKK((2-[2-(2- 341 4847.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 327 F-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2- 342 4861.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 328 F-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2- 343 4847.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFIEYLIEAGPSSGAPPPS-NH.sub.2 329 (D-Tyr)-Aib-EGT-αMeF- 344 4877.5 N/I TSDYSILLDKK((2-[2-(2-Ainino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-AFIEYLIEGGPSSGAPPPS- NH.sub.2 330 Y-Aib-EGTFTSDYSILLDEK((2-[2-(2- 345 4806.4 4805.4 Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 331 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 346 4878.5 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 332 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 347 4820.4 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 333 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 348 4935.6 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIEGGPSSGAPPPS-NH.sub.2 334 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 349 4877.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2FI)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 335 (D-Tyr)-Aib-EGT-αMeF-TSDYSI-αMeL- 350 4891.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIEGGPSSGAPPPS-NH.sub.2 336 (D-Tyr)-Aib-EGT-αMeF(2F)-TSDYSI- 351 4909.5 N/I αMeL-LDKK((2-[2-(2-Amino-ethoxy)- ethoxy]-acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18- CO.sub.2H)AQ-Aib-AFIEYLIEGGPSSGAPPPS- NH.sub.2 337 F-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2-(2- 352 4803.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 338 F-Aib-EGTFTSDYSl-αMeL-LDKK((2-[2-(2- 353 4861.5 N/I Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)-CO- (CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 339 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 354 4732.4 4732.2 (2-Amino-ethoxy)-ethoxy]-acetyl)-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 340 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 355 4819.5 4818.8 LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 341 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 356 4820.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 342 (D-Tyr)-Aib-EGTFTSDYSl-αMeL- 357 4878.5 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 343 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 358 4820.4 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFI-(D-Glu)- YLIAGGPSSGAPPPS-NH.sub.2 344 Y-Aib-EGTFTSDYSI-αMeL-LDEK((2-[2- 359 4864.4 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- DFIEYLIAGGPSSGAPPPS-NH.sub.2 345 (D-Tyr)-Aib-EGT-αMeF-TSDYSI-αMeL- 360 4891.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 346 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 361 4805.5 4804.8 K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 347 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Dab- 362 4791.4 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 348 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Dap- 363 4807.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIEYLIAGGPSSGAPPPS-NH.sub.2 349 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 364 4863.5 4862.7 K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 350 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Dab- 365 4849.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 351 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Dap- 366 4835.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 352 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 367 4819.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFI-(D-Glu)-YLIAGGPSSGAPPPS-NH.sub.2 353 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 368 4935.6 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 354 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 369 4863.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIAGGPSSGAPPPS-NH.sub.2 355 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 370 4921.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 356 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 371 4877.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFI-(D-Glu)-YL1EGGPSSGAPPPS-NH.sub.2 357 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 372 4863.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFI-(D- Glu)-YLIEGGPSSGAPPPS-NH.sub.2 358 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 373 4791.4 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFVEYLIAGGPSSGAPPPS-NH.sub.2 359 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 374 4849.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)A0-Aib- EFVEYLIAGGPSSGAPPPS-NH.sub.2 360 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 375 4849.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFVEYLIEGGPSSGAPPPS-NH.sub.2 361 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 376 4805.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFV-(D-Glu)-YLIAGGPSSGAPPPS-NH.sub.2 362 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 377 4791.4 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFV-(D- Glu)-YLIAGGPSSGAPPPS-NH.sub.2 363 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 378 4777.4 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFI-(D- Glu)-YLIAGGPSSGAPPPS-NH.sub.2 364 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 379 4763.4 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFV-(D- Glu)-YLIAGGPSSGAPPPS-NH.sub.2 365 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 380 4833.5 4832.4 LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIE-αMeY-LIAGGPSSGAPPPS-NH.sub.2 366 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 381 4819.5 4818.3 K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-AFIE- αMeY-LIAGGPSSGAPPPS-NH.sub.2 367 Y-Aib-EGTFTSDYSI-αMeL-LDKK((2-[2- 382 4891.6 N/I (2-Amino-ethoxy)-ethoxy]-acetyl).sub.2-(γ-Glu)- CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFIE-αMeY- LIAGGPSSGAPPPS-NH.sub.2 368 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 383 4835.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 369 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 384 4849.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- DFIEYLIAGGPSSGAPPPS-NH.sub.2 370 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 385 4414 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSG-NH.sub.2 371 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 386 4718.3 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl)- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIEYLIAGGPSSGAPPPS-NH.sub.2 372 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 387 4746.4 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIE-αMeY-LIAGGPSSGAPPPS-NH.sub.2 373 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 388 4688.3 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIE-αMeY-LIAGGPSSGAPPPS-NH.sub.2 374 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 389 4863.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFIE-αMeY-LIAGGPSSGAPPPS-NH.sub.2 375 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 390 4849.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-EFIE- αMeY-LIAGGPSSGAPPPS-NH.sub.2 376 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 391 4805.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- AFiE-αMeY-LIAGGPSSGAPPPS-NH.sub.2 377 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 392 4791.4 4790.7 K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib-AFIE- αMeY-LIAGGPSSGAPPPS-NH.sub.2 378 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 393 4732.4 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl)-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- efieyliaggpssgappps-NH.sub.2 379 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 394 4949.5 N/I LDKK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- EFIE-αMeY-LIEGGPSSGAPPPS-NH.sub.2 380 (D-Tyr)-Aib-EGTFTSDYSI-αMeL-LD-Orn- 395 4935.5 N/I K((2-[2-(2-Amino-ethoxy)-ethoxy]-acetyl).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib-EFIE- αMeY-LIEGGPSSGAPPPS-NH.sub.2 381 (D-Tyr)-Aib-EGTFTSDYSI-αMeL- 396 4934.4 N/I LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acetyl).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ-Aib- AFIE-αMeY-LIAGGPSSGAPPPS-NH.sub.2  N/I means Not Included

[0303] Binding Assays

[0304] Glucagon (referred to as Gcg) is a Reference Standard prepared at Eli Lilly and Company. GLP-1, 7-36-NH.sub.2 (referred to as GLP-1) is obtained from CPC Scientific (Sunnyvale, Calif., 97.2% purity, 100 μM aliquots in 100% DMSO). GIP 1-42 (referred to as GIP) is prepared at Lilly Research Laboratories using peptide synthesis and HPLC chromatography as described above (>80% purity, 100 μM aliquots in 100% DMSO). [.sup.125I]-radiolabeled Gcg, GLP-1, or GIP is prepared using [.sup.125I]-lactoperoxidase and obtained from Perkin Elmer (Boston, Mass.).

[0305] Stably transfected cell lines are prepared by subcloning receptor cDNA into a pcDNA3 expression plasmid and transfected into human embryonic kidney (HEK) 293 (hGcgR and hGLP-1R) or Chinese Hamster Ovary (CHO) (hGIPR) cells followed by selection with Geneticin (hGLP-1R and hGIPR) or hygromycin B (hGcgR).

[0306] Two methods are used for the preparation of crude cell membranes.

[0307] Method 1: Frozen cell pellets are lysed on ice in hypotonic buffer containing 50 mM Tris HCl, pH 7.5, and Roche Complete™ Protease Inhibitors with EDTA. The cell suspension is disrupted using a glass Potter-Elvehjem homogenizer fitted with a Teflon® pestle for 25 strokes. The homogenate is centrifuged at 4° C. at 1100×g for 10 minutes. The supernatant is collected and stored on ice while the pellets are resuspended in homogenization buffer and rehomogenized as described above. The homogenate is centrifuged at 1100×g for 10 minutes. The second supernatant is combined with the first supernatant and centrifuged at 35000×g for 1 hour at 4° C. The resulting membrane pellet is resuspended in homogenization buffer containing protease inhibitors at approximately 1 to 3 mg/mL, quick frozen in liquid nitrogen and stored as aliquots in a −80° C. freezer until use.

[0308] Method 2: Frozen cell pellets are lysed on ice in hypotonic buffer containing 50 mM Tris HCl, pH 7.5, 1 mM MgCl.sub.2, Roche Complete™ EDTA-free Protease Inhibitors and 25 units/ml DNAse I (Invitrogen). The cell suspension is disrupted using a glass Potter-Elvehjem homogenizer fitted with a Teflon® pestle for 20 to 25 strokes. The homogenate is centrifuged at 4° C. at 1800×g for 15 minutes. The supernatant is collected and stored on ice while the pellets are resuspended in homogenization buffer (without DNAse I) and rehomogenized as described above. The homogenate is centrifuged at 1800×g for 15 minutes. The second supernatant is combined with the first supernatant and centrifuged an additional time at 1800×g for 15 minutes. The overall supernatant is then centrifuged at 25000×g for 30 minutes at 4° C. The resulting membrane pellet is resuspended in homogenization buffer (without DNAse I) containing protease inhibitors at approximately 1 to 3 mg/mL and stored as aliquots in a −80° C. freezer until use.

[0309] Binding Determination Methods

[0310] The equilibrium binding dissociation constants (K.sub.d) for the various receptor/radioligand interactions are determined from homologous competition binding analysis instead of saturation binding due to high propanol content in the [.sup.125I] stock material. The K.sub.d values determined for the receptor preparations were as follows: hGcgR (3.9 nM), hGLP-1R (1.2 nM) and hGIPR (0.14 nM).

[0311] [.sup.125I]-Glucagon Binding

[0312] The human Gcg receptor binding assays are performed using a Scintillation Proximity Assay (SPA) format with wheat germ agglutinin (WGA) beads (Perkin Elmer). The binding buffer contains 25 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES), pH 7.4, 2.5 mM CaCl.sub.2), 1 mM MgCl.sub.2, 0.1% (w/v) bacitracin (Research Products), 0.003% (w/v) Polyoxyethylenesorbitan monolaurate (TWEEN®-20), and Roche Complete™ Protease Inhibitors without EDTA. Peptides and Gcg are thawed and 3-fold serially diluted in 100% DMSO (10 point concentration response curves). Next, 5 μL serially diluted compound or DMSO is transferred into Corning® 3632 clear bottom assay plates containing 45 μL assay binding buffer or unlabeled Gcg control (non-specific binding or NSB, at 1 μM final). Then, 50 μL [.sup.125I]-Gcg (0.15 nM final), 50 μL human GcgR membranes (1.5 μg/well) and 50 μL of WGA SPA beads (80 to 150 μg/well) are added with a Biotek Multiflo dispenser. Plates are sealed and mixed on a plate shaker (setting 6) for 1 minute and read with a PerkinElmer Trilux MicroBeta® scintillation counter after 12 hours of incubation/settling time at room temperature. Final assay concentration ranges for peptides tested in response curves is typically 1150 nM to 0.058 nM and for the control Gcg from 1000 nM to 0.05 nM.

[0313] [.sup.125I]-GLP-1 Binding

[0314] The human GLP-1 receptor binding assay is performed using an SPA format with WGA beads. The binding buffer contains 25 mM HEPES, pH 7.4, 2.5 mM CaCl.sub.2, 1 mM MgCl.sub.2, 0.1% (w/v) bacitracin, 0.003% (w/v) TWEEN®-20, and Roche Complete™ Protease Inhibitors without EDTA. Peptides and GLP-1 are thawed and 3-fold serially diluted in 100% DMSO (10 point concentration response curves). Next, 5 μL serially diluted compound or DMSO is transferred into Corning® 3632 clear bottom assay plates containing 45 μL assay binding buffer or unlabeled GLP-1 control (non-specific binding or NSB, at 0.25 μM final). Then, 50 μL [.sup.125I]-GLP-1 (0.15 nM final), 50 μL human GLP-1R membranes (0.5 μg/well and 50 μL of WGA SPA beads (100 to 150 μg/well) are added with a Biotek Multiflo dispenser. Plates are sealed and mixed on a plate shaker (setting 6) for 1 minute and read with a PerkinElmer Trilux MicroBeta® scintillation counter after 5 to 12 hours of incubation/settling time at room temperature. Final assay concentration ranges for peptides tested in response curves are typically 1150 nM to 0.058 nM and for the control GLP-1, 250 nM to 0.013 nM.

[0315] [125I]-GIP Binding

[0316] The human GIP receptor binding assay is performed using an SPA format with WGA beads. The binding buffer contains 25 mM HEPES, pH 7.4, 2.5 mM CaCl.sub.2), 1 mM MgCl.sub.2, 0.1% (w/v) bacitracin, 0.003% (w/v) TWEEN®-20, and Roche Complete™ Protease Inhibitors without EDTA. Peptides and GIP are thawed and 3 fold serially diluted in 100% DMSO (10 point concentration response curves). Next, 5 μL serially diluted compound or DMSO is transferred into Corning® 3632 clear bottom assay plates containing 45 μL assay binding buffer or unlabeled GIP control (non-specific binding or NSB, at 0.25 μM final). Then, 50 μL [.sup.125I]-GIP (0.075-0.15 nM final), 50 μL human GIPR membranes (3 μg/well) and 50 μL of WGA SPA beads (100 to 150 μg/well) are added with a Biotek Multiflo dispenser. Plates are sealed and mixed on a plate shaker (setting 6) for 1 minute and read with a PerkinElmer Trilux MicroBeta® scintillation counter after 2.5 to 12 hours of incubation/settling time at room temperature. Final assay concentration ranges for peptides tested in response curves is typically 1150 to 0.058 nM or 115 nM to 0.0058 nM and for the control GIP, 250 nM to 0.013 nM.

[0317] Binding Assay Data Analysis

[0318] Raw CPM data for concentration curves of peptides, Gcg, GLP-1, or GIP are converted to percent inhibition by subtracting nonspecific binding (binding in the presence of excess unlabeled Gcg, GLP-1, or GIP, respectively) from the individual CPM values and dividing by the total binding signal, also corrected by subtracting nonspecific binding. Data are analyzed using four-parameter (curve maximum, curve minimum, IC.sub.50, Hill slope) nonlinear regression routines (Genedata Screener, version 12.0.4, Genedata AG, Basal, Switzerland). The affinity constant (K.sub.i) is calculated from the absolute IC.sub.50 value based upon the equation K.sub.i=IC.sub.50/(1+D/K.sub.d) where D is the concentration of radioligand used in the experiment, IC.sub.50 is the concentration causing 50% inhibition of binding and K.sub.d is the equilibrium binding dissociation constant of the radioligand (described above). Values for K.sub.i are reported as the geometric mean, with error expressed as the standard error of the mean (SEM) and n is equal to the number of independent replicates (determined in assays performed on different days). Geometric Means are calculated as follows:

Geometric Mean=10.sup.(Arithmetic Mean of Log Ki Values))

The Ki Ratio (Ki for native control peptide/Ki for test compound) at each receptor and each species is calculated. The Ki Ratio is a rapid indication of the apparent affinity of a peptide compared to the native control peptide. A Ki Ratio<1 indicates that the test peptide has a lower affinity (higher Ki value) for the receptor than the native peptide, whereas a Ki Ratio>1 indicates that the test peptide has a higher affinity (lower Ki value) for the receptor than the native peptide.

[0319] n=1/x means that only one value out of the total number of replicates (x) is used to express the mean. SEM is only calculated when n=2 or greater non-qualified results exist. Means are expressed as GeoMetric means with the standard error of the mean (SEM) and the number of replicates (n) indicated in parenthesis.

TABLE-US-00015 TABLE 1 In vitro Binding Affinity (K.sub.i) of indicated Examples and comparator molecules for human GLP-1R, GcgR and GIPR. hGLcgR hGIPR hGLP1R Example or Ki, nM Ki, nM Ki, (nM) comparator (SEM, n) (SEM, n) (SEM, n) hGcg 3.65 (0.26, n = 10) hGIP amide 0.0922 (0.0085, n = 11) hGLP-1 amide 0.614 (0.066, n = 12) 1 207 0.0546 6.67 (13.8, n = 5) (0.0120, n = 5) (1.25, n = 6) 2 361 0.0600 2.35 (55.1, n = 5) (0.0150, n = 5) (0.220, n = 5) 3 242 0.0458 2.23 (56.2, n = 6) (0.00357, n = 6) (0.366, n = 6) 4 686 0.0528 1.63 (n = ⅕) (0.00647, n = 5) (0.260, n = 5) 5 519 0.0611 0.902 (109, n = 4) (0.00592, n = 4) (0.114, n = 4) 6 55.8 0.0835 6.71 (10.2, n = 2) (0.00437, n = 2) (1.25, n = 2) 7 198 0.252 43.3 8 206 0.0772 2.84 (25.7, n = 2) (0.0155, n = 2) (0.753, n = 2) 9 375 0.127 14.9 (87.5, n = 2) (0.0118, n = 2) (2.15, n = 2) 10 226 0.109 9.33 (67.4, n = 2) (0.0927, n = 2) (1.49, n = 2) 11 174 0.226 15.7 (25.3, n = 2) (0.0728, n = 2) (4.37, n = 2) 12 684 0.167 12.9 (141, n = 2) (0.0853, n = 2) (2.71, n = 2) 13 >1060 0.296 31.1 (n = ½) (0.0291, n = 2) (11.9, n = 2) 14 160 0.0494 29.6 15 130 0.284 2.19 16 371 0.0841 2.78 17 261 0.606 7.63 (115, n = 2) (0.363, n = 2) (2.47, n = 2) 18 50.1 0.0798 0.319 19 60.5 0.0518 0.24 20 228 0.0849 3.30 (65.3, n = 2) (0.0168, n = 2) (1.01, n = 2) 21 149 0.529 14.5 22 53.4 0.624 23.1 23 >1010 0.258 6.32 24 49.8 0.232 5.04 25 81.1 0.179 4.8 26 >960 0.176 4.22 27 315 0.103 3.68 28 >902 0.24 21.1 29 132 0.377 8 30 123 0.151 6.2 31 290 0.0275 6.58 32 44.7 0.0205 3.96 33 >979 6.4 361 34 134 0.0467 3.41 35 >964 0.0358 54.6 36 413 0.141 16.4 37 255 0.0523 3.84 38 >974 0.104 31.3 39 161 0.0499 16.8 40 150 0.0345 7.56 41 165 0.0551 13.4 42 160 0.0514 13.2 43 134 0.101 11.8 44 121 0.0516 10.6 45 11.1 0.0463 5.65 46 133 0.0852 13.4 48 111 0.074 15.7 49 236 0.087 12.3 50 220 0.0568 4.71 (61.2, n = 2) (0.00744, n = 2) (1.22, n = 2) 51 195 0.0620 5.62 (65.9, n = 2) (0.0131, n = 2) (0.658, n = 2) 52 >1100 0.0342 5.81 53 216 0.188 1.23 54 333 0.965 1.66 55 >1100 6.24 7.29 56 >1060 0.148 10.3 57 26.1 0.0583 3.00 (4.31, n = 2) (0.0131, n = 2) (0.293, n = 2) 58 339 0.105 2.77 59 292 0.136 8.20 (11.8, n = 2) (0.00422, n = 2) (4.13, n = 2) 60 237 0.0655 9.55 61 110 0.102 11.1 62 168 0.0545 2.03 63 273 0.141 7.79 64 260 0.0866 4.86 65 194 0.0643 4.53 66 93.7 0.106 7.53 67 270 0.061 10.2 68 99.2 0.0243 1.58 69 22.1 0.0300 1.22 (4.18, n = 3) (0.00657, n = 3) (0.353, n = 3) 74 69.8 0.0279 5.99 75 283 0.103 24.4 76 14.4 0.0659 2.64 78 215 0.163 3.94 (66.2, n = 3) (0.0356, n = 2) (1.21, n = 2) 79 429 (n = ½) 0.0313 2.69 80 347 (n = ½) 0.0931 2.16 81 344 0.198 2.88 82 >1060 14.9 6.82 83 320 0.142 7.1 84 >1100 0.143 10.2 85 >894 (n = ½) 0.621 1.87 86 >1060 0.0401 3.74 87 278 0.0340 1.79 (n = ½) (0.00150, n = 2) (0.417, n = 2) 88 545 0.0717 4.24 (57.8, n = 2) 89 324 0.045 2.64 (22.9, n = 2) 90 245 0.0472 4.76 (7.55, n = 2) 91 540 1.8 5.23 93 15.7 0.0859 1.89 99 23.6 0.027 1.15 100 44 0.115 4.13 101 117 0.0953 8.1 103 40.3 0.0645 6.68 104 123 0.0565 3.91 (17.1, n = 5) (0.0153, n = 5) (0.955, n = 5) 105 20.4 0.119 0.871 106 515 0.179 1.2 107 303 0.0425 0.867 108 171 0.0732 3 109 43.1 0.0279 1.34 110 73.9 0.0395 4.38 115 9.89 0.0302 3.43 116 137 0.0597 6.80 (13.9, n = 2) (0.0486, n = 2) (1.85, n = 2) 117 192 0.0497 6.96 (14.6, n = 3) (0.0111, n = 3) (1.95, n = 3) 118 53.0 0.0859 6.10 (7.07, n = 3) (0.00402, n = 3) (0.870, n = 3) 119 30.6 0.0925 9.87 120 93.6 0.11 11.7 121 51.9 0.177 3.16 122 43.3 0.190 3.36 (8.07, n = 2) (0.0189, n = 2) (0.799, n = 2) 123 80.1 0.0469 1.31 (11.7, n = 6) (0.00804, n = 6) (0.197, n = 6) 124 41.5 0.0424 4.87 (9.39, n = 2) (0.00200, n = 2) (0.277, n = 2) 125 54.4 0.0624 3.19 (0.365, n = 2) (0.0117, n = 2) (0.123, n = 2) 126 101 0.0644 1.46 (11.5, n = 2) (0.0267, n = 2) (0.299, n = 2) 127 43.6 0.126 1.86 128 433 0.0625 1.88 (203, n = 2) (0.0355, n = 2) (0.296, n = 2) 129 14.9 0.0278 1 130 >1060 0.177 3.66 133 216 0.157 11.4 (2.31, n = 2) 134 60.5 0.14 12.7 (0.947, n = 2) 135 454 0.161 3.01 137 98.1 0.0373 1.24 (14.8, n = 3) (0.00200, n = 3) (0.341, n = 3) 138 61.2 0.0295 0.926 (4.65, n = 2) (0.00145, n = 2) (0.201, n = 2) 139 105 0.0360 1.25 (6.68, n = 2) (0.00446, n = 2) (0.0904, n = 2) 140 175 0.0474 1.46 (40.1, n = 3) (0.00461, n = 3) (0.0630, n = 3) 142 53.1 0.0275 1.06 (1.60, n = 2) (0.00210, n = 2) (0.300, n = 2) 143 65.5 0.0304 1.15 144 77 0.0341 1.78 145 158 0.0652 2.22 147 64.9 0.0981 4.47 (19.9, n = 2) (0.0285, n = 2) (0.742, n = 2) 149 127 0.0708 26.1 150 63.2 0.0649 30.5 152 93.4 0.117 48 153 43.8 0.0578 22.2 154 762 0.0610 5.64 (51.7, n = 3) (0.00457, n = 3) (2.52, n = 3) 157 179 0.0937 8.97 (82.9, n = 3) (0.0160, n = 3) (2.28, n = 3) 158 285 0.114 11.8 (17.4, n = 2) (0.0193, n = 2) (5.32, n = 2) 160 >1060 5.98 14.4 (n = ½) (1.46, n = 2) (3.72, n = 2) 163 117 0.116 10.8 181 413 0.145 7.28 (132, n = 2) (0.0856, n = 2) (0.798, n = 2) 182 565 0.0669 4.64 (335, n = 2) (0.0311, n = 2) (0.655, n = 2) 183 304 0.0869 4.11 (128, n = 2) (0.0118, n = 2) (0.369, n = 2) 189 146 0.128 8.81 (7.81, n = 2) (0.0817, n = 2) (0.434, n = 2) 191 348 0.144 4.52 (54.7, n = 2) (0.0676, n = 2) (1.95, n = 2) 192 >1110 0.118 2.89 (n = ½) (0.108, n = 2) (0.516, n = 2) 202 394 0.0579 5.38 203 845 0.0337 3.90 (n = ½) (0.00260, n = 2) (1.10, n = 2) 204 >1150 0.0704 1.9 205 438 0.0367 3.05 206 176 0.0814 5.27 (126, n = 2) (0.00608, n = 2) (0.359, n = 2) 207 74.2 0.0786 1.37 208 >1060 0.0537 2.13 209 >1060 0.0664 1.43 (n = ½) (0.0267, n = 2) (0.466, n = 2) 210 >1010 0.0399 1.58 211 131 0.0243 2.64 212 205 0.0978 2.76 (1.77, n = 2) (0.0730, n = 2) (0.561, n = 2) 213 544 0.365 2.75 214 126 0.0304 1.99 215 75.2 0.0666 6.85 216 45.2 0.0559 2.34 217 516 0.0376 2.02 218 270 0.0593 2.54 219 373 0.0689 2.01 220 377 0.0919 2.71 221 154 0.0414 1.77 (n = ½) (0.00291, n = 2) (0.900, n = 2) 222 71.3 0.0495 3.59 (11.9, n = 2) (0.0210, n = 2) (0.660, n = 2) 223 46.5 0.0921 5.62 224 627 0.0482 6.86 (267, n = 2) (0.0174, n = 2) (1.85, n = 2) 225 714 0.0622 8.79 (n = ½) (0.0208, n = 2) (4.24, n = 2) 226 200 0.0254 4.1 227 113 0.0146 2.01 228 182 0.028 2.43 229 >1100 2.47 36.2 230 494 0.042 4.68 231 440 0.0394 3.03 232 >1150 0.0544 5.62 233 >1150 0.0445 5.99 234 >1100 0.0563 10.9 235 >1200 0.0581 7.65 236 200 0.0425 1.05 (15.1, n = 2) (0.00194, n = 2) (0.173, n = 2) 237 >1060 0.131 1.04 238 230 0.0403 0.548 239 596 0.101 2.71 (215, n = 3) (0.0172, n = 3) (0.0420, n = 3) 240 204 0.0284 0.552 241 167 0.0420 0.799 (45.6, n = 2) (0.0118, n = 2) (0.401, n = 2) 242 95.9 0.0604 0.853 (14.1, n = 2) (0.00642, n = 2) (0.0475, n = 2) 243 145 0.0325 0.670 (5.05, n = 2) (0.00840, n = 2) (0.0478, n = 2) 244 87.8 0.0308 0.820 (2.39, n = 2) (0.0150, n = 2) (0.141, n = 2) 246 >1010 0.0509 0.812 (n = ⅓) (0.0147, n = 3) (0.0900, n = 3) 247 >1100 >55.1 4.39 248 >1050 0.0397 2.4 249 >1000 0.0394 2.35 250 198 0.0171 1.72 251 21.2 0.0249 1.09 252 26 0.00971 0.383 253 >912 0.138 2.57 254 148 0.108 2.58 255 257 0.0772 2.58 264 388 0.015 0.412 265 567 0.0224 0.537 266 193 0.0666 2.01 (28.2, n = 2) (0.0189, n = 2) (0.256, n = 2) 267 349 0.0628 1.57 (178, n = 2) (0.00765, n = 2) (0.109, n = 2) 268 >1190 0.0814 3.98 269 >1100 0.152 7.1 270 >1190 0.117 8.27 271 >1150 0.107 5.09 272 550 0.0353 1.22 (243, n = 2) (0.00276, n = 2) (0.291, n = 2) 273 724 0.0698 1.13 288 345 0.0580 1.60 (35.7, n = 3) (0.0105, n = 3) (0.866, n = 3) 289 >1050 0.0457 2.63 (n = ⅓) (0.0220, n = 3) (1.74, n = 3) 290 308 0.0617 2.44 (n = ⅓) (0.0115, n = 3) (0.162, n = 3) 291 >872 0.129 3.16 (n = ½) (0.0346, n = 3) (0.270, n = 3) 292 595 0.0547 1.19 293 668 0.0775 1.64 294 629 0.205 2.92 295 >1000 0.181 4.12 296 >1000 0.444 3.33 297 >1240 0.0958 2.98 298 >1370 0.0578 3.03 299 >1040 0.734 54.3 300 251 0.0504 2.13 301 44.4 0.0273 0.875 (6.17, n = 3) (0.00127, n = 3) (0.0889, n = 3) 302 18.5 0.0289 0.617 303 502 0.0580 3.69 (189, n = 3) (0.0151, n = 3) (1.86, n = 3) 304 >855 0.0499 4.44 305 352 0.0250 0.830 (30.8, n = 2) (0.00586, n = 2) (0.481, n = 2) 306 >1040 0.0349 2.86 307 117 0.0773 5.1 308 94.2 0.0288 1.01 309 64.1 0.0264 1.04 310 174 0.0315 1.70 (8.97, n = 2) (0.00162, n = 2) (0.144, n = 2) 311 115 0.0497 11.5 312 106 0.0348 1.63 313 27.6 0.0261 0.815 314 116 0.027 0.717 315 539 0.0677 2.28 316 654 0.0418 0.957 (76.5, n = 3) (0.00224, n = 3) (0.180, n = 3) 317 253 0.0215 2.63 318 730 (n = ½) 0.0452 7.52 (0.00883, n = 2) (0.256, n = 2) 319 >984 0.0349 3.61 320 >1040 0.136 5.17 321 770 0.064 4.2 322 1030 0.175 2.31 323 300 0.0516 1.65 324 449 0.0278 0.609 325 13 0.0209 0.475 326 207 0.251 2.92 327 114 0.0667 2.10 (8.53, n = 2) (0.0211, n = 2) (0.287, n = 2) 328 >1450 0.136 3.98 (n = ½) (0.0602, n = 2) (0.339, n = 2) 329 17.0 0.0439 3.28 (2.51, n = 2) (0.0105, n = 2) (0.327, n = 2) 330 >1050 0.114 12.7 331 >969 0.0851 11.4 (n = ½) (0.00508, n = 2) (0.160, n = 2) 332 397 0.0497 7.87 (272, n = 2) (0.00681, n = 2) (0.333, n = 2) 333 578 0.0634 4.25 (68.8, n = 2) (0.00255, n = 2) (0.180, n = 2) 334 192 0.0646 2.17 335 27.1 0.0444 2.54 336 17.1 0.0277 2.44 337 335 0.0363 1.61 338 >1060 0.0831 3.23 339 873 0.0388 2.69 (19.4, n = 2) (0.0198, n = 2) (0.218, n = 2) 340 250 0.0507 2.08 (60.8, n = 2) (0.0177, n = 2) (0.0742, n = 2) 341 39.7 0.0559 6.49 342 >1000 0.129 15.4 343 >1070 0.0374 13.3 344 >1080 0.0507 14.8 346 310 0.0559 1.67 (26.0, n = 3) (0.0248, n = 2) (0.911, n = 2) 349 >1060 0.0800 1.72 (n = ⅓) (0.0215, n = 3) (0.0730, n = 3) 352 >1030 0.0726 3.03 (n = ½) (0.00687, n = 3) (0.673, n = 3) 354 >953 0.175 7.85 (0.0209, n = 2) (0.190, n = 2) 356 >1010 0.350 10.3 (0.0397, n = 2) (1.53, n = 2) 357 >977 0.316 7.02 (0.0233, n = 2) (1.19, n = 2) 358 915 0.0636 1.37 (n = ½) (0.00684, n = 3) (0.189, n = 3) 359 >982 0.0874 2.59 (n = ½) (0.0159, n = 3) (0.833, n = 3) 360 485 0.128 1.74 (0.00895, n = 2) (0.0269, n = 2) 362 >1050 0.337 6.95 (0.00484, n = 2) (0.446, n = 2) 363 >1020 0.170 3.89 (n = ½) (0.0113, n = 3) (0.864, n = 3) 364 >1150 0.672 17.2 (n = ½) (0.0431, n = 3) (2.26, n = 3) 367 777 0.0282 0.809
Functional Activity (with BSA)

[0320] Functional activity is determined in hGLP-1R, hGcgR and hGIP-R expressing HEK-293 clonal cell lines. Each receptor over-expressing cell line is treated with peptide (20 point CRC, 2.75-fold Labcyte Echo direct dilution) in DMEM (Gibco Cat #31053) supplemented with 1× GlutaMAX™ supplement (L-alanyl-L-glutamine dipeptide Gibco®), 0.25% FBS (Fetal Bovine Serum), 0.05% fraction V BSA (Bovine Serum Albumin), 250 μM 3-isobutyl-1-methylxanthine (IBMX) and 20 mM 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) in a 20 μl assay volume.

[0321] After 60-minute incubation at room temperature, the resulting increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 homogeneous time-resolved fluorescence (HTRF) Assay Kit. The cAMP levels within the cell are detected by adding the cAMP-d2 conjugate in cell lysis buffer followed by the antibody anti-cAMP-Eu.sup.3+-Cryptate, also in cell lysis buffer. The resulting competitive assay is incubated for at least 60 minutes at room temperature and then detected using an instrument with excitation at 320 nm and emission at 665 nm and 620 nm. Envision units (emission at 665 nm/620 nm*10,000) are inversely proportional to the amount of cAMP present and are converted to nM cAMP per well using a cAMP standard curve.

[0322] The amount of cAMP generated (nM) in each well is converted to a percent of the maximal response observed with either human GLP-1(7-36)NH.sub.2, human Gcg, or human GIP(1-42)NH.sub.2. A relative EC.sub.50 value is derived by non-linear regression analysis using the percent maximal response vs. the concentration of peptide added, fitted to a four-parameter logistic equation.

[0323] EC.sub.50 determination of human GLP-1(7-36)NH.sub.2 at human GLP-1R, human Gcg at human GcgR, and human GIP(1-42)NH.sub.2 at human GIP-R: the peptide concentration ranges were 448 pM to 99.5 nM. EC.sub.50 determination of Examples at human GLP-1R, human GcgR, and human GIP-R: the peptide concentration ranges are 51.5 fM to 11.4 μM.

TABLE-US-00016 TABLE 2 Functional cAMP Potency (EC.sub.50) for Example and comparator peptides (hGcg, hGIP amide, and hGLP-1 amide) in the presence of FBS. Example or cAMP EC.sub.50, nM (SEM, n) comparator GcgR GIPR GLP-1R hGcg 0.0125 ± 0.0011 (n = 12) hGIP amide 0.0979 (0.0088, n = 12) hGLP-1 0.0424 (0.0043, amide n = 12) Example 1 >11400 (n = 1/9) 38.5 (20.2, n = 12) 53.3 (21.4, n = 12) Example 2 >10900 (n = 1/12) 2.64 (0.696, n = 12) 6.52 (1.76, n = 11) Example 3 >10900 (n = 1/7) 9.24 (2.23, n = 7) 19.4 (7.02, n = 7) Example 4 >10900 (n = ⅕) 1.03 (0.181, n = 5) 2.02 (0.596, n = 4) Example 5 >10900 1.98 1.61
cAMP Pharmacological Functional Assay in Presence of Casein

[0324] An additional set of cAMP assays are conducted in HEK293 cells expressing the human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), Glucagon receptor (GcgR). Pharmacological activity of the hGLP1R/GIPR peptides are determined in HEK293 cells stably expressing the human GLP-1 receptor (GLP-1R), gastric inhibitory peptide receptor (GIPR), or GLP-2 receptor (GLP-2R). Each receptor over-expressing cell line (20 μl) is treated with the test peptide in DMEM (Gibco Cat #31053) supplemented with 0.1% Casein (Sigma Cat #C4765), 250 μM IBMX, 1× GlutaMAX™ (Gibco Cat #35050), and 20 mM HEPES (HyClone Cat #SH30237.01) in a 20 μl assay volume. After 60 minute incubation at room temperature, the resulting increase in intracellular cAMP is quantitatively determined using the CisBio cAMP Dynamic 2 HTRF Assay Kit (62AM4PEJ). The Lysis buffer containing cAMP-d2 conjugate (20 μl) and the antibody anti-cAMP-Eu3+-Cryptate (20 μl) are then added to determine the cAMP level. After 1 h-incubation at room temperature, HTRF signal is detected with an Envision 2104 plate reader (PerkinElmer). Fluorescent emission at 620 nm and at 665 nm is measured and the ratio between 620 nm and at 665 nm is calculated and then are converted to nM cAMP per well using a cAMP standard curve. Dose response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter non-liner regression fit with a variable slope (Genedata Screener 13). EC50 is the concentration of compound causing half-maximal simulation in a dose response curve. A relative EC.sub.50 value is derived by non-linear regression analysis using the percent maximal response vs. the concentration of peptide added, fitted to a four-parameter logistic equation.

[0325] Using Homogeneous Time Resolved Fluorescence methods, assays are conducted to determine the intrinsic potency of Example and comparator molecules performed in the presence of casein (instead of serum albumin) as a nonspecific blocker, which does not interact with the fatty acid moieties of the analyzed molecules.

Intracellular cAMP levels are determined by extrapolation using a standard curve. Dose response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter non-linear regression fit with a variable slope (Genedata Screener 13). EC.sub.50 is the concentration of compound causing half-maximal simulation in a dose response curve. Each relative EC50 value for the Geometric mean calculation is determined from a curve fitting.

[0326] Concentration response curves of compounds are plotted as the percentage of stimulation normalized to minimum (buffer only) and maximum (maximum concentration of each control ligand) values and analyzed using a four parameter non-liner regression fit with a variable slope (Genedata Screener 13). EC50 is the concentration of compound causing half-maximal simulation in a dose response curve.

The EC.sub.50 summary statistics are computed as follows:
Geometric mean:

GM=10{circumflex over ( )}(arithmetic mean of log.sub.10 transformed EC.sub.50 values).

The standard error of the mean is reported:

SEM=geometric mean×(standard deviation of log.sub.10 transformed EC.sub.50 values/square root of the # of runs)×log.sub.e of 10.

The log transform accounts for the EC.sub.50 values falling on a multiplicative, rather than an arithmetic scale.

[0327] Each day, the assay is run, the test peptides are run plus the native ligands GIP and GLP-1, buffer only as baseline (minimum) and the highest concentration of the respective GIP and GLP-1 standard is used as maximum for calculations. For illustration, as shown by Example 1, the test peptide is tested in 8 runs of the assay. For avoidance of doubt, hGIP amide and hGLP-1 amide EC50 in Table 3 are illustrative of geometric mean values from a series of 18 assay values, and values will vary each day compared to the zero buffer. Accordingly, each Example will use the geometric mean of those values to normalize the Example assay runs.

TABLE-US-00017 TABLE 3 Functional activation of hGLP-1R, hGIPR, hGcgR in the presence of 0.1% Casein. hGIPR cAMP Example or Rel EC.sub.50 nM hGIPR cAMP hGLP1R cAMP hGLP1R cAMP comparator (SEM, n) EC.sub.50 ratio (SEM, n) Rel EC.sub.50 nM (SEM, n) EC.sub.50 ratio (SEM, n) hGIP 0.170 amide (0.012, n = 18) hGLP-1 0.0396 amide (0.0030, n = 16) 1 0.0356 4.65 0.0410 1.12 (0.00576, n = 8) (0.514, n = 8) (0.00720, n = 7) (0.0949, n = 7) 2 0.0339 5.89 0.0441 0.888 (0.00650, n = 5) (1.10, n = 5) (0.00670, n = 5) (0.0993, n = 5) 3 0.0411 4.51 0.0338 1.25 (0.00541, n = 5) (0.355, n = 5) (0.00156, n = 4) (0.0916, n = 4) 4 0.0272 5.95 0.0297 1.41 (0.00358, n = 6) (0.466, n = 6) (0.00319, n = 6) (0.241, n = 6) 5 0.0309 6.27 0.0164 2.69 (0.00402, n = 5) (0.808, n = 5) (0.00219, n = 5) (0.547, n = 5) 6 0.0899 2.09 0.374 0.185 (0.0196, n = 2) (0.301, n = 2) (0.0100, n = 2) (0.00340, n = 2) 7 0.461 0.317 0.470 0.130 (0.0988, n = 2) (0.0215, n = 2) 8 0.0848 1.97 0.148 0.419 (0.00744, n = 6) (0.170, n = 6) (0.00926, n = 6) (0.0352, n = 6) 9 0.210 0.768 0.194 0.314 (0.0335, n = 6) (0.122, n = 6) (0.0284, n = 6) (0.0384, n = 6) 10 1.28 0.151 7.64 0.00912 (0.270, n = 2) (0.0416, n = 2) (0.786, n = 2) (0.000859, n = 2) 11 0.486 0.399 6.89 0.0111 (0.108, n = 2) (0.114, n = 2) (2.68, n = 3) (0.00387, n = 3) 12 0.300 0.659 1.15 0.0603 (0.0827, n = 2) (0.221, n = 2) (0.00296, n = 2) (0.000359, n = 2) 13 1.05 0.180 5.39 0.0133 (0.236, n = 2) (0.0272, n = 2) (1.35, n = 2) (0.00338, n = 2) 14 0.284 0.545 1.87 0.0306 (0.0828, n = 2) (0.161, n = 2) (0.534, n = 2) (0.00519, n = 2) 15 0.613 0.273 0.0336 1.65 (0.141, n = 2) (0.00678, n = 2) (0.0000222, (0.0634, n = 2) n = 2) 16 0.975 0.157 0.0437 1.43 (0.241, n = 2) (0.0401, n = 2) (0.00494, n = 4) (0.260, n = 3) 17 5.81 0.0257 0.152 0.398 (0.758, n = 2) (0.00368, n = 2) (0.0166, n = 2) (0.0260, n = 2) 18 0.610 0.275 0.0945 0.589 (0.200, n = 2) (0.0204, n = 2) (0.00823, n = 2) (0.0732, n = 2) 19 0.386 0.436 0.104 0.532 (0.0583, n = 2) (0.0449, n = 2) (0.00342, n = 2) (0.0375, n = 2) 20 0.0556 2.81 0.117 0.577 (0.00518, n = 5) (0.293, n = 5) (0.0121, n = 8) (0.0706, n = 8) 21 0.0748 1.95 0.160 0.402 (0.00682, n = 8) (0.145, n = 8) (0.00495, n = 7) (0.0178, n = 7) 22 0.0842 1.86 0.206 0.290 (0.0103, n = 4) (0.109, n = 4) (0.0172, n = 5) (0.0233, n = 5) 23 0.204 0.754 0.190 0.342 (0.0160, n = 5) (0.0348, n = 5) (0.00766, n = 7) (0.0255, n = 7) 24 0.762 0.228 13.0 0.00416 (0.206, n = 2) (0.0443, n = 2) (n = ½) (n = ½) 25 0.230 0.636 0.356 0.197 (0.0191, n = 6) (0.0564, n = 6) (0.0415, n = 6) (0.0287, n = 6) 26 0.251 0.585 0.293 0.238 (0.0264, n = 6) (0.0531, n = 6) (0.0442, n = 5) (0.0309, n = 5) 27 0.0789 1.90 0.557 0.123 (0.00792, n = 6) (0.295, n = 6) (0.0717, n = 5) (0.0102, n = 5) 28 1.66 0.106 32.7 0.00166 (0.257, n = 2) (0.0238, n = 2) (n = ½) (n = ½) 29 0.320 0.536 0.999 0.0671 (0.0548, n = 2) (0.0522, n = 2) (0.336, n = 2) (0.0283, n = 2) 30 0.114 1.50 1.84 0.0331 (0.00650, n = 2) (0.0246, n = 2) (0.280, n = 2) (0.00127, n = 2) 31 0.388 0.456 0.891 0.0708 (0.0773, n = 2) (0.121, n = 2) (0.147, n = 2) (0.0192, n = 2) 32 0.179 0.840 0.498 0.136 (0.0200, n = 5) (0.0750, n = 5) (0.0124, n = 5) (0.00728, n = 5) 33 63.3 0.00222 251 0.000256 (6.65, n = 2) (0.000125, (n = ½) (n = ½) n = 2) 34 0.360 0.393 1.56 0.0392 (0.0200, n = 2) (0.00105, n = 2) (0.132, n = 2) (0.00119, n = 2) 35 0.0905 1.58 8.38 0.00728 (0.00717, n = 2) (0.215, n = 2) (0.707, n = 2) (0.000221, n = 2) 36 0.309 0.458 2.29 0.0268 (0.0126, n = 2) (0.00789, n = 2) (0.390, n = 2) (0.00309, n = 2) 37 0.269 0.532 1.15 0.0533 (0.0546, n = 2) (0.0765, n = 2) (0.216, n = 2) (0.00707, n = 2) 38 0.147 0.967 2.82 0.0217 (0.0217, n = 2) (0.0861, n = 2) (0.0832, n = 2) (0.00181, n = 2) 39 0.133 1.07 1.92 0.0323 (0.0242, n = 2) (0.132, n = 2) (0.447, n = 2) (0.00571, n = 2) 40 0.136 1.06 0.746 0.0801 (0.0164, n = 2) (0.188, n = 2) (0.118, n = 2) (0.0105, n = 2) 41 0.229 0.637 0.960 0.0637 (0.0451, n = 2) (0.159, n = 2) (0.0203, n = 2) (0.00478, n = 2) 42 0.161 0.897 1.45 0.0471 (0.00967, n = 2) (0.149, n = 2) (0.328, n = 2) (0.0107, n = 2) 43 0.112 1.28 0.862 0.0777 (0.0129, n = 2) (0.0105, n = 2) (0.0963, n = 2) (0.00826, n = 2) 44 0.128 1.11 0.752 0.0918 (0.0118, n = 2) (0.0174, n = 2) (0.201, n = 2) (0.0245, n = 2) 45 0.106 1.75 1.03 0.0569 (0.0158, n = 2) (0.164, n = 2) (0.194, n = 2) (0.00591, n = 2) 46 0.172 0.828 0.687 0.0969 (0.0231, n = 2) (0.0222, n = 2) (0.0147, n = 2) (0.00159, n = 2) 47 0.287 0.654 0.702 0.0890 (0.0529, n = 2) (0.0819, n = 2) (0.197, n = 2) (0.0310, n = 2) 48 0.168 0.863 0.691 0.0966 (0.0126, n = 2) (0.156, n = 2) (0.0491, n = 2) (0.00733, n = 2) 49 0.0868 1.69 0.597 0.112 (0.0288, n = 2) (0.372, n = 2) (0.0314, n = 2) (0.00642, n = 2) 50 0.0794 1.96 0.0961 0.675 (0.0104, n = 5) (0.179, n = 5) (0.00519, n = 7) (0.0492, n = 7) 51 0.0960 1.69 0.153 0.426 (0.0106, n = 7) (0.201, n = 7) (0.0110, n = 7) (0.0376, n = 7) 52 0.0997 1.40 0.132 0.514 (0.0119, n = 6) (0.154, n = 6) (0.0143, n = 5) (0.0413, n = 5) 53 0.628 0.287 0.0339 1.80 (0.161, n = 2) (0.0912, n = 2) (0.000266, n = 2) (0.190, n = 2) 54 1.57 0.110 0.0242 2.55 (0.144, n = 2) (0.0181, n = 2) (0.00711, n = 2) (0.456, n = 2) 55 5.45 <0.00159 0.0286 2.33 (n = ½) (0.000346, n = 2) (0.0282, n = 2) 56 0.167 1.02 0.136 0.491 (0.0132, n = 2) (0.00567, n = 2) (0.00964, n = 2) (0.0347, n = 2) 57 0.0849 1.74 0.0668 0.996 (0.0107, n = 6) (0.148, n = 6) (0.00654, n = 7) (0.0730, n = 7) 58 0.266 0.522 0.180 0.378 (0.0307, n = 5) (0.0439, n = 5) (0.0151, n = 5) (0.0347, n = 5) 59 0.0922 1.54 0.0840 0.812 (0.0134, n = 5) (0.186, n = 5) (0.00742, n = 5) (0.0816, n = 5) 60 0.135 1.06 0.287 0.237 (0.0107, n = 2) (0.0296, n = 2) (0.0377, n = 3) (0.0270, n = 3) 61 0.0739 1.94 0.371 0.187 (0.0140, n = 2) (0.158, n = 2) (0.0664, n = 3) (0.0341, n = 3) 62 0.0601 2.33 0.159 0.463 (0.00469, n = 5) (0.234, n = 5) (0.0151, n = 5) (0.0644, n = 5) 63 0.0925 1.58 0.190 0.386 (0.0106, n = 7) (0.156, n = 7) (0.0195, n = 5) (0.0466, n = 5) 64 0.0916 1.57 0.172 0.429 (0.0104, n = 6) (0.192, n = 6) (0.0184, n = 5) (0.0598, n = 5) 65 0.143 1.04 0.289 0.233 (0.0264, n = 2) (0.295, n = 2) (0.0215, n = 3) (0.0144, n = 3) 66 0.0743 1.89 0.285 0.255 (0.00740, n = 5) (0.209, n = 5) (0.0291, n = 5) (0.0245, n = 5) 67 0.0913 1.61 0.447 0.123 (0.00577, n = 2) (0.0648, n = 2) (0.0958, n = 2) (0.0314, n = 2) 68 0.0881 1.67 0.153 0.354 (0.00725, n = 2) (0.0990, n = 2) (0.0169, n = 2) (0.0550, n = 2) 69 0.0712 2.73 0.0844 0.850 (0.0156, n = 4) (0.431, n = 3) (0.00548, n = 4) (0.0870, n = 4) 70 0.480 0.351 0.283 0.207 (0.0706, n = 2) (0.0135, n = 2) (0.0281, n = 3) (0.0330, n = 3) 71 0.166 1.02 1.02 0.0604 (0.0417, n = 2) (0.0668, n = 2) (0.227, n = 3) (0.0170, n = 3) 72 0.252 0.715 0.906 0.0645 (0.0456, n = 2) (0.251, n = 2) (0.127, n = 3) (0.0103, n = 3) 73 0.979 0.174 2.55 0.0225 (0.317, n = 2) (0.0239, n = 2) (0.337, n = 3) (0.00178, n = 3) 74 0.0866 1.70 0.467 0.115 (0.00653, n = 2) (0.166, n = 2) (0.00217, n = 2) (0.00580, n = 2) 75 0.214 0.690 1.49 0.0359 (0.0234, n = 2) (0.0905, n = 2) (0.00142, n = 2) (0.00168, n = 2) 76 0.124 1.24 0.125 0.630 (0.000853, (0.0255, n = 2) (0.00942, n = 2) (0.0992, n = 2) n = 2) 77 135 0.00102 >2000 <0.0000325 (22.8, n = 2) (0.000331, (n = ½) (n = ½) n = 2) 78 0.532 0.293 0.544 0.143 (0.120, n = 2) (0.0571, n = 2) (0.0263, n = 2) (0.00495, n = 2) 79 0.0732 2.11 2.02 0.0410 (0.0127, n = 2) (0.305, n = 2) (0.562, n = 2) (0.0142, n = 2) 80 0.140 1.09 0.351 0.227 (0.0130, n = 2) (0.0709, n = 2) (0.0522, n = 2) (0.0516, n = 2) 81 0.428 0.373 1.29 0.0630 (0.0445, n = 2) (0.0131, n = 2) (0.00950, n = 2) (0.00192, n = 2) 82 24.3 0.00679 26.1 0.00325 (8.06, n = 2) (0.00175, n = 2) (6.81, n = 2) (0.000941, n = 2) 83 0.182 0.804 0.387 0.166 (0.0176, n = 2) (0.0637, n = 2) (0.0648, n = 2) (0.0265, n = 2) 84 0.0915 1.59 0.374 0.173 (0.00451, n = 2) (0.0514, n = 2) (0.0762, n = 2) (0.0337, n = 2) 85 1.67 0.111 0.0518 1.13 (0.143, n = 2) (0.00296, n = 2) (0.00318, n = 2) (0.0246, n = 2) 86 0.0452 3.29 0.271 0.243 (0.00765, n = 2) (0.605, n = 2) (0.0756, n = 2) (0.0647, n = 2) 87 0.0945 1.1 0.0801 0.786 (0.0277, n = 2) 88 0.475 0.392 0.640 0.0918 (0.00187, n = 2) (0.0215, n = 2) (0.00544, n = 2) (0.00840, n = 2) 89 0.119 1.57 0.335 0.175 (0.0150, n = 2) (0.107, n = 2) (0.00771, n = 2) (0.0105, n = 2) 90 0.0361 5.17 0.532 0.110 (0.000915, (0.434, n = 2) (0.0564, n = 2) (0.00250, n = 2) n = 2) 91 19.2 0.0103 >5000 <0.0000108 (n = ½) (n = ½) (n = ½) (n = ½) 92 0.338 0.546 0.257 0.258 93 0.185 0.956 0.115 0.498 (0.0241, n = 2) (0.292, n = 2) (0.0143, n = 3) (0.0199, n = 3) 94 0.425 0.434 0.338 0.196 95 1.17 0.145 1.01 0.0576 (0.0326, n = 2) (0.0227, n = 2) (0.229, n = 3) (0.00824, n = 3) 96 0.712 0.238 0.590 0.0977 (0.0736, n = 2) (0.0195, n = 2) (0.0509, n = 3) (0.0101, n = 3) 97 1.85 0.0953 2.18 0.0268 (0.214, n = 2) (0.0278, n = 2) (0.347, n = 3) (0.00442, n = 3) 98 0.0718 2.43 0.157 0.384 99 0.0643 2.27 0.0986 0.629 (0.0120, n = 5) (0.208, n = 5) (0.0104, n = 4) (0.0938, n = 4) 100 0.120 1.48 0.0790 0.724 (0.0169, n = 2) (0.191, n = 2) (0.00439, n = 2) (0.0809, n = 2) 101 0.0704 2.07 0.0579 1.06 (0.00913, n = 5) (0.138, n = 5) (0.00589, n = 4) (0.131, n = 4) 102 0.178 0.983 0.0628 0.913 (0.00458, n = 2) (0.118, n = 2) 103 0.0693 2.01 0.101 0.655 (0.0165, n = 4) (0.183, n = 4) (0.0132, n = 3) (0.108, n = 3) 104 0.0323 4.93 0.0248 1.85 (0.00474, n = 8) (0.595, n = 8) (0.00679, n = 6) (0.242, n = 6) 105 1.85 0.101 0.0401 1.51 (0.133, n = 2) (0.00134, n = 2) (0.00740, n = 2) (0.396, n = 2) 106 6.54 0.0302 0.0413 1.42 (n = ½) (n = ½) (0.000823, n = 2) (0.0898, n = 2) 107 0.241 0.747 0.0539 1.10 (0.0209, n = 5) (0.0859, n = 5) (0.00678, n = 5) (0.128, n = 5) 108 0.0885 2.19 0.294 0.218 (0.00413, n = 2) (0.0798, n = 2) (0.0441, n = 2) (0.0253, n = 2) 109 0.109 1.83 0.350 0.182 (0.0252, n = 2) (0.397, n = 2) (0.0142, n = 2) (0.0134, n = 2) 110 0.218 0.929 0.179 0.358 (0.0657, n = 2) (0.263, n = 2) (0.0168, n = 2) (0.0452, n = 2) 111 0.141 1.1 0.308 0.209 (0.0253, n = 2) (0.0144, n = 2) (0.0151, n = 2) 112 0.124 1.53 0.160 0.402 (0.00217, n = 2) (0.0115, n = 2) (0.0185, n = 2) 113 0.166 1.39 0.233 0.275 (0.0364, n = 2) (0.0133, n = 2) (0.0228, n = 2) 114 0.133 1.65 0.267 0.234 (0.0220, n = 2) 115 0.102 1.85 0.0880 0.743 (0.0163, n = 5) (0.319, n = 5) (0.00660, n = 4) (0.0516, n = 4) 116 0.0867 2.13 0.0703 0.956 (0.147, (0.0141, n = 5) (0.255, n = 5) (0.0111, n = 4) n = 4) 117 0.0648 2.44 0.0615 0.998 (0.00602, n = 7) (0.263, n = 6) (0.00275, n = 7) (0.0681, n = 7) 118 0.0538 3.42 0.0588 1.13 (0.00395, n = 7) (0.247, n = 6) (0.00577, n = 6) (0.115, n = 6) 119 0.216 0.901 0.0913 0.702 (0.0107, n = 2) (0.0541, n = 2) (0.00729, n = 2) (0.0788, n = 2) 120 0.122 1.67 0.201 0.319 (0.0397, n = 2) (0.509, n = 2) (0.0318, n = 2) (0.0398, n = 2) 121 0.0760 1.44 0.0849 0.760 (0.0189, n = 2) (0.0136, n = 2) (0.128, n = 2) 122 0.0923 1.73 0.0760 0.856 (0.0122, n = 2) (0.399, n = 2) (0.0221, n = 2) (0.223, n = 2) 123 0.0423 4.04 0.0344 1.58 (0.00604, n = 8) (0.586, n = 8) (0.00562, n = 5) (0.180, n = 5) 124 0.0762 2.18 0.0475 1.29 (0.00816, n = 4) (0.283, n = 4) (0.00318, n = 4) (0.0473, n = 4) 125 0.0381 3.79 0.0478 1.31 (0.00482, n = 5) (0.152, n = 5) (0.00569, n = 4) (0.229, n = 4) 126 0.0685 2.53 0.0715 0.869 (0.00653, n = 4) (0.361, n = 3) (0.00249, n = 4) (0.0332, n = 4) 127 0.158 0.917 0.145 0.443 (0.0401, n = 2) (0.00951, n = 2) (0.0176, n = 2) 128 0.0694 2.46 0.0924 0.700 (0.00856, n = 4) (0.344, n = 3) (0.0147, n = 4) (0.119, n = 4) 129 0.106 1.88 0.121 0.543 (0.00707, n = 2) (0.0220, n = 2) (0.112, n = 2) 130 1.55 0.116 0.368 0.182 131 0.183 1.03 0.156 0.425 132 0.0657 2.88 0.26 0.255 133 0.0879 1.89 0.0436 1.52 (0.0298, n = 2) (1.13, n = 2) 134 0.104 1.43 0.0654 0.942 (0.00639, n = 2) (0.244, n = 2) (0.00394, n = 2) (0.00985, n = 2) 135 0.373 0.482 0.131 0.509 136 3.39 0.0544 0.06 1.1 137 0.0333 4.47 0.0397 1.25 (0.00461, n = 8) (0.381, n = 8) (0.00540, n = 5) (0.114, n = 5) 138 0.0581 2.18 0.0471 1.12 (0.00498, n = 3) (0.423, n = 3) (0.00784, n = 3) (0.105, n = 3) 139 0.0370 3.61 0.0417 1.13 (0.00460, n = 5) (0.444, n = 5) (0.00760, n = 5) (0.105, n = 5) 140 0.0349 3.76 0.0424 1.16 (0.00428, n = 5) (0.415, n = 5) (0.00487, n = 5) (0.0926, n = 5) 141 0.2 0.538 0.0975 0.414 142 0.0489 2.84 0.0426 1.22 (0.00436, n = 2) (0.637, n = 2) (0.00626, n = 2) (0.0942, n = 2) 143 0.0515 2.78 0.0745 0.714 (0.0105, n = 2) (0.920, n = 2) (0.0109, n = 2) (0.152, n = 2) 144 0.0375 3.60 0.0608 0.851 (0.00249, n = 3) (0.373, n = 3) (0.00352, n = 3) (0.0845, n = 3) 145 0.0514 2.46 0.0427 1.22 (0.0124, n = 3) (0.300, n = 3) (0.00108, n = 2) (0.116, n = 2) 146 0.0583 1.98 0.0604 0.951 147 0.0304 4.14 0.0527 1.13 (0.00146, n = 3) (0.241, n = 3) (0.00623, n = 3) (0.117, n = 3) 148 0.0430 2.70 0.0626 0.859 (0.00713, n = 3) (0.462, n = 3) (0.00751, n = 3) (0.167, n = 3) 149 0.0711 1.82 0.0916 0.484 (0.0109, n = 2) (0.0572, n = 2) (0.0149, n = 2) (0.0343, n = 2) 150 0.0511 2.64 0.0575 0.790 (0.00569, n = 2) (0.761, n = 2) (0.00855, n = 2) (0.186, n = 2) 151 0.41 0.262 1.60 0.0278 (0.338, n = 2) (0.00331, n = 2) 152 0.0504 2.57 0.0915 0.484 (0.00566, n = 2) (0.188, n = 2) (0.0128, n = 2) (0.0236, n = 2) 153 0.0634 1.7 0.0904 0.501 (0.0113, n = 2) (0.107, n = 2) 154 0.0266 5.90 0.0393 1.23 (0.00348, n = 7) (0.513, n = 7) (0.00511, n = 5) (0.117, n = 5) 155 0.266 0.584 0.495 0.0978 156 >30.0 <0.00519 0.638 0.0759 157 0.0453 3.15 0.0431 1.25 (0.00495, n = 6) (0.444, n = 6) (0.00557, n = 4) (0.135, n = 4) 158 0.0454 3.22 0.0374 1.34 (0.0102, n = 5) (0.527, n = 5) (0.00374, n = 5) (0.0947, n = 5) 159 4.6 0.039 0.33 0.176 160 21.0 0.00712 0.0461 1.24 (0.568, n = 2) (0.00165, n = 2) (0.00206, n = 2) (0.0824, n = 2) 161 0.254 0.706 4.8 0.0121 162 4.56 0.0393 36 0.00161 163 0.121 1.29 0.0316 1.54 164 3.09 0.0581 15.6 0.00373 165 1.04 0.172 5.81 0.01 166 0.355 0.504 4.08 0.0143 167 0.617 0.291 1.2 0.0487 168 0.572 0.313 1.8 0.0323 169 0.86 0.122 3.37 0.0136 170 0.569 0.185 10.4 0.00438 171 0.223 0.471 0.75 0.0609 172 1.05 0.1 1.2 0.038 173 0.586 0.179 1.23 0.0373 174 0.217 0.483 0.472 0.0968 175 0.0881 1.19 1.11 0.0412 176 0.523 0.201 1.07 0.0427 177 1.4 0.0749 6.79 0.00673 178 3.08 0.0341 13.1 0.00349 179 1.83 0.0575 2.7 0.0169 180 0.79 0.133 2.16 0.0212 181 0.0459 4.10 0.0592 0.718 (0.0122, n = 5) (0.698, n = 5) (0.00966, n = 6) (0.0586, n = 6) 182 0.0442 4.37 0.0463 0.873 (0.0133, n = 5) (0.940, n = 5) (0.00578, n = 6) (0.0433, n = 6) 183 0.0615 3.10 0.0551 0.843 (0.0175, n = 5) (0.600, n = 5) (0.0125, n = 5) (0.121, n = 5) 184 0.0477 2.45 0.392 0.135 185 0.632 0.185 7.16 0.00739 186 0.0939 0.572 187 0.0371 4.61 0.0577 0.702 (0.00593, n = 6) (0.839, n = 6) (0.00695, n = 6) (0.0431, n = 6) 188 0.121 0.969 0.13 0.408 189 0.0775 2.41 0.0608 0.668 (0.0140, n = 5) (0.314, n = 5) (0.00976, n = 6) (0.0450, n = 6) 190 0.738 0.158 0.0241 2.2 191 0.0645 2.53 0.0356 1.60 (0.0139, n = 3) (0.131, n = 3) (0.00490, n = 3) (0.182, n = 3) 192 0.0615 2.83 0.0289 1.73 (0.0139, n = 5) (0.340, n = 5) (0.00261, n = 5) (0.0510, n = 5) 193 0.336 0.538 0.162 0.359 194 0.423 0.427 0.284 0.205 195 0.193 0.936 0.0966 0.602 196 0.277 0.653 0.175 0.332 197 0.211 0.855 0.248 0.189 198 >30.0 <0.00602 0.139 0.337 199 >30.0 <0.00602 0.0422 1.11 200 12.3 0.0146 0.0818 0.573 201 >30.0 <0.00602 0.0385 1.22 202 0.0392 4.79 0.0608 0.712 (0.00958, n = 3) (0.700, n = 3) (0.00408, n = 2) (0.0866, n = 2) 203 0.0387 4.95 0.0679 0.671 (0.00465, n = 4) (0.383, n = 4) (0.0116, n = 3) (0.130, n = 3) 204 0.0424 4.58 0.0654 0.689 (0.0132, n = 3) (1.01, n = 3) (0.0166, n = 2) (0.207, n = 2) 205 0.0281 5.71 0.0261 1.46 (0.000581, (0.519, n = 2) (0.00703, n = 3) (0.102, n = 3) n = 2) 206 0.0409 4.75 0.0270 1.42 (0.00271, n = 2) (0.0828, n = 2) (0.00477, n = 3) (0.139, n = 3) 207 0.0395 4.76 0.0359 1.23 (0.0103, n = 3) (0.715, n = 3) (0.00622, n = 2) (0.275, n = 2) 208 0.0371 5.33 0.0753 0.587 (0.00797, n = 4) (0.808, n = 4) (0.00608, n = 3) (0.0362, n = 3) 209 0.0308 5.73 0.0374 1.12 (0.00636, n = 5) (0.721, n = 5) (0.00451, n = 4) (0.108, n = 4) 210 0.0383 5.40 0.0432 1.03 (0.0124, n = 4) (1.22, n = 4) (0.00554, n = 3) (0.118, n = 3) 211 0.0442 4.59 0.0337 1.28 (0.00939, n = 5) (0.656, n = 5) (0.00481, n = 4) (0.203, n = 4) 212 0.0501 4.17 0.0572 0.771 (0.0132, n = 4) (0.999, n = 4) (0.00467, n = 3) (0.0330, n = 3) 213 0.0523 3.87 0.0710 0.694 (0.0140, n = 4) (0.721, n = 4) (0.0146, n = 4) (0.110, n = 4) 214 0.0251 6.92 0.0221 1.74 (0.00459, n = 4) (0.628, n = 4) (0.00364, n = 5) (0.122, n = 5) 215 0.0525 3.53 0.0529 0.813 (0.00720, n = 3) (0.379, n = 3) (0.00177, n = 2) (0.0175, n = 2) 216 0.0401 4.91 0.0327 1.31 (0.0151, n = 3) (1.22, n = 3) (0.00291, n = 2) (0.0447, n = 2) 217 0.0563 3.41 0.0383 1.14 (0.0165, n = 3) (0.665, n = 3) (0.00448, n = 2) (0.193, n = 2) 218 0.0413 4.43 0.0423 1.02 (0.00450, n = 3) (0.113, n = 3) (0.00335, n = 2) (0.137, n = 2) 219 0.0341 5.86 0.0403 1.03 (0.00595, n = 5) (0.825, n = 5) (0.00221, n = 4) (0.0601, n = 4) 220 0.0315 6.30 0.0312 1.36 (0.00564, n = 5) (0.786, n = 5) (0.00267, n = 4) (0.176, n = 4) 221 0.0445 4.50 0.0570 0.795 (0.0102, n = 4) (0.773, n = 4) (0.0101, n = 3) (0.138, n = 3) 222 0.0306 5.84 0.0248 1.55 (0.00648, n = 4) (0.924, n = 4) (0.00375, n = 5) (0.110, n = 5) 223 0.0670 2.93 0.0363 0.962 (0.00561, n = 2) (0.487, n = 2) (0.00532, n = 3) (0.0435, n = 3) 224 0.0545 3.52 0.0349 1.06 (0.00995, n = 3) (0.580, n = 3) (0.00788, n = 4) (0.145, n = 4) 225 0.101 1.99 0.0670 0.523 (0.0194, n = 2) (0.536, n = 2) (0.0107, n = 3) (0.0355, n = 3) 226 0.0461 4.27 0.0284 1.25 (0.00446, n = 2) (0.762, n = 2) (0.00805, n = 3) (0.167, n = 3) 227 0.0414 4.73 0.0329 1.07 (0.00954, n = 2) (0.688, n = 2) (0.00627, n = 3) (0.0870, n = 3) 228 0.0503 3.86 0.0282 1.10 (0.00265, n = 2) (0.119, n = 2) (0.00274, n = 2) (0.218, n = 2) 229 4.79 0.0298 2.11 0.0139 230 0.0431 3.31 0.0491 0.599 231 0.0253 5.64 0.0611 0.481 232 0.027 5.28 0.0724 0.406 233 0.0288 4.95 0.0549 0.535 234 0.0372 3.83 0.0926 0.317 235 0.0372 3.83 0.136 0.216 236 0.0249 6.76 0.0231 1.65 (0.00475, n = 5) (0.804, n = 5) (0.00333, n = 5) (0.260, n = 5) 237 0.0883 2.16 0.0187 2.34 238 0.0296 7.33 0.0241 1.15 239 0.0353 5.27 0.0376 0.987 (0.00282, n = 4) (0.434, n = 4) (0.00836, n = 4) (0.213, n = 4) 240 0.0223 9.73 0.0393 0.706 241 0.0257 7.12 0.0175 1.89 (0.00164, n = 3) (0.471, n = 3) (0.00373, n = 3) (0.340, n = 3) 242 0.0333 5.58 0.0164 1.96 (0.00196, n = 3) (0.823, n = 3) (0.00209, n = 3) (0.186, n = 3) 243 0.0214 8.69 0.0265 1.22 (0.00212, n = 3) (1.21, n = 3) (0.00423, n = 3) (0.158, n = 3) 244 0.0225 8.27 0.0252 1.29 (0.00136, n = 3) (1.30, n = 3) (0.00415, n = 3) (0.174, n = 3) 245 0.0552 2.82 0.0222 1.55 246 0.0258 6.36 0.0144 2.56 (0.00180, n = 6) (0.340, n = 6) (0.00106, n = 5) (0.216, n = 5) 247 0.0622 2.58 0.0491 0.614 248 0.0328 5.08 0.0428 0.800 (0.000561, (0.118, n = 2) (0.00493, n = 2) (0.00908, n = 2) n = 2) 249 0.0437 3.84 0.0446 0.778 (0.00337, n = 2) (0.449, n = 2) (0.0131, n = 2) (0.129, n = 2) 250 0.0376 4.27 0.0306 0.985 251 0.0292 5.12 0.081 1.37 252 0.093 1.61 0.0483 1.44 253 0.219 0.684 0.109 0.638 254 0.215 0.695 0.0553 1.26 255 0.102 1.47 0.0407 1.71 256 0.643 0.233 0.0506 1.38 257 0.474 0.316 0.0779 0.895 258 2.43 0.0616 0.174 0.401 259 0.257 0.582 0.145 0.482 260 0.617 0.242 0.408 0.171 261 0.16 0.936 0.0948 0.75 262 0.13 1.15 0.0943 0.754 263 0.317 0.473 0.0785 0.906 264 0.0196 8.40 0.0229 3.19 (0.00197, n = 2) (1.51, n = 2) (0.00180, n = 2) (0.327, n = 2) 265 0.0229 7.56 0.0223 3.27 (0.00918, n = 2) (2.21, n = 2) (0.00115, n = 2) (0.0894, n = 2) 266 0.0442 2.82 0.0883 0.627 (0.0109, n = 6) (0.430, n = 6) (0.0104, n = 6) (0.103, n = 6) 267 0.108 1.50 0.0540 0.974 (0.0203, n = 5) (0.0726, n = 5) (0.0118, n = 5) (0.256, n = 5) 268 0.239 0.851 0.0572 0.935 (0.00366, n = 3) (0.0652, n = 3) (0.0135, n = 5) (0.247, n = 5) 269 0.257 0.825 0.0595 0.828 (0.0546, n = 3) (0.187, n = 3) (0.0158, n = 3) (0.202, n = 3) 270 0.328 0.627 0.128 0.400 (0.0226, n = 3) (0.0795, n = 3) (0.0355, n = 4) (0.132, n = 4) 271 0.334 0.614 0.0352 1.35 (0.0609, n = 3) (0.0761, n = 3) (0.00104, n = 2) (0.0587, n = 2) 272 0.0464 2.97 0.0435 1.19 (0.0119, n = 6) (0.286, n = 6) (0.0117, n = 4) (0.355, n = 4) 273 0.0790 2.15 0.0352 1.85 (0.0165, n = 5) (0.333, n = 5) (0.0230, n = 3) (0.845, n = 3) 274 >30.0 <0.00741 14.5 0.00353 (5.14, n = 2) (0.000807, n = 2) 275 >30.0 <0.00741 14.0 0.00357 (0.390, n = 2) (0.000336, n = 2) 276 0.0757 1.43 0.108 0.491 (0.0236, n = 2) (0.117, n = 2) 277 0.0554 2.02 0.133 0.536 278 0.293 0.845 0.123 0.517 (0.0121, n = 2) (0.0592, n = 2) 279 0.564 0.439 0.11 0.461 280 0.204 1.53 0.0767 0.663 281 0.166 1.87 0.16 0.318 282 0.323 0.962 0.247 0.23 283 0.301 1.03 0.155 0.329 284 0.113 2.74 0.0462 1.1 285 0.0884 3.52 0.072 0.706 286 0.184 1.69 0.0602 0.845 287 0.15 2.08 0.112 0.455 288 0.0732 1.20 0.172 0.393 (0.0140, n = 7) (0.268, n = 7) (0.0288, n = 4) (0.128, n = 4) 289 0.0228 4.13 0.0544 1.33 (0.00219, n = 5) (0.741, n = 5) (0.00661, n = 6) (0.325, n = 6) 290 0.0629 1.09 0.179 0.279 (0.0118, n = 5) (0.176, n = 5) (0.0336, n = 6) (0.0844, n = 6) 291 0.118 0.746 0.150 0.188 (0.0226, n = 4) (0.0858, n = 4) (0.0253, n = 5) (0.0294, n = 5) 292 0.0682 1.10 0.183 0.143 (0.0192, n = 2) (0.0631, n = 2) (0.0328, n = 2) (0.0191, n = 2) 293 0.0562 1.36 0.132 0.197 (0.00736, n = 2) (0.278, n = 2) (0.000967, n = 2) (0.00743, n = 2) 294 0.183 0.75 0.185 0.249 295 0.281 0.481 0.116 0.398 296 0.198 0.564 0.0867 0.82 297 0.0451 3.00 0.111 0.445 (0.00597, n = 4) (0.569, n = 4) (0.0151, n = 5) (0.0482, n = 5) 298 0.0430 2.87 0.0957 0.507 (0.00578, n = 6) (0.349, n = 6) (0.0139, n = 7) (0.0734, n = 7) 299 0.932 0.146 2.54 0.0244 (0.507, n = 2) (0.0780, n = 2) (0.629, n = 4) (0.00551, n = 4) 300 0.0234 5.38 0.0867 0.636 (0.00482, n = 7) (1.40, n = 7) (0.0105, n = 9) (0.0568, n = 9) 301 0.0346 4.11 0.0441 1.61 (0.00764, (0.921, n = 11) (0.00684, n = 7) (0.433, n = 7) n = 12) 302 0.0308 3.78 0.0275 1.96 (0.00225, n = 8) (0.554, n = 7) (0.00247, n = 6) (0.175, n = 6) 303 0.0254 4.20 0.104 0.602 (0.00381, n = 9) (1.10, n = 9) (0.0157, n = 6) (0.0702, n = 6) 304 0.0296 2.68 0.191 0.481 (0.00440, n = 7) (0.425, n = 7) (0.0386, n = 5) (0.151, n = 5) 305 0.0225 4.28 0.107 0.685 (0.00306, n = 7) (0.953, n = 7) (0.0149, n = 6) (0.0980, n = 6) 306 0.0191 3.97 0.0711 0.912 (0.00502, n = 4) (0.582, n = 4) (0.0202, n = 4) (0.339, n = 4) 307 0.0285 2.48 0.0437 1.29 (0.00345, n = 5) (0.481, n = 5) (0.00943, n = 4) (0.238, n = 4) 308 0.0262 4.06 0.0392 1.45 (0.00432, n = 8) (1.01, n = 8) (0.00818, n = 4) (0.307, n = 4) 309 0.0389 1.64 0.0330 1.27 (0.00473, n = 4) (0.313, n = 4) (0.00555, n = 3) (0.312, n = 3) 310 0.0176 5.56 0.0283 1.43 (0.00109, n = 4) (1.23, n = 4) (0.00985, n = 3) (0.262, n = 3) 311 0.0334 3.50 0.0393 1.04 (0.00431, n = 4) (0.928, n = 4) (0.0132, n = 3) (0.220, n = 3) 312 0.0207 4.76 0.0262 1.53 (0.00251, n = 5) (1.32, n = 5) (0.00799, n = 3) (0.342, n = 3) 313 0.0233 2.87 0.0388 0.867 (0.00223, n = 2) (0.830, n = 2) (0.00647, n = 3) (0.197, n = 3) 314 0.0290 2.81 0.0290 1.48 (0.0123, n = 2) (0.669, n = 2) (0.00867, n = 3) (0.476, n = 3) 315 0.0408 2.06 0.0651 1.00 (0.00771, n = 4) (0.452, n = 4) (0.0141, n = 4) (0.245, n = 4) 316 0.0240 3.75 0.122 0.644 (0.00478, n = 7) (0.723, n = 7) (0.00791, n = 6) (0.146, n = 6) 317 0.0948 1.01 0.172 0.333 (0.0240, n = 4) (0.478, n = 4) (0.00643, n = 3) (0.104, n = 3) 318 0.0547 1.69 0.124 0.482 (0.00365, n = 4) (0.536, n = 4) (0.0271, n = 4) (0.188, n = 4) 319 0.0540 2.77 0.113 0.522 (0.0220, n = 4) (2.07, n = 4) (0.00689, n = 3) (0.171, n = 3) 320 0.161 0.241 0.397 0.224 321 0.0752 0.517 0.204 0.437 322 0.146 0.266 0.711 0.125 323 0.0251 3.24 0.0597 1.32 (0.00551, n = 4) (0.508, n = 4) (0.00797, n = 4) (0.527, n = 4) 324 0.0374 2.13 0.0926 0.798 (0.00637, n = 4) (0.185, n = 4) (0.0147, n = 4) (0.264, n = 4) 325 0.0301 2.65 0.0586 1.16 (0.00366, n = 5) (0.180, n = 5) (0.0119, n = 5) (0.224, n = 5) 326 0.0754 1.5 0.0369 1.4 327 0.0548 1.47 0.27 0.191 (0.0274, n = ⅔) (0.273, n = ⅔) 328 0.0965 0.94 0.117 0.575 329 0.132 0.687 0.125 0.535 330 0.0919 0.562 0.199 0.255 331 0.0547 1.40 0.0929 0.808 (0.0162, n = 2) (0.145, n = 2) (0.0237, n = 2) (0.277, n = 2) 332 0.0745 0.949 0.184 0.345 (0.0143, n = 3) (0.0533, n = 3) (0.0348, n = 3) (0.0711, n = 3) 333 0.0492 2.31 0.131 0.487 334 0.0718 0.844 0.303 0.151 335 0.0477 1.27 0.122 0.374 336 0.0312 1.95 0.0874 0.523 337 0.0515 1.18 0.173 0.265 338 0.0472 1.29 0.174 0.262 339 0.0219 3.18 0.0986 0.574 (0.00722, n = 3) (0.768, n = 3) (0.0180, n = 4) (0.231, n = 4) 340 0.0823 0.852 0.252 0.183 (0.0288, n = 3) (0.312, n = 3) (0.00594, n = 4) (0.0554, n = 4) 341 0.238 0.213 0.373 0.0674 342 0.159 0.32 0.127 0.198 343 0.0422 1.84 0.124 0.662 344 0.0433 1.79 0.044 1.86 345 0.0649 2.16 0.035 0.937 346 0.144 0.604 0.128 0.210 (0.0284, n = 2) (0.00648, n = 2) (0.0378, n = 3) (0.0493, n = 3) 347 0.0827 0.872 0.102 0.245 (0.0247, n = 2) (0.0142, n = 2) 348 0.193 0.373 0.113 0.224 (0.00703, n = 2) (0.0269, n = 2) 349 0.117 0.756 0.121 0.214 (0.00129, n = 2) (0.131, n = 2) (0.0287, n = 3) (0.0378, n = 3) 350 0.189 0.741 0.107 0.307 351 0.298 0.47 0.149 0.22 352 0.127 0.815 0.142 0.201 (0.0116, n = 2) (0.193, n = 2) (0.0267, n = 3) (0.0439, n = 3) 353 0.497 0.145 1.09 0.0231 (0.0881, n = 2) (0.00235, n = 2) 354 0.233 0.441 0.540 0.0517 (0.0309, n = 2) (0.0871, n = 2) (0.126, n = 3) (0.00657, n = 3) 355 0.685 0.111 0.896 0.0285 (0.318, n = 2) (0.0498, n = 2) (0.00185, n = 2) (0.00509, n = 2) 356 0.386 0.364 0.506 0.0647 357 0.384 0.366 0.181 0.181 358 0.183 0.662 0.117 0.260 (0.0347, n = 2) (0.0284, n = 2) (0.0257, n = 2) (0.0901, n = 2) 359 0.172 0.706 0.131 0.227 (0.0235, n = 2) (0.00679, n = 2) (0.0201, n = 2) (0.0647, n = 2) 360 0.197 0.53 0.145 0.171 361 0.401 0.261 0.955 0.0259 362 0.302 0.347 0.365 0.0805 (n = ½) (n = ½) (0.0425, n = 2) (0.0202, n = 2) 363 0.145 0.835 0.208 0.146 (0.0185, n = 2) (0.0159, n = 2) (0.0485, n = 2) (0.0522, n = 2) 364 0.351 0.347 1.00 0.0303 (0.0809, n = 2) (0.0290, n = 2) (0.213, n = 2) (0.0103, n = 2) 365 0.0678 0.784 0.175 0.155 366 0.0889 0.598 0.366 0.074 367 0.0179 5.85 0.0641 0.386 368 0.0757 0.109 0.108 0.299 369 0.166 0.499 0.101 0.319 370 0.117 0.704 0.186 0.172 371 0.135 0.393 0.132 0.206 372 0.0781 0.68 0.365 0.0741 373 0.185 0.287 0.436 0.0621 374 0.0468 1.76 0.190 0.169 375 0.0471 1.13 0.152 0.178 376 0.0723 0.734 0.170 0.159 377 0.0544 0.976 0.136 0.199 378 0.067 0.793 0.191 0.142 379 0.079 0.672 0.238 0.114 380 0.142 0.374 0.236 0.115

[0328] As demonstrated by data in Table 3, Example compounds stimulate cAMP from human GLP-1R and GIPR in the presence of 0.1% casein.

In Vivo Studies

Pharmacokinetics in Male CD-1 Mice

[0329] The pharmacokinetics of select Examples are evaluated following a single subcutaneous administration of 200 nMol/kg to male CD-1 mice. Blood samples are collected over 168 hours and resulting individual plasma concentrations are used to calculate pharmacokinetic parameters. Plasma (K.sub.3 EDTA) concentrations are determined using a qualified LC/MS method that measures the intact mass of the Examples. Each Example and an analog as an internal standard are extracted from 100% mouse plasma using immunoaffinity based precipitation with anti-GIP/GLP1 antibodies. Instruments are combined for LC/MS detection. Mean pharmacokinetic parameters are shown in Table 4.

TABLE-US-00018 TABLE 4 Mean Pharmacokinetic Parameters of peptides Following a Single Subcutaneous Administration of 200 nMol/kg to Male CD-1 mice (N = 2/timepoint non-serial sampling). C.sub.max/D AUCINF_D_obs T.sub.max (kg*nmol/ (hr*kg*nmol/ Cl/F Example T.sub.1/2 (hr) (hr) L/nmol) L/nmol) (mL/hr/Kg) Example 1 17.54 12 4.84 135.61 7.37 Example 2 7.55 6 5.4 77.23 12.95 Example 3 15.04 6 4.42 158.49 6.31 Abbreviations: T.sub.1/2 = half-life, T.sub.max = time to maximal concentration, C.sub.max = maximal plasma concentration, AUCINF_D_obs = AUCinf divided by dose, CL/F = clearance/bioavailability. Notes: Data are the mean, where n = 2/timepoint/group.
Results from this study for Examples tested are consistent with an extended pharmacokinetic profile.

Pharmacokinetics in Male Cynomolgus Monkeys

[0330] The pharmacokinetics of select Examples are evaluated following a single subcutaneous administration of 50 nMol/kg to male cynomolgus monkeys. Blood samples are collected over 336 hours and resulting individual plasma concentrations are used to calculate pharmacokinetic parameters. Peptide plasma (K.sub.3 EDTA) concentrations are determined using a qualified LC/MS method that measured the intact mass of the compound. Each peptide and an analog as an internal standard are extracted from 100% cynomolgus monkey plasma using immunoaffinity based precipitation with anti-GIP/GLG1 antibodies. Instruments are combined for LC/MS detection. Mean pharmacokinetic parameters are shown in Table 5.

TABLE-US-00019 TABLE 5 Mean Pharmacokinetic Parameters of peptides Following a Single Subcutaneous Administration of 50 nMol/kg to Male Cynomolgus Monkeys. C.sub.max/D AUCINF_D_obs (kg*nmol/ (hr*kg*nmol/ Cl/F Example T.sub.1/2 (hr) T.sub.max (hr) L/nmol) L/nmol) (mL/hr/Kg) Example 1 125.0 18 6.5 1458 0.69 Example 2 102.1 24 11.7 2059 0.49 Example 3 180.6 30 11.38 3420 0.29 Abbreviations: T.sub.1/2 = half-life, T.sub.max = time to maximal concentration, C.sub.max = maximal plasma concentration, AUCINF_D_obs = AUCinf divided by dose, CL/F = clearance/bioavailability. Notes: Data are the mean, where n = 2/group. Notes: Data are the mean, where n = 2/group. As seen in Table 5, results from this study for Example peptides tested are consistent with an extended pharmacokinetic profile.

Pharmacokinetics in Male Sprague Dawley Rats Following Subcutaneous or Intrajejunal Administration

[0331] The pharmacokinetics of select Examples are evaluated following a single subcutaneous (SC) administration of 50 nMol/kg (dissolved in PBS, pH 7.4) or single 1 μmol/kg (mixed with 250 mM sodium decanoate (“C10”) and 12 mg/mL soybean trypsin inhibitor (SBTI)) intrajejunal (IJ) administration to male Sprague Dawley rats. Blood samples are collected over 168 hours following SC administration and 72 hours following U dosing. Pharmacokinetic parameters are calculated using individual plasma concentrations. A qualified LC/MS method that measures the intact mass of the Example is used to determine plasma (K.sub.3 EDTA) concentrations. Each Example is tested with an analog peptide as an internal standard. Immunoaffinity based precipitation with anti-GIP/GLP1 antibodies is used to extract each test peptide and analog. Mean pharmacokinetic parameters for the Examples are shown in Table 6 and Table 7.

TABLE-US-00020 TABLE 6 Mean (+/−SD) Pharmacokinetic Parameters of peptides Following a Single Subcutaneous Administration of 50 nMol/kg to Male Sprague Dawley rats. C.sub.max/D AUCINF_D_obs Cl/F Exam- T.sub.1/2 T.sub.max (kg*nmol/ (hr*kg*nmol/ (mL/hr/ ple (hr) (hr) L/nmol) L/nmol) Kg) Exam- 44.7 21.3 3.34 (0.22) 294.2 (30.0) 3.42 (0.33) ple 1 (6.2) (4.6) Exam- 20.3 14.7 5.19 (0.20) 231.7 (9.6) 4.32 (0.17) ple 2 (0.9) (2.3) Exam- 32.1 21.3 4.71 (0.50) 371.8 (21.8) 2.70 (0.16) ple 3 (1.9) (4.6) Abbreviations: T.sub.1/2 = half-life, T.sub.max = time to maximal concentration, C.sub.max = maximal plasma concentration, AUCINF_D_obs = AUCinf divided by dose, CL/F = clearance/bioavailability. Notes: Data are the mean, where n = 3/group (Table 6) As seen in table 6, results from this study using these Example peptides are consistent with an extended pharmacokinetic profile.

TABLE-US-00021 TABLE 7 Mean (+/−SD) Pharmacokinetic Parameters of peptides Following a Single Intrajejunal Administration of 1 μmol/kg to Male Sprague Dawley rats. C.sub.max/D AUCINF_D_obs Example T.sub.max (hr) (kg*nmol/L/nmol) (hr*kg*nmol/L/nmol) Example 1 1.33 (0.82) 0.08 (0.05) 1.31 (0.85) Example 2 0.25 (0.13) 0.56 (0.40)  6.6 (4.4) Example 3 0.33 (0) 0.47 (0.16) 8.45 (3.1) Data are the mean, where n = 3/group n = 6/group (Table 7).
As illustrated by results in Table 7, these Examples are consistent with an exposure following intrajejunal administration. Intrajejunal exposure in this assay supports that the Examples may be suitable for oral formulation and administration.

In Vivo Effect on Insulin Secretion in Male Wistar Rats

[0332] Male Wistar rats with femoral artery and femoral vein canulas (Envigo, Indianapolis, Ind.) (280-320 grams) are single-housed in polycarbonate cages with filter tops. Rats maintained on a 12:12 h light-dark cycle (lights on at 6:00 A.M.) at 21° C. and receive food and deionized water ad libitum. Rats are randomized by body weight and dosed 1.5 ml/kg s.c. at doses of 0.04, 0.1, 0.3, 1, 3, and 10 nmol/kg 16 hours prior to glucose administration then fasted. Animals are weighed and anesthetized with sodium pentobarbital dosed i.p. (65 mg/kg, 30 mg/ml). A time 0 blood sample is collected into EDTA tubes after which glucose is administered i.v. (0.5 mg/kg, 5 ml/kg). Blood samples are collected for glucose and insulin levels at time 2, 4, 6, 10, 20 and 30 min post intravenous administration of glucose. Plasma glucose levels are determined using a clinical chemistry analyzer. Plasma insulin is determined using an electrochemiluminescence assay (Meso Scale, Gaithersburg, Md.). Glucose and insulin AUC are examined compared to the vehicle control with n=5 animals per group. Results are presented (SEM)(N).

TABLE-US-00022 TABLE 8 The effect of Example compounds on insulin secretion during intravenous glucose tolerance test. Dose (nmol/kg, s.c.) Example 0.0 0.04 0.1 0.3 1.0 3 10 1 31.3 32.2 31.5 24.7 35.1 43.5 63.9 (2.8) (5.7) (4.5) (5) (3.0) (5) (4.0) (5) (4.9) (5) (6.5) (5) (5) (5) 2 18.9 32.8 49.1 82.2 110.9 108.2 77.3 (4.3) (3.9) (4.8) (5) (21.1) (5) (23.1) (20.2) (8.8) (5) (5) (5) (5) (5) 3 18.5 26.0 24.6 44.9 60.1 95.5 87.7 (1.0) (3.4) (3.9) (5) (9.6) (5) (4.0) (5) (18.4) (7.9) (5) (5) (5) (5) 4 33.7 34.0 42.0 86.3 90.2 108.7 114.6 (5.3, 5) (3.4, 5) (3.8, 5) (4.5, 5) (9.2, 5) (9.8, 5) (16.1, 5) 5 24.4 28.2 40.2 41.1 44.1 54.3 94.2 (30, 5) (42, 5) (60, 5) (27, 5) (45, 5) (119, 5) (10.1, 5)

[0333] The data provided by Table 8 demonstrate a dose dependent increase in insulin secretion.

TABLE-US-00023 TABLE 9 ivGTT Insulin Secretion shown by the following data: Insulin secretion (ivGTT) Example (ED.sub.50, nmol/kg) (SEM, n) 1 >10 2 0.1 (0.05, 5) 3 0.7 (0.3, 5) 4 0.2 (0.05, 5) 5 3 < ED.sub.50 < 10

[0334] The data provided by Table 9 demonstrate dose dependent increase in insulin secretion.

Studies in Diet-Induced Obese C.SUB.57./B16 Mice

[0335] C.sub.57/B16 diet-induced obese (DIO) male mice (Taconic, Germantown, N.Y.) weighing 41-50 g are used. Animals are individually housed in a temperature-controlled (24° C.) facility with a 12 hour light/dark photoperiod (lights off at 10:00 AM and lights on at 10:00 PM), with free access to food and water. After 2 week acclimatization to the facility, mice are randomized to treatment groups (n=6/group) based on body weight so each group has similar starting mean body weight.

[0336] Mice are treated with either vehicle (40 mM Tris-HCl at pH 8.0) or several peptides between the dose ranges of 0.03 nmol/kg to 10 nmol/kg. Treatments are subcutaneously administered to ad libitum fed DIO mice 30-90 minutes prior to the onset of the dark cycle daily (QD) for 14 days. During the course of the study, body weight and food intake are monitored daily.

[0337] All data are expressed as mean±SEM of 5-6 rats per group. Statistical analyses are assessed by one-way ANOVA followed by Dunnett's multiple comparison test to compare treatment groups to vehicle group or each other. Significant differences are identified at p<0.05.

[00001]$\mathrm{Percent}\mathrm{Body}\mathrm{Weight}=\frac{\mathrm{Body}\mathrm{weight}\mathrm{after}14\text{-}\mathrm{day}\mathrm{treatment}}{\mathrm{Body}\mathrm{weight}\mathrm{before}\mathrm{treatment}\mathrm{started}}\times 100$

“0” dose group represents the vehicle-treated mice during each study. All data are expressed as mean±SEM of 5-6 mice per group. Statistical analyses are assessed by one-way ANOVA followed by Dunnett's multiple comparison test to compare treatment groups to ‘0’ dose (vehicle). *Significant differences are identified at p<0.05. Body weight change after treatment with Example compounds after 15 days. “Δ from vehicle” refers to difference between body weight at day 15 between test and vehicle groups. “% change” refers to percent decrease in body weight between days 1 and 15 in test groups. Percent decrease in body weight for animals receiving vehicle is recorded, and is less than about 1% in each study. The Δ from vehicle and % change data are statistically significantly different (p<0.05) than control for all Examples at all doses tested.

TABLE-US-00024 TABLE 10 The effect of GIP/GLP-1 receptor co-agonists on percent body weight in diet- induced obese mice after 14-day of treatment. Dose (nmol/kg, s.c., QD) Peptide 0 0.03 0.1 0.3 1 3 10 Example 1 99.2 ± 0.8 96.2 ± 1.2 95.6 ± 0.9  86.7 ± 1.3* 86.3 ± 1.9* 74.0 ± 3.8* 64.7 ± 2.6* Example 2 100.5 ± 1.4  101.5 ± 0.2  95.0 ± 1.2  86.5 ± 0.8* 76.4 ± 4.0* 76.4 ± 2.4* 68.1 ± 3.1* Example 3 98.0 ± 0.7 99.1 ± 1.3 95.6 ± 1.3 93.0 ± 1.1 85.6 ± 0.8* 75.9 ± 4.3* 73.6 ± 1.7* Example 4 98.3 ± 1.1 96.6 ± 0.5 94.7 ± 1.8  88.5 ± 1.2* 76.9 ± 1.4* 66.6 ± 3.9* 64.5 ± 2.2* Example 5  98.3 ± 11.1 96.0 ± 1.3 96.7 ± 1.1 94.1 ± 1.8 82.4 ± 1.6* 83.8 ± 1.6* 74.9 ± 2.3* Example 104 99.2 ± 0.8 94.0 ± 0.6 94.1 ± 0.8  89.0 ± 0.9* 82.7 ± 1.5* 70.8 ± 4.2* 71.3 ± 4.1* Example 123 99.2 ± 0.8 94.7 ± 0.9  90.5 ± 1.6*  86.5 ± 1.1* 81.3 ± 2.0* 75.1 ± 1.8* 68.6 ± 1.9*

[0338] As illustrated by data provided in Table 10 above, Example compounds tested in the assay dose-dependently reduce body weight in the studies described.

Proteolytic Stability Assay

[0339] The proteolytic stability assay is a useful for assessing potential for oral delivery of peptides. The stability of peptides are compared in 1% rat small intestinal fluid (rSIF). The amount of intact peptide is measured for a sample peptide at 0, 3, 15, and 30 minutes to assess proteolytic stability. The amount of intact peptide for a sample peptide is measured in 90% pig small intestinal fluid (pSIF) at 0, 30, 45, and 60 minutes to assess the proteolytic stability.

[0340] Sample preparation when rat small intestinal fluid (rSIF) is used:

[0341] Peptides are prepared at 0.4 mg/mL in 50 mM Tris pH8.0. Rat small intestinal fluid is added at a ratio of 1% (v/v). The mixture is incubated at 37° C. at 150 rpm. Thirty μL of each sample are removed and placed into a new tube before the rSIF is added and at 3, 15, and 60 min. At each time point, the reaction was quenched by 1% TFA in 50% ACN at 1:1. The samples are diluted 100 times using dilution buffer (1:1 of 1% TFA in 50% ACN: 50 mM Tris pH8) and ready for analysis using mass spectrometry (MS).

[0342] Sample preparation when pig small intestinal fluid (pSIF) is used:

[0343] Peptides are diluted to a concentration of 0.4 mg/mL in 90% pig small intestinal fluid. After the mixing, 20 μL are immediately removed (time 0 for the time point of pre-incubation). The mixture is then incubated at 37° C. at 150 rpm. Twenty μL of each sample are removed and placed into a new tube at 30, 45, and 60 min. At each time point (0, 30, 45, 60), the reaction is quenched by 1% TFA in 50% ACN at 1:1. The sample is centrifuged at 20,000×g for 20 min at 4° C. The supernatant is diluted 100 times using dilution buffer (1:1 of 1% TFA in 50% ACN: 50 mM Tris pH 8) and ready for analysis using mass spectrometry (MS).

[0344] MS Conditions: The liquid chromatography separation is carried out on a Waters Acquity UPLC using mobile phase A (0.1% formic acid in water) and B (0.1% formic acid in acetonitrile and an ACQUITY UPLC Protein BEH C4 Column (300 Å, 1.7 μm, 1 mm×50 mm) at 40° C. The gradient is 5% of B during 0-1.5, 5-90% of B during 1.5-1.8, 90-95% of B during 1.8-3.0, 95-95% of B during 3.0-3.5, 95-5% of B during 3.5-4.0, and 5-5% of B during 4.0-5.0. The MS analysis is carried out on a Waters Xevo G2-XS QTOF. The data is acquired using MSe Continuum in the range of 50-2000 m/z in positive and sensitivity mode. The data analysis is performed using MassLynx.

TABLE-US-00025 TABLE 11 The percentage of each peptide not cleaved at different time points using rSIF. 0 min 3 min 15 min 60 min Example 1 100 82.4 41.4 1.6 Example 2 100 75.5 18.3 0.3 Example 3 100 68.8 25.8 0.3 Example 4 100 97.9 99.3 89.4 Example 69 100 2.2 0.0 0.0

[0345] The proteolytic peptide results provided in Table 11 suggest that the peptide of Example 4 may be suitable for oral formulation and delivery.

TABLE-US-00026 TABLE 12 The percentage of each peptide not cleaved at different time points using pSIF. 0 min 30 min 45 min 60 min Example 4 100 73.4 56.4 60.0 Example 5 100 76.9 56.8 60.7
The proteolytic peptide results provided in Table 12 suggest that both the peptides of Examples 4 and 5 may be suitable for oral formulation and delivery.

In Vivo Studies

[0346] The purpose of this study is to determine the relative potential for clinical immunogenicity of a compound.

Methods:

[0347] CD8+ T cell depleted peripheral blood mononuclear cells are prepared and labeled with Carboxyfluorescein Diacetate Succinimidyl Ester (CFSE, Invitrogen) from a cohort of 10 healthy donors. Samples are tested in triplicate with 2.0 mL media control, keyhole limpet hemocyanin (“KLH”) (0.33 μM), anti-chemokine receptor type 4 (“CD4+”) (0.33 μM), and a compound of Examples 1, 2, and 3 (10 Cultures are incubated for 7 days at 37° C. with 5% CO.sub.2. On day 7, samples are analyzed by flow cytometry using High Throughput Sampler (HTS). Data is analyzed using FlowJo® Software (FlowJo, LLC, TreeStar).

Results and Discussion

[0348] All donors produce a positive T cell response against KLH (100%). Analysis of the frequency and magnitude of the CD4+ T cell response for Example compounds is shown in Table 13.

TABLE-US-00027 TABLE 13 CD4+ T Cell Responses for Example compounds and Positive Control (KLH). Median Response % Donor Strength in Response positive donors (CDI) KLH 100% (n = 11) 391 (n = 10) Example 1 (GG-212) 9% (n = 11) 0.7 (n = 1) Example 2 (GG-353) 22% (n = 9) 3.68 (n = 2) Example 3 (GG-362) 0% (n = 9) NA (n = 0) Example 4 (GG-427) 0% (n = 9) NA (n = 0) Example 288 (GG-709) 10% (n = 10) 5.42 (n = 1) Example 289 (GG-731) 0% (n = 10) NA (n = 0) Example 301 (GG-650) 0% (n = 10) NA (n = 0) Example 303 (GG-679) 0% (n = 10) NA (n = 0) Example 316 (GG-698) 0% (n = 10) NA (n = 0) Cell Division Index (“CDI”): proportion of divided CD4+ T cells to the total number of CD4+ T cells in stimulated versus unstimulated samples.
These data show that the frequency of positive CD+ T cell response (CDI>2.5) was low for the compounds of Examples 1, 2, 3, 4, 288, 289, 301, 303 and 316, and the magnitude of the response in the few positive donors was low (CDI<6), indicating a low risk of immunogenicity using the CD4+ T cell assay.

GLP-1R HEK293 Cell Membrane [.SUP.35.S]GTPγS Binding Assay

[0349] The GLP-1 receptor is a G-protein coupled receptor that increases GTP-bound Gα.sub.s upon ligand induced receptor activation. The potency of peptides to stimulate-GLP-1R induced activation of Gα.sub.s is determined using preparations of purified membranes from HEK293 cells expressing the human GLP-1R. The assay is performed similarly to that as previously described (Bueno et al., J. Biol. Chem., (2016) 291, 10700 and Willard et al., Mol. Pharmacol. (2012) 82, 1066). The test peptides are solubilized in DMSO and diluted in reaction buffer containing 5 μg of membrane in 20 mM HEPES pH 7.4, 50 mM NaCl, 5 mM MgCl.sub.2 40 μg/ml saponin, 0.1% BSA, and 500 pM .sup.35S-labeled GTPγS for 30 minutes at room temperature. Reactions are terminated by addition of 0.2% Nonidet P-40 detergent containing rabbit anti-Gα.sub.s polyclonal antibody and 0.5 mg of anti-rabbit polyvinyltoluene beads. Mixtures are developed for 30 minutes, centrifuged at 80×g for 10 minutes, and counted for 1 minute/well using a MicroBeta TriLux instrument. Peptide concentration-response curves are fit to a four-parameter logistic model to calculate potency as an EC.sub.50. Data normalization to % stimulation is performed using DMSO and GLP-1(7-36) as minimum and maximum controls for the receptor (Campbell et al, Assay Guidance Manual 2017). The potency of a sample peptide to stimulate GIPR induced activation of Gα.sub.s is reported in the Table 14. Assay results identify a peptide that is a partial agonist on the GLP-1R with respect to GLP-1R induced activation of Gα.sub.s.

GLP-1R CHO Cell β-Arrestin Recruitment Assay

[0350] Activated G-protein coupled receptors can interact with the β-arrestin family of signalling proteins. The potency of peptides for GLP-1R induced arrestin recruitment is determined using the PathHunter Enzyme Fragment Complementation approach substantially as described (von Degenfeld et al., FASEB J., 2007 (14):3819-26 and Hamdouchi et al., J. Med Chem., 2016 59(24):10891-10916). CHO-K1 cells expressing Pro-Link-tagged Human GLP-1R and enzyme-acceptor-tagged β-arrestin-2 may be obtained from DiscoveRx and prepared as assay-ready frozen cells. Test peptides are solubilized in DMSO and serial dilutions are performed using the Echo acoustic dispenser (LabCyte). Assay media is the PathHunter Cell Assay Buffer (DiscoveRx) containing 0.1% w/v hydrolyzed Casein (Sigma). 100 nl of peptide is dispensed into 10 μl of assay media in a 384 well plate and then 10 μl of cells in assay media are added to give 5000 cells per well. Plates are incubated for 90 minutes in a 37′C/5% CO.sub.2 incubator and 10 μl of PathHunter detection reagent is added (DiscoveRx) and plates are incubated at room temperature for 60 minutes. Luminescence signal is measured. Peptide concentration-response curves fit to a four-parameter logistic model to calculate potency as an EC.sub.50. Data normalization to % stimulation is performed using DMSO and GLP-1(7-36) as minimum and maximum controls (Campbell et al, Assay Guidance Manual 2017). The potency of a sample peptide to stimulate GLP-1R induced β-arrestin recruitment is reported in Table 14. The assay results identify a peptide that is a partial agonist on the GLP-1R with respect to β-arrestin-2 recruitment.

TABLE-US-00028 TABLE 14 hGLP1R hGLP1R B- GTPgS Rel hGLP1R Arrestin2 Rel hGLP1R B- EC50 nM GTPgS % EC50 uM Arrestin2 % Example (SEM, n) Top (SEM, n) (SEM, n) Top (SEM, n) 0.475 99.2 0.00274 104 (0.0322, n = 115) (0.659, n = 115) (0.000359, n = 42) (3.45, n = 42) 1 0.235 91.1 0.005 105 (0.0201, n = 5) (1.77, n = 5) 2 0.642 95.9 0.00882 96.1 (0.0294, n = 2) (0.553, n = 2) (0.00269, n = 2) (0.742, n = 2) 3 0.421 95.4 (0.181, n = 2) (2.20, n = 2) 4 0.245 86.9 0.00480 92.4 (0.0638, n = 3) (5.93, n = 3) (0.000138, n = 2) (14.0, n = 2) 5 0.196 91.3 (0.0375, n = 3) (6.90, n = 3) 266 0.865 63.4 0.016 17.1 (0.328, n = 2) (1.31, n = 2) 267 0.867 62.3 0.00901 16.5 272 0.651 66.5 >12.0 ND (0.0427, n = 2) (0.741, n = 2) 298 1.03 57.3 300 0.405 85.6 0.0054 38.4 301 0.435 91.4 0.00267 93.7 (0.0848, n = 3) (3.63, n = 3) 302 0.268 98.6 0.00219 98.4 303 0.547 74.3 0.0179 47.7 (0.0998, n = 2) (2.99, n = 2) 304 0.561 77.1 305 0.389 76.3 306 0.378 76.1 315 0.601 44.2 0.0199 25.4 316 0.766 56.7 0.00608 26.1 (0.0469, n = 2) (3.14, n = 2) 317 0.536 53.7 318 0.415 58.4 288 0.666 66.7 0.00674 21.3 (0.104, n = 3) (4.09, n = 3) (0.00278, n = 3) (1.94, n = 3) 319 0.657 65.7 323 0.79 81.9 324 0.475 84.5 289 0.404 83.7 0.0124 51.3 (0.0247, n = 3) (3.81, n = 3) (0.00151, n = 3) (6.05, n = 3) 325 0.414 97.9 326 0.663 61.6 327 0.287 75.6 0.00379 41.6 328 0.481 66.3 329 0.343 83.6 0.00473 63.4 330 1.05 47.8 >10.9 ND (0.275, n = 2) (1.16, n = 2) 331 0.375 80.9 0.0128 44.3 (0.0274, n = 4) (2.54, n = 4) 332 0.453 81.5 0.0171 45.6 (0.0479, n = 4) (4.65, n = 4) 333 0.442 83.4 0.0548 58.2 (0.00535, n = 2) (0.439, n = 2) 334 0.432 70.2 >10.3 ND 335 0.285 89.3 0.00531 73 336 0.377 90.2 0.00778 82.5 290 0.466 66.2 0.0238 20.0 (0.0664, n = 9) (3.12, n = 9) (0.00530, n = 4) (1.15, n = 4) 337 0.322 59.5 0.0174 34.1 338 0.0189 47 339 0.326 74.1 0.0107 44.0 (0.0357, n = 3) (7.97, n = 3) (0.00238, n = 2) (2.40, n = 2) 340 0.450 67.4 0.0107 20.1 (0.0182, n = 5) (5.12, n = 5) (0.00711, n = 4) (2.31, n = 4) 341 0.496 78.9 0.0188 21.9 342 0.414 77.2 0.035 20.7 343 0.522 74.9 0.0455 41.4 344 0.423 85.8 0.0343 46 345 0.684 62 0.00308 74.7 (0.000666, n = 2) (2.86, n = 2) 346 0.737 56.6 0.00325 19.3 (0.201, n = 3) (3.94, n = 3) (0.00105, n = 3) (0.767, n = 3) 347 0.759 46.9 0.00542 24.6 (0.00152, n = 2) (2.81, n = 2) 348 0.66 47.7 0.00346 19.8 (n = ½) 349 0.464 64.5 0.0151 18.4 (0.0290, n = 4) (1.68, n = 4) (0.00111, n = 2) (0.337, n = 2) 350 0.589 64.1 0.0108 21.8 351 0.563 66.5 0.0196 23.5 352 0.552 63.5 0.00421 17.4 (0.0267, n = 2) (1.51, n = 2) (n = ½) 353 1.96 63.1 0.559 23.0 (0.108, n = 2) (0.408, n = 2) 291 0.466 65.0 >10.0 ND (0.0476, n = 6) (2.15, n = 6) (n = ¼) 354 0.967 53.3 0.255 22.7 (n = ½) 355 1.76 50.6 0.363 18.3 356 >10.5 ND 357 0.118 18.2 358 0.414 72.3 0.00938 21.4 (0.00356, n = 2) (1.27, n = 2) (0.00413, n = 3) (2.47, n = 3) 359 0.496 69.7 0.0841 28.4 360 0.0395 25.8 361 0.269 20.2 (n = ½) 362 >11.0 ND 363 0.943 69.6 0.135 22.1 364 >12.0 ND 292 0.429 71.5 0.00774 29.0 (0.0190, n = 4) (3.33, n = 4) (0.00199, n = 4) (3.96, n = 4) 293 0.368 70.6 0.00719 29.5 (0.0304, n = 4) (0.715, n = 4) (0.00168, n = 4) (6.23, n = 4) 365 0.464 66.9 0.00703 20.8 (0.0178, n = 3) (1.35, n = 3) (0.00233, n = 4) (1.78, n = 4) 366 0.409 67.6 0.00557 21.2 (0.0308, n = 3) (3.55, n = 3) (0.00363, n = 2) (0.163, n = 2) 367 0.289 89.7 0.00666 70.6 (0.00118, n = 2) (8.61, n = 2) 368 0.495 68.9 0.0479 21.3 (0.0205, n = 2) (4.03, n = 2) 369 0.381 58.8 0.0414 19.9 (n = ½) 370 0.428 63.7 0.00990 23.0 (0.00149, n = 2) (0.470, n = 2) 371 0.27 62.5 0.0142 21.7 (0.00333, n = 2) (0.711, n = 2) 372 0.379 69.1 0.00981 32.9 (0.00630, n = 2) (1.65, n = 2) 373 0.336 65.6 0.00954 22.9 (0.00348, n = 2) (5.88, n = 2) 374 0.345 67.1 0.0218 34.7 375 0.419 70.4 0.0114 24.2 376 0.326 72.6 0.0123 25.6 377 0.356 68.4 0.00532 16.7 378 0.359 68.6 >10.2 ND 379 0.239 71 0.0181 31.9 380 0.188 66.8 0.0137 35 381 0.273 73.6 0.0155 25.8 Comparator 0.442 62.9 >10.5 ND Tirzepatide (se = 0.0311, n = 9( (se = 1.28, n = 9) (n = ⅕) hGLP1R B-Arrestin2 hGLP1R B-Arrestin2 Example Rel EC50 uM (SEM, n) % Top (SEM, n) 0.00274 104 (0.000359, n = 42) (3.45, n = 42) 1 0.005 105 2 0.00882 96.1 (0.00269, n = 2) (0.742, n = 2) 3 4 0.00480 92.4 (0.000138, n = 2) (14.0, n = 2) 266 0.016 17.1 267 0.00901 16.5 272 >12.0 ND 300 0.0054 38.4 301 0.00267 93.7 302 0.00219 98.4 303 0.0179 47.7 315 0.0199 25.4 316 0.00608 26.1 288 0.00674 21.3 (0.00278, n = 3) (1.94, n = 3) 289 0.0124 51.3 (0.00151, n = 3) (6.05, n = 3) 327 0.00379 41.6 329 0.00473 63.4 330 >10.9 ND 331 0.0128 44.3 332 0.0171 45.6 333 0.0548 58.2 334 >10.3 ND 335 0.00531 73 336 0.00778 82.5 290 0.0238 20.0 (0.00530, n = 4) (1.15, n = 4) 337 0.0174 34.1 338 0.0189 47 339 0.0107 44.0 (0.00238, n = 2) (2.40, n = 2) 340 0.0107 20.1 (0.00711, n = 4) (2.31, n = 4) 341 0.0188 21.9 342 0.035 20.7 343 0.0455 41.4 344 0.0343 46 345 0.00308 74.7 (0.000666, n = 2) (2.86, n = 2) 346 0.00325 19.3 (0.00105, n = 3) (0.767, n = 3) 347 0.00542 24.6 (0.00152, n = 2) (2.81, n = 2) 348 0.00346 19.8 (n = ½) 349 0.0151 18.4 (0.00111, n = 2) (0.337, n = 2) 350 0.0108 21.8 351 0.0196 23.5 352 0.00421 17.4 (n = ½) 353 0.559 23.0 (0.108, n = 2) (0.408, n = 2) 291 >10.0 ND (n = ¼) 354 0.255 22.7 (n = ½) 355 0.363 18.3 356 >10.5 ND 357 0.118 18.2 358 0.00938 21.4 (0.00413, n = 3) (2.47, n = 3) 359 0.0841 28.4 360 0.0395 25.8 361 0.269 20.2 (n = ½) 362 >11.0 ND 363 0.135 22.1 364 >12.0 ND 292 0.00774 29.0 (0.00199, n = 4) (3.96, n = 4) 293 0.00719 29.5 (0.00168, n = 4) (6.23, n = 4) 365 0.00703 20.8 (0.00233, n = 4) (1.78, n = 4) 366 0.00557 21.2 (0.00363, n = 2) (0.163, n = 2) 367 0.00666 70.6 (0.00118, n = 2) (8.61, n = 2) 368 0.0479 21.3 (0.0205, n = 2) (4.03, n = 2) 369 0.0414 19.9 (n = ½) 370 0.00990 23.0 (0.00149, n = 2) (0.470, n = 2) 371 0.0142 21.7 (0.00333, n = 2) (0.711, n = 2) 372 0.00981 32.9 (0.00630, n = 2) (1.65, n = 2) 373 0.00954 22.9 (0.00348, n = 2) (5.88, n = 2) 374 0.0218 34.7 375 0.0114 24.2 376 0.0123 25.6 377 0.00532 16.7 378 >10.2 ND 379 0.0181 31.9 380 0.0137 35 381 0.0155 25.8

Composition for Oral Administration

[0351] A peptide is dissolved in Tris buffer (pH 8.0, 50 mM). A Permeation enhancer (“PE”) is prepared as follows: C10 is dissolved in Tris buffer (pH 8.0, 50 mM), LC, DPC, C12-maltoside and Rhamnolipid are each dissolved in phosphate buffered saline (“PBS”) (1×, pH 7.2). A solution of peptide, a PE, and a protease inhibitor is mixed to reach a final peptide concentration of 300 uM, PE at 100 mM (5% w/v for Rhamnolipid) and 1% (v/v) for the protease inhibitor.

[0352] A peptide is incubated at 37° C. in 1% (v/v) rat small intestinal fluid or 50% (v/v) pig small intestinal fluid with and without a peptidase inhibitor. At different time points, samples are taken out, followed by quenching with 1% TFA in 50% ACN/water to stop the enzyme activity. The intact peptide at different time points is analyzed by high-performance liquid chromatography (HPLC) equipped with an ultraviolet (UV) detector or LC-MS/MS and normalized to the amount of peptide before mixing with the enzyme solution. A study using a peptide of Example 2 and a peptide of Example 4 are reported in Table 15.

TABLE-US-00029 TABLE 15 % peptide intact Recombinant protease inhibitor Small (concentration) intestinal fluid 0 min 15 min 30 min 60 min rSBTI (5 mg/mL) + Peptide (Example 4) 50% v/v pig 100.00 96.96 96.28 88.57 Peptide Example 4 (no PI; control) 50% v/v pig 100.00 72.52 41.44 18.98 rSBTI (5 mg/mL) + Peptide Example 2 50% v/v pig 100.00 103.02 112.69 87.33 Peptide Example 2 (no PI; control) 50% v/v pig 100.00 2.42 1.90 3.09 rSBTCI (0.5 mg/mL) + Peptide Example 2 50% v/v pig 100.00 131.71 126.53 123.70
Table 15 results support that an oral formulation composition for a peptide of Example 4 may be prepared using a PE and no PI.

Oral Formulation Composition

[0353] Examples of formulation compositions for a peptide of this invention are provided by Table 16. The formulation compositions for peptides of this invention are in no way limited by the examples provided.

TABLE-US-00030 TABLE 16 Formulation Formulation composition Concentration 1 Peptide (Example 1; or 2.4 mg/mL Example 4 or Example 3) C10 250 mM SBTI 75 mg/mL 2 Peptide (Example 1) 2.4 mg/mL LC 500 mM Citric acid 500 mM 3 Peptide (Example 1) 2.4 mg/mL NaTDC 250 mM SBTI 75 mg/mL 4 Peptide (Example 1, 2.4 mg/mL Example 2, or Example 4) C10 250 mM SBTI 12 mg/mL 5 Peptide (Example 1 or 2.4 mg/mL Example 2) C10 125 mM SBTI 12 mg/mL 6 Peptide (Example 1) 2.4 mg/mL C10 125 mM SBTI 24 mg/mL 7 Peptide (Example 4) 2.4 mg/mL C10 250 mM SFTI 12 mg/mL
The effect of formulation composition on a peptide exposure is evaluated in rats via intrajejunal (IJ) administration using liquid formulations. To prepare liquid formulations for a rat IJ administration, a peptide, C10 or NaTDC and SBTI is dissolved in 50 mM Tris buffer pH 8.0 and mixed to achieve final desired concentration. For LC/citric acid formulation, LC and citric acid are dissolved in water and mixed with a peptide dissolved in Tris buffer. Formulation compositions provided in Table 16 may be administered as an oral composition.

Enteric Capsules

[0354] An enteric capsule composition may be desired for certain peptides of this invention and may be prepared using methods for example, as set forth by Table 17. Enteric compositions may be prepared by blending ingredients together and filling the blend in enteric capsules.
An enteric composition of Table 17 is prepared adding half of the stated amount of sodium decanoate to a mortar. SBTI (for Examples 382-385) or SFTI (for Examples 386 and 387), and a peptide (peptides of Examples 1-4), as shown in Table 17. A remaining half of the sodium decanoate is added. A mixture is gently blended together using pestle, and spatula. If desired, additional mixing using pestle provides a homogenous blend. A capsule may be manually filled by individually weighing the required amount of blend, filling in capsules, and securely closing the capsule caps to the capsule bodies.
Dissolution testing of a single capsule is completed using known methods. A peptide of this invention may be formulated as an entric oral composition.

TABLE-US-00031 TABLE 17 Composition of Individual Enteric Capsule for Formulation Enteric Enteric Enteric Enteric Enteric Enteric Peptide- Example Example Example Example Example Example Component 382 383 384 385 386 387 Example 2 12.50 12.50 Example 4 12.50 12.50 Example 1 12.50 Example 3 12.50 Sodium 250.00 250.00 250.00 250.00 250.00 250.00 decanoate (C10) SBTI 62.50 62.50 62.50 62.50 SFTI 62.50 62.50 Total Capsule 325.00 325.00 325.00 325.00 325.00 325.00 Fill Weight Capsule Size Size 00 Size 00 Size 00 Size 00 Size 00 Size 00

TABLE-US-00032 Amino Acid Sequences GIP (Human) SEQ ID NO: 1 YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ GLP-1 (7-36) (Human) SEQ ID NO: 2 HAEGTFTSDVSSYLEGQAAKEFIAWLVKGR-NH.sub.2 SEQ ID NO: 3 R.sub.1X.sub.1 X.sub.2 X.sub.3GT X.sub.6TSD X.sub.10 X.sub.11 X.sub.12 X.sub.13 X.sub.14D X.sub.16X.sub.17AX.sub.19 X.sub.20 X.sub.21 X.sub.22X.sub.23 X.sub.24 X.sub.25 X.sub.26 X.sub.27 X.sub.28 X.sub.29 X.sub.30X.sub.31 SEQ ID NO: 4 PX.sub.32 X.sub.33 X.sub.34-R.sub.2 SEQ ID NO: 5 PX.sub.32X.sub.33X.sub.34X.sub.35X.sub.36X.sub.37X.sub.38X.sub.39-R.sub.2 SEQ ID NO: 6 PX.sub.32 X.sub.33 X.sub.34 X.sub.35X.sub.36 X.sub.37 X.sub.38 X.sub.39 X.sub.40-R.sub.2 SEQ ID NO: 7 K[(2-[2-(2-Amino-ethoxy)-ethoxy]-acety1).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.q-CO.sub.2H]X.sub.32 X.sub.33 X.sub.34-R.sub.2 SEQ ID NO: 8 K[(2-[2-(2-Amino-ethoxy)-ethoxy]-acety1).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.q-CO.sub.2H]X.sub.32 X.sub.33 X.sub.34 X.sub.35X.sub.36 X.sub.37 X.sub.38 X.sub.39-R.sub.2 SEQ ID NO: 9 K[(2-[2-(2-Amino-ethoxy)-ethoxy]-acety1).sub.2- (γ-Glu)-CO-(CH.sub.2).sub.q-CO.sub.2H]X.sub.32 X.sub.33 X.sub.34 X.sub.35X.sub.36 X.sub.37 X.sub.38 X.sub.39 X.sub.40-R.sub.2 Example 1 SEQ ID NO: 10 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- LDEK((2-[2-(2-Amino-ethoxy)-ethoxy]- acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ- Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 Example 2 SEQ ID NO: 11 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL- LD-Orn-K((2-[2-(2-Amino-ethoxy)- ethoxy]-acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16- CO.sub.2H)AQ-Aib-EFI-(D-Glu)- YLIEGGPSSGAPPPS-NH.sub.2 Example 3 SEQ ID NO: 12 Y-Aib-EGT-αMeF(2F)-TSDYSI-αMeL-LD- Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.18-CO.sub.2H)AQ- Aib-EFI-(D-Glu)-YLIEGGPSSGAPPPS-NH.sub.2 Example 4 SEQ ID NO: 13 Y-Aib-EGT-αMeF(2F)-TSD-4Pal-SI-αMeL- LD-Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 Example 5 SEQ ID NO: 14 Y-Aib-EGT-αMeF(2F)-TSDVSI-αMeL-LD- Orn-K((2-[2-(2-Amino-ethoxy)-ethoxy]- acety1).sub.2-(γ-Glu)-CO-(CH.sub.2).sub.16-CO.sub.2H)AQ-Aib- EFI-(D-Glu)-αMeY-LIEGGPSSGAPPPS- NH.sub.2 SEQ ID NO: 297 PSSG-R2 SEQ ID NO: 298 PSSGAPPPS-R2 SEQ ID NO: 299 PSSG SEQ ID NO: 300 PSSG-NH.sub.2 SEQ ID NO: 301 PSSGAPPPS SEQ ID NO: 302 PSSGAPPPS-NH.sub.2