METHOD OF PREDICTING A PREDISPOSITION TO QT PROLONGATION

Abstract

The present invention describes an association between genetic polymorphisms in the ABCC2 gene and a predisposition to prolongation of the QT interval, and provides related methods for the prediction of such a predisposition, the administration of QT interval-prolonging compounds to individuals having such a predisposition, and determining whether a compound is capable of inducing QT prolongation.

Claims

1. A method of administering to an individual a compound capable of prolonging the individual's QT interval, the method comprising: determining at least a portion of an individual's ABCC2 gene sequence; and in the case that a portion of the individual's ABCC2 gene sequence is associated with an increased risk of QT prolongation, administering to the individual a quantity of the compound less than would be administered to an individual having a ABCC2 gene sequence not associated with an increased risk of QT prolongation.

2. The method of claim 1, wherein determining includes determining the individual's genotype at the rs7067971 locus.

3. The method of claim 2, wherein the genotype associated with an increased risk of QT prolongation is GG.

4. The method of claim 1, further comprising: determining the individual's CYP2D6 genotype.

5. The method of claim 1, wherein the compound is iloperidone, a metabolite of iloperidone, or a pharmaceutically acceptable salt of iloperidone or the metabolite thereof.

6. A method of determining whether an individual is predisposed to prolongation of the QT interval, the method comprising: determining at least a portion of an individual's ABCC2 gene sequence.

7. The method of claim 6, further comprising: in the case that a portion of the individual's ABCC2 gene sequence is associated with an increased risk of QT prolongation, administering to the individual a compound not known or suspected to cause QT prolongation.

8. The method of claim 6, wherein determining includes determining the individual's genotype at the rs7067971 locus.

9. The method of claim 8, wherein the genotype associated with an increased risk of QT prolongation is GG.

10. The method of claim 6, further comprising: determining the individual's CYP2D6 genotype.

11. A method of administering a compound capable of prolonging a QT interval to an individual suffering from long QT syndrome (LQTS), the method comprising: determining at least a portion of an individual's ABCC2 gene sequence; and administering to the individual a quantity of the compound based on the individual's ABCC2 gene sequence.

12. The method of claim 11, wherein determining includes determining the individual's genotype at the rs7067971 locus.

13. The method of claim 12, wherein the genotype associated with an increased risk of QT prolongation is GG.

14. The method of claim 11, further comprising: determining the individual's CYP2D6 genotype.

15. The method of claim 11, wherein the compound is iloperidone, a metabolite of iloperidone, or a pharmaceutically acceptable salt of iloperidone or the metabolite thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0017] As indicated above, the invention provides a method of predicting an individual's predisposition to QT prolongation based on the sequence of the individual's ABCC2 (ATP-binding cassette, sub-family C, member 2) gene.

[0018] At least one single nucleotide polymorphism (SNP) within the ABCC2 gene has been found to have a significant correlation to a predisposition to drug-induced QT prolongation. Table 1, below, shows such SNPs and the genotypes associated with QT prolongation following the administration of iloperidone.

TABLE-US-00001 TABLE 1 ABCC2 SNP Genotypes and QT Prolongation Following Administration of Iloperidone Affymetrix SNP Lowest QTc Allele Allele No. rs_number Position change P value A B SNP_A-2253129 rs4919395 101532953 non-BB 0.009208217 C T SNP_A-2262953 rs2804398 101548624 non-BB 0.000421121 A T SNP_A-1928598 rs2273697 101553805 AB 0.479636886 C T SNP_A-1927451 rs3740065 101595683 AB 0.760583618 C T SNP_A-2068049 rs7067971 101606569 non-BB 4.02462E−07 A G SNP_A-4268713 rs2256700 101623437 non-BB 0.595645464 A G SNP_A-2004488 rs2256678 101623769 non-BB 0.003956423 C T

[0019] A genotype of GG at the rs7067971 locus was found to most accurately predict a predisposition to QT prolongation. This genotype is included amongst all genotypes associated with a predisposition to QT prolongation. Therefore, individuals having a genotype of GG at the rs7067971 locus may be considered predisposed to QT prolongation following the administration of a compound capable of prolonging the QT interval.

[0020] Since the QT interval changes with changes in heart rate, the QT interval is often measured as a corrected QT (QTc) interval. Any number of formulas may be employed to calculate the QTc, including, for example, the Fridericia formula (QTcF), the Bazett formula (QTcB), and the Rautaharju formula (QTp), among others. In the studies described herein, QT was calculated using the Fridericia formula. However, the present invention includes the use of any such formula or method for calculating a QTc or an uncorrected QT.

[0021] As noted above, a large number of compounds are known or suspected to be capable of inducing QT prolongation in some individuals, including individuals not suffering from LQTS. Such compounds may include compounds of Formula (1):

##STR00001##

wherein:

[0022] R is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, lower hydroxyketone, lower alkanol, hydroxyl acetic acid, pyruvic acid, ethanediol, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoaklylaminocarbonyl, dialkylaminocarbonyl, formyl,

##STR00002##

[0023] alkyl is lower alkyl, branched or straight and saturated or unsaturated;

[0024] acyl is lower alkyl or lower alkyloxy bonded through a carbonyl;

[0025] aryl is phenyl or phenyl substituted with at least one group, R.sub.5, wherein each R.sub.5 is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

[0026] heteroaryl is a five- or six-membered aryl ring having at least one heteroatom, Q.sub.3, wherein each Q.sub.3 is, independently, —O—, —S—, —N(H)—, or —C(H)═N—

[0027] W is CH.sub.2 or CHR.sub.8 or N—R.sub.9;

R.sub.1 is —H, lower alkyl, —OH, halo, lower alkoxy, trifluormethyl, nitro, or amino;
R.sub.2 is C.sub.2-C.sub.5 alkylene, alkenylene (cis or trans), or alkynylene, optionally substituted by at least one C.sub.1-C.sub.6 linear alkyl group, phenyl group or

##STR00003##

where Z.sub.1 is lower alkyl, —OH, lower alkoxy, —CF.sub.3, —NO.sub.2, —NH.sub.2, or halogen;
R.sub.3 is lower alkyl or hydrogen;
R.sub.7 is hydrogen, lower alkyl, or acyl;
R.sub.8 is lower alkyl;
R.sub.9 is hydroxy, lower alkoxy, or —NHR.sub.10;
R.sub.10 is hydrogen, lower alkyl, C.sub.1-C.sub.3 acyl, aryl,

##STR00004##

X.sub.1, X.sub.2, and X.sub.3 are, independently, —O—, —S—, ═N—, or —N(R.sub.3)—, or X.sub.1 and X.sub.2 are not covalently bound to each other and are, independently, —OH, ═O, —R.sub.3, or ═NR.sub.3; lower is 1-4 carbon atoms;
m is 1, 2, or 3; and
n is 1 or 2.

[0028] The compound may further include a compound of Formula (1), wherein:

[0029] R is —C(O)CH.sub.2OH, —CH(OH)C(O)CH.sub.2OH, —C(O)OH, CH(OH)CH.sub.3, or C(O)CH.sub.3;

[0030] R.sub.1 is halo;

[0031] X.sub.1 and X.sub.2 are different and are ═O, —OH, ═N—, or —O—;

[0032] R.sub.2 is C.sub.2-C.sub.4 alkylene or alkenylene;

[0033] R.sub.3 is hydrogen, methyl, or ethyl;

[0034] X.sub.3 is —O—; and

[0035] R is Formula (1A):

##STR00005##

[0036] In a further embodiment, the compound may be iloperidone, which is also referred to as 1-[4-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, as shown in Formula 1B:

##STR00006##

[0037] Iloperidone is disclosed in U.S. Pat. Nos. 5,364,866, 5,658,911, and 6,140,345, each of which is incorporated herein by reference. Metabolites of iloperidone may also be capable of prolonging a QT interval. Metabolites of Iloperidone, e.g., 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol, as shown in Formula 1C:

##STR00007##

are described in International Patent Application Publication No. WO03020707, which is also incorporated herein by reference.

[0038] Other iloperidone metabolites include: 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxyphenyl]ethanone; 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]-2-hydroxyethanone; 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-hydroxy-α-methylbenzene methanol; 4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxyl-2-hydroxy-5-methoxy-α-methylbenzenemethanol; 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2-hydroxy-5-methoxyphenyl]ethanone; and 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-2,5-dihydroxyphenyl]ethanone. See U.S. Pat. No. 5,364,866 and International Patent Application Publication Nos. WO9309276 and WO9511680, which are incorporated herein by reference.

[0039] Using the genotypes at the SNP loci above, it is possible, with a high degree of certainty, to predict an individual's predisposition to QT prolongation. Table 2 below shows the results of a study of 174 individuals, each of whom was genotyped at the rs7067971 locus and their QT interval measured following the oral administration of 24 mg/day B.I.D. of iloperidone for a period of two weeks.

TABLE-US-00002 TABLE 2 QT Prolongation and Presence or Absence of a Genotype for SNP_A-2068049, rs7067971 Associated with a Predisposition to QT Prolongation Change negative positive Threshold Low QT High QT Odds predictive predictive (msec) −test +test −test +test Ratio p value sensitivity specificity value value QT > 5 64 0 101 13 0.969 0.11 1.00 0.39 1.00 QT > 15 104 2 61 11 9.38 0.0044 0.15 0.98 0.63 0.85 QT > 30 144 7 21 6 5.88 0.0033 0.22 0.95 0.87 0.46

[0040] As can be seen in Table 2, an individual's ABCC2 sequence at the SNP_A-2068049, rs7067971 locus is highly predictive of whether the individual will experience QT prolongation following the administration of iloperidone. For example, using the lowest threshold of a change in QTc interval (between baseline and the end of the second week) greater than 5 milliseconds (normal QTc intervals are between 0.30 and 0.44 seconds for males and between 0.30 and 0.45 for females), 13 of those individuals with the GG genotype (test is considered positive if the genotype for SNP_A-2068049, rs7067971 is GG) experienced QT prolongation while no such individuals did not. The resulting sensitivity (probability that the individual will have a SNP genotype associated with a predisposition to QT prolongation, given that he/she experienced QT prolongation) of 0.11, specificity (probability that the individual will not have a SNP genotype associated with a predisposition to QT prolongation, given that he/she did not experience QT prolongation) of 1.0, negative predictive value (probability that the individual will not experience QT prolongation, given that he/she does not have a SNP genotype associated with a predisposition to QT prolongation) of 0.39, and a positive predictive value (probability that the individual will experience QT prolongation, given that he/she has a SNP genotype associated with a predisposition to QT prolongation) of 1.0, permit one to predict with great accuracy that an individual possessing the GG genotype is likely to experience QT prolongation.

[0041] The use of higher thresholds (i.e., QTs greater than 15 and 30 milliseconds) yielded markedly increased negative predictive values (0.63 and 0.87, respectively). The associated decrease in positive predictive values, from 1.0 for QTs greater than 5 milliseconds to 0.46 for QTs greater than 30 milliseconds) suggests that additional factors affect more severe QT prolongation.

[0042] As the data in Table 2 show, an individual's ABCC2 sequence at the SNP loci above may be used to predict whether an individual is predisposed to QT prolongation due to the administration of a compound capable of prolonging the QT interval. That is, individuals having a genotype of GG at the rs7067971 locus may reliably be predicted to experience a prolonged QT interval (i.e., a change in QT interval of at least 5 milliseconds) following the administration of a compound capable of prolonging the QT interval. Similarly, individuals having a genotype other than GG at the rs7067971 locus may reliably be predicted to not experience severe QT prolongation (i.e., a change in QT interval of greater than 15 milliseconds) following the administration of a compound capable of prolonging the QT interval.

[0043] The ability to make such predictions may be used in deciding whether to treat an individual with a particular compound and/or in determining the dosage appropriate for the individual. For example, an individual predicted to experience QT prolongation may be treated with an alternative compound not known or suspected to cause QT prolongation or may be administered a lower dose of a compound capable of causing QT prolongation than would be administered to an individual not predicted to experience QT prolongation.

[0044] The present invention also includes the administration of another compound useful in treating LQTS, in addition to one or more of the compounds above. Compounds useful in treating LQTS and/or preventing cardiac events resulting from LQTS, include, for example, beta blockers, such as propranolol, nadolol, atenolol, metoprolol.

[0045] The present invention also includes the prediction of an individual's predisposition for QT prolongation based on one or more of the SNP loci above in combination with the individual's genotype or gene sequence at one or more additional genes or loci. For example, International Patent Application Publication No. WO2006039663, incorporated herein by reference, describes a method of treating an individual with a compound capable of inducing QT prolongation based on the individual's CYP2D6 genotype. Other genotypes and/or gene sequences may similarly be used in combination with the SNP loci above, including those associated with LQTS. It should also be understood that the present invention includes the characterization of an expression product of the ABCC2 gene rather than, or in addition to, the determination of one or more SNP genotypes within the ABCC2 gene. For example, by determining a sequence of an mRNA strand transcribed from the ABCC2 gene, it is possible to determine the sequence of the ABCC2 gene itself and, as described above, determine whether the ABCC2 gene sequence is associated with a predisposition to QT prolongation.

[0046] Similarly, by properly characterizing a functional peptide or protein, including the ABCC2 enzyme, translated from the mRNA strand above, it is possible to determine the sequence of the ABCC2 gene itself and, as described above, determine whether the ABCC2 gene sequence is associated with a predisposition to QT prolongation. In addition, the present invention includes determining whether a compound is capable of prolonging a QT interval in an individual. This may be done, for example, by measuring a change in QT interval in a test organism (e.g., human, animal model, cell line) known to possess a ABCC2 genotype associated with a predisposition to QT prolongation following the administration of a quantity of compound under study.

[0047] Preferably, the compound is also administered to a test organism known to possess an ABCC2 genotype not associated with a predisposition to QT prolongation.

[0048] Thus, in addition to other illustrative embodiments, this invention can be seen to comprise one or more of the following illustrative embodiments:

[0049] 1. A method of administering to an individual a compound capable of prolonging the individual's QT interval, the method comprising: determining at least a portion of an individual's ABCC2 gene sequence; and in the case that a portion of the individual's ABCC2 gene sequence is associated with an increased risk of QT prolongation, administering to the individual a quantity of the compound less than would be administered to an individual having a ABCC2 gene sequence not associated with an increased risk of QT prolongation.

[0050] 2. The method of embodiment 1, wherein determining includes determining the individual's genotype at the rs7067971 locus.

[0051] 3. The method of embodiment 2, wherein the genotype associated with an increased risk of QT prolongation is GG.

[0052] 4. The method of embodiment 1, further comprising: determining the individual's CYP2D6 genotype.

[0053] 5. The method of embodiment 1, wherein the compound is selected from a group consisting of: amiodarone, arsenic trioxide, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, iloperidone, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine; alfuzosin, amantadine, azithromycin, chloral hydrate, clozapine, dolasetron, felbamate, flecainide, foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, granisetron, indapamide, isradipine, levofloxacin, lithium, moexipril, moxifloxacin, nicardipine, octreotide, ofloxacin, ondansetron, quetiapine, ranolazine, risperidone, roxithromycin, tacrolimus, tamoxifen, telithromycin, tizanidine, vardenafil, venlafaxine, voriconazole, ziprasidone; albuterol, amitriptyline, amoxapine, amphetamine, dextroamphetamine, atomoxetine, chloroquine, ciprofloxacin, citalopram, clomipramine, cocaine, desipramine, dexmethylphenidate, dobutamine, dopamine, doxepin, ephedrine, epinephrine, fenfluramine, fluconazole, fluoxetine, galantamine, imipramine, isoproterenol, itraconazole, ketoconazole, levalbuterol, metaproterenol, methylphenidate, mexiletine, midodrine, norepinephrine, nortriptyline, paroxetine, phentermine, phenylephrine, phenylpropanolamine, protriptyline, pseudoephedrine, ritodrine, salmeterol, sertraline, sibutramine, solifenacin, terbutaline, tolterodine, trimethoprim-sulfa, trimipramine, and metabolites, pharmaceutically-acceptable salts, and combinations thereof.

[0054] 6. The method of embodiment 5, wherein the compound has the formula:

##STR00008##

wherein:
R is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, lower hydroxyketone, lower alkanol, hydroxyl acetic acid, pyruvic acid, ethanediol, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoaklylaminocarbonyl, dialkylaminocarbonyl, formyl,

##STR00009##

[0055] alkyl is lower alkyl, branched or straight and saturated or unsaturated;

[0056] acyl is lower alkyl or lower alkyloxy bonded through a carbonyl;

[0057] aryl is phenyl or phenyl substituted with at least one group, R.sub.5, wherein each R.sub.5 is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

[0058] heteroaryl is a five- or six-membered aryl ring having at least one heteroatom, 03, wherein each 03 is, independently, —O—, —S—, —N(H)—, or —C(H)═N—

[0059] W is CH.sub.2 or CHR.sub.8 or N—R.sub.9;

##STR00010##

##STR00011##

[0060] 7. The method of embodiment 6, wherein:

[0061] R is —C(O)CH.sub.2OH, —CH(OH)C(O)CH.sub.2OH, —C(O)OH, CH(OH)CH.sub.3, or C(O)CH.sub.3;

[0062] R.sub.1 is halo;

[0063] X.sub.1 and X.sub.2 are different and are ═O, —OH, ═N—, or —O—;

[0064] R.sub.2 is C.sub.2-C.sub.4 alkylene or alkenylene;

[0065] R.sub.3 is hydrogen, methyl, or ethyl;

[0066] X.sub.3 is —O—;

[0067] R is

##STR00012##

(1A).

[0068] 8. The method of embodiment 7, wherein the compound of Formula 1 is 1-[4-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, as shown in Formula 1B:

##STR00013##

[0069] 9. The method of embodiment 7, wherein the compound of Formula 1 is 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol, as shown in Formula 1C:

##STR00014##

[0070] 10. A method of determining whether an individual is predisposed to prolongation of the QT interval, the method comprising: determining at least a portion of an individual's ABCC2 gene sequence.

[0071] 11. The method of embodiment 10, further comprising: in the case that a portion of the individual's ABCC2 gene sequence is associated with an increased risk of QT prolongation, administering to the individual a compound not known or suspected to cause QT prolongation.

[0072] 12. The method of embodiment 10, wherein determining includes determining the individual's genotype at the rs7067971 locus.

[0073] 13. The method of embodiment 12, wherein the genotype associated with an increased risk of QT prolongation is GG.

[0074] 14. The method of embodiment 10, further comprising: determining the individual's CYP2D6 genotype.

[0075] 15. A method of administering a compound capable of prolonging a QT interval to an individual suffering from long QT syndrome (LQTS), the method comprising: determining at least a portion of an individual's ABCC2 gene sequence; and administering to the individual a quantity of the compound based on the individual's ABCC2 gene sequence.

[0076] 16. The method of embodiment 15, wherein determining includes determining the individual's genotype at the rs7067971 locus.

[0077] 17. The method of embodiment 16, wherein the genotype associated with an increased risk of QT prolongation is GG.

[0078] 18. The method of embodiment 15, further comprising: determining the individual's CYP2D6 genotype.

[0079] 19. The method of embodiment 15, wherein the compound is selected from a group consisting of: amiodarone, arsenic trioxide, bepridil, chloroquine, chlorpromazine, cisapride, clarithromycin, disopyramide, dofetilide, domperidone, droperidol, erythromycin, halofantrine, haloperidol, ibutilide, iloperidone, levomethadyl, mesoridazine, methadone, pentamidine, pimozide, procainamide, quinidine, sotalol, sparfloxacin, thioridazine; alfuzosin, amantadine, azithromycin, chloral hydrate, clozapine, dolasetron, felbamate, flecainide, foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, granisetron, indapamide, isradipine, levofloxacin, lithium, moexipril, moxifloxacin, nicardipine, octreotide, ofloxacin, ondansetron, quetiapine, ranolazine, risperidone, roxithromycin, tacrolimus, tamoxifen, telithromycin, tizanidine, vardenafil, venlafaxine, voriconazole, ziprasidone; albuterol, amitriptyline, amoxapine, amphetamine, dextroamphetamine, atomoxetine, chloroquine, ciprofloxacin, citalopram, clomipramine, cocaine, desipramine, dexmethylphenidate, dobutamine, dopamine, doxepin, ephedrine, epinephrine, fenfluramine, fluconazole, fluoxetine, galantamine, imipramine, isoproterenol, itraconazole, ketoconazole, levalbuterol, metaproterenol, methylphenidate, mexiletine, midodrine, norepinephrine, nortriptyline, paroxetine, phentermine, phenylephrine, phenylpropanolamine, protriptyline, pseudoephedrine, ritodrine, salmeterol, sertraline, sibutramine, solifenacin, terbutaline, tolterodine, trimethoprim-sulfa, trimipramine, and metabolites, pharmaceutically-acceptable salts, and combinations thereof.

[0080] 20. The method of embodiment 19, wherein the compound has the formula:

##STR00015##

wherein: R is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxyl, carboxyl, lower hydroxyketone, lower alkanol, hydroxyl acetic acid, pyruvic acid, ethanediol, chlorine, fluorine, bromine, iodine, amino, lower mono or dialkylamino, nitro, lower alkyl thio, trifluoromethoxy, cyano, acylamino, trifluoromethyl, trifluoroacetyl, aminocarbonyl, monoaklylaminocarbonyl, dialkylaminocarbonyl, formyl,

##STR00016##

[0081] alkyl is lower alkyl, branched or straight and saturated or unsaturated;

[0082] acyl is lower alkyl or lower alkyloxy bonded through a carbonyl;

[0083] aryl is phenyl or phenyl substituted with at least one group, R.sub.5, wherein each R.sub.5 is, independently, hydrogen, lower alkyl, lower alkoxy, hydroxy, chlorine, fluorine, bromine, iodine, lower monoalkylamino, lower dialkylamino, nitro, cyano, trifluoromethyl, or trifluoromethoxy;

[0084] heteroaryl is is a five- or six-membered aryl ring having at least one heteroatom, Q.sub.3, wherein each Q.sub.3 is, independently, —O—, —S—, —N(H)—, or —C(H)═N—

[0085] W is CH.sub.2 or CHR.sub.8 or N—R.sub.9;

##STR00017##

##STR00018##

[0086] 21. The method of embodiment 20, wherein:

[0087] R is —C(O)CH.sub.2OH, —CH(OH)C(O)CH.sub.2OH, —C(O)OH, CH(OH)CH.sub.3, or C(O)CH.sub.3;

[0088] R.sub.1 is halo;

[0089] X.sub.1 and X.sub.2 are different and are ═O, —OH, ═N—, or —O—;

[0090] R.sub.2 is C.sub.2-C.sub.4 alkylene or alkenylene;

[0091] R.sub.3 is hydrogen, methyl, or ethyl;

[0092] X.sub.3 is —O—,

[0093] R is

##STR00019##

[0094] 22. The method of embodiment 21, wherein the compound of Formula 1 is 1-[4-3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanone, as shown in Formula 1B:

##STR00020##

[0095] 23. The method of embodiment 21, wherein the compound of Formula 1 is 1-[4-[3-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]-3-methoxyphenyl]ethanol, as shown in Formula 10:

##STR00021##

[0096] 24. A method of administering to an individual a compound capable of prolonging the individual's QT interval, the method comprising: characterizing an expression product of an individual's ABCC2 gene; and in the case that the characterized expression product is associated with an increased risk of QT prolongation, administering to the individual a quantity of the compound less than would be administered to an individual having an expression product not associated with an increased risk of QT prolongation.

[0097] 25. The method of embodiment 24, wherein the expression product includes at least one expression product selected from a group consisting of: mRNA, a peptide, and a protein.

[0098] 26. A method of determining whether an individual is predisposed to prolongation of the QT interval, the method comprising: characterizing an expression product of an individual's ABCC2 gene.

[0099] 27. The method of embodiment 26, wherein the expression product includes at least one expression product selected from a group consisting of: mRNA, a peptide, and a protein.

[0100] 28. A method of administering a compound capable of prolonging a QT interval to an individual suffering from long QT syndrome (LQTS), the method comprising: characterizing an expression product of an individual's ABCC2 gene; and administering to the individual a quantity of the compound based on the characterized expression product.

[0101] 29. The method of embodiment 28, wherein the expression product includes at least one expression product selected from a group consisting of: mRNA, a peptide, and a protein.

[0102] 30. A method of determining whether a compound is capable of prolonging a QT interval in an individual, the method comprising: measuring an expression product of the individual's ABCC2 gene; administering to the individual a quantity of the compound; re-measuring the expression product of the individual's ABCC2 gene; and determining whether the compound is capable of prolonging the individual's QT interval based on a difference in the measurements of the expression product of the individual's ABCC2 gene.

[0103] 31. The method of embodiment 30, wherein the expression product includes at least one expression product selected from a group consisting of: mRNA, a peptide, and a protein.

[0104] 32. A method of determining whether a compound is capable of prolonging a QT interval in an individual, the method comprising: measuring a QT interval of each of a plurality of test organisms, the plurality including a first test organism having a ABCC2 genotype associated with a predisposition for prolongation of QT interval and a second organism having a ABCC2 genotype not associated with a predisposition for prolongation of QT interval; administering a quantity of the compound to each of the plurality of test organisms; re-measuring a QT interval of at least the first test organism; and determining that the compound is capable of prolonging a QT interval in an individual in the case that the remeasured QT interval is greater than the measured QT interval.

[0105] 33. The method of embodiment 32, wherein each of the plurality of test organisms is selected from a group consisting of: humans, animals, and cell lines.

[0106] The foregoing description of various aspects of the invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed, and obviously, many modifications and variations are possible. Such modifications and variations that may be apparent to a person skilled in the art are intended to be included within the scope of the invention as defined by the accompanying claims.

METHOD OF PREDICTING A PREDISPOSITION TO QT PROLONGATION

Inventors

Cpc classification

Classification Explorer

A61K31/519

HUMAN NECESSITIES

Classification Explorer

C12Q2600/106

CHEMISTRY; METALLURGY

Classification Explorer

A61P9/00

HUMAN NECESSITIES

Classification Explorer

C07D413/04

CHEMISTRY; METALLURGY

Classification Explorer

C12Q1/6883

CHEMISTRY; METALLURGY

Classification Explorer

C12Q2600/156

CHEMISTRY; METALLURGY

Classification Explorer

A61P25/00

HUMAN NECESSITIES

International classification

Classification Explorer

C12Q1/68

CHEMISTRY; METALLURGY

Classification Explorer

C07D413/04

CHEMISTRY; METALLURGY

Classification Explorer

A61K31/519

HUMAN NECESSITIES

Abstract

Claims

Description