Methods and compositions for treating metabolic syndrome

Abstract

Provided are methods, compositions, systems, and kits for treating metabolic syndrome or a disorder associated with metabolic syndrome, e.g., obesity, dyslipidemia, and/or a diabetic condition, comprising administering systemically to a subject one or more compounds of the Formula (I) and/or (II): ##STR00001##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof, wherein , L, R.sub.1, R.sub.2, Z, X, A and B are defined herein.

Claims

1. A method for reducing body fat in an individual, the method comprising administering systemically to the skin of the individual a pharmaceutical composition comprising a compound of formula: ##STR00084## or a pharmaceutically acceptable salt thereof, wherein the individual suffers from an excess of body fat.

2. The method of claim 1, wherein the individual suffers from obesity.

3. The method of claim 1, wherein the body fat comprises subcutaneous fat.

4. The method of claim 1, wherein the pharmaceutical composition is administered topically.

5. The method of claim 1, wherein the pharmaceutical composition is administered transdermally.

6. The method of claim 1, wherein the pharmaceutical composition is administered to the skin in an implantable depot.

7. The method of claim 1, wherein the pharmaceutical composition is administered to the skin in a sustained-release formulation.

8. The method of claim 1, wherein the method reduces body weight.

9. The method of claim 1, wherein the method reduces weight gain.

10. The method of claim 1, wherein the pharmaceutical composition further comprises tromethamine.

11. The method of claim 1, wherein the pharmaceutical composition comprises greater than or equal to 0.3% (w/v) of the compound, or pharmaceutically acceptable salt thereof.

12. The method of claim 1, wherein the pharmaceutical composition comprises between 0.3% and 10% (w/v), inclusive, of the compound, or pharmaceutically acceptable salt thereof.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 depicts a randomized, controlled, repeat-dose, 4-week trial conducted on (db/db) mice, which are defective for the leptin receptor (Jackson Laboratories). These mice are genetically obese, dyslipidemic, and diabetic. Mice were obtained from Jackson Laboratories and acclimated to the facility. At about 5 weeks of age, mice were prospectively randomized into groups and assigned to the treatment conditions shown in FIG. 1. Topical treatments were applied in a thin film to the right flank skin without occlusive dressings; subcutaneous injections were also administered to the right flank. Mice were observed for condition and weighed daily. They were housed in the same room, in 11 cages according to group, and fed ad libitum. Skin tissue was sampled and serum lipids tested on day 28. Tissue was fixed in formalin and stained with hematoxylin and eosin.

(2) FIG. 2 shows mean weight gain of the mice treated in FIG. 1 for days 0 to 28, by group. Animals treated with vehicle only (Groups 1 and 2) showed an expected amount of weight gain for the strain (normative data, Jackson Laboratories). Transdermal bimatoprost isopropyl ester (BIE) and bimatoprost free acid (BFA) reduced weight gain significantly and in a dose-dependent manner, but topical bimatoprost did not. Subcutaneous BIE, subcutaneous BFA, and intraperitoneal BFA had no significant effect on weight gain.

(3) FIG. 3 shows representative histologic sections of skin and subcutaneous fat from untreated (left) and treated (right) flanks of animals assigned to vehicle only (Group 1), topical bimatoprost 0.3% (Group 4), and topical BIE 0.3% (Group 11). All sections are shown at the same magnification (scale bar at top right=640 microns). The surface of the skin is oriented toward the top and left of each panel. Arrows in each section denote the panniculus carnosus, an anatomic layer that separates the first layer of subdermal fat from deeper, subpannicular fat (separation artifact is commonly seen deep to the panniculus and is not an in vivo process).

(4) FIG. 4 shows mean, unfasted, serum lipid concentrations for each group (day 28), expressed as a percent reduction relative to control (Group 1).

(5) FIG. 5 charts the triglyceride and total cholesterol results (mg/dl) for the topical treatment conditions of FIG. 4 as follows: Group 1=C, 3=D, 4=E, 5=F, 6=G, 10=H, 11=I.

(6) FIG. 6 depicts a controlled, repeat-dose, 4-week, dose-ranging study of latanoprost transdermal cream was conducted in Zucker Diabetic Fatty (ZDF) rats (ZDF-Lepr.sup.fa/Crl), which are defective for the leptin receptor, obese, hyperlipidemic, and diabetic. Male ZDF rats, approximately 8 weeks old, were obtained from Jackson Laboratories and acclimated to the facility. They were prospectively assigned to treatment conditions shown in FIG. 6. There were 3 animals per treatment arm. Test articles were applied in a thin film to the right flank without occlusive dressings, at 0.3 ml daily for 28 days. Rats were fed ad libitum and housed in the same room in 4 cages according to group. They were observed for condition and weighed daily. Food consumption was measured by residual weight of chow. Animals were fasted overnight prior to day 29, and Oral Glucose Tolerance Tests were conducted on day 29 (1 g glucose per kg body weight). Skin tissue and serum chemistries were collected at day 29.

(7) FIG. 7 depicts shows mean weight gain, by group, for days 0 to 29. Compared to vehicle, topical latanoprost 0.5%, 0.05%, 0.005% caused a dose-dependent reductions in weight gain, which were statistically significant for the 0.5% and 0.05% concentrations.

(8) FIG. 8 shows representative histologic sections of skin and subcutaneous fat from untreated (left) and treated (right) flanks of animals assigned to vehicle only (Group 1), latanoprost 0.005% (Group 2), and latanoprost 0.5% (Group 4). All sections are shown at the same magnification (scale bar at top right=500 microns). The surface of the skin is oriented toward the top of each panel.

(9) FIG. 9 summarizes serum lipid levels by group, as measured on day 29. Compared to vehicle-treated control animals, latanoprost was associated with dose-dependent reductions in triglycerides and LDL, and dose-dependent increases in HDL and HDL:LDL ratio. These benefits were seen at the 0.5% and 0.05% concentrations, and were absent at the 0.005% concentration. Because of the small sample size, these differences did not reach statistical significance, except for the HDL:LDL ratio of Latanoprost 0.5% vs. vehicle (one-sided p<0.05).

(10) FIG. 10 shows the results of oral glucose tolerance testing on day 29. Latanoprost caused dose-dependent improvements in oral glucose tolerance, seen at the 0.5% and 0.05% concentration.

(11) FIG. 11 indicates the serum glucose Area Under the Curve from 15 to 120 minutes post-glucose load (AUC.sub.15-120) was 12% and 26% lower in animals treated with latanoprost 0.05% and 0.5%, respectively, compared to vehicle-treated animals. There was no effect on oral glucose tolerance with latanoprost 0.005%.

(12) FIG. 12 compares various topical doses of latanoprost in mouse, rat, and human, with respect to projected systemic dose.

DETAILED DESCRIPTION OF CERTAIN EMBODIMENTS OF THE INVENTION

(13) The present invention describes uses of certain prostaglandins, i.e., one or more compounds of compounds of Formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof, as described herein, to reduce, or eliminate altogether, body fat, for example, adipose tissue and/or adipocytes, in a subject, for example, a human. The invention further relates to uses of said compounds to reduce the concentration of lipid (e.g., triglycerides, cholesterol, lipoproteins (e.g., low density lipoprotein and very low density lipoprotein)), and/or increase HDL, in the blood of a subject.

(14) Previously members of the genus of F-series prostaglandins were recognized as hypotensive agents. For example, see U.S. Pat. Nos. 5,688,819 and 6,403,649, incorporated herein by reference. These compounds were shown to effect vasodilation and thereby were predicted to relieve symptoms of various diseases associated with increased blood pressure, including acute myocardial infarction, vascular thrombosis, hypertension, pulmonary hypertension, ischemic heart disease, congestive heat failure, and angina pectoris. These compounds were also shown to be effective ocular hypotensive agents useful for the treatment of elevated intraocular pressure, for example, glaucoma.

(15) Previous studies have shown that the use of bimatoprost eyedrops for the treatment of glaucoma does decrease intraocular pressure, but also induces unwanted side effects, which were eventually understood to be due to the atrophy of the fat normally present around the eye, i.e., the orbital fat. The use of bimatoprost to reduce unwanted fat by local administration was disclosed in U.S. Pat. No. 7,666,912, incorporated herein by reference.

(16) The present invention arises in part from a new finding that administration of certain F-series prostaglandins to obese, dyslipidemic, and/or diabetic animals has beneficial effects on disorders associated with metabolic syndromes in these animals. The observed effects include reduced obesity, reduced weight gain, reduce serum triglycerides, reduced serum LDL, increased serum HDL, reduced serum glucose, and/or improved glucose tolerance.

(17) The present invention also arises from the observation that systemic administration of certain F-series prostaglandins to obese animals reduces weight and/or weight gain in those animals.

(18) The present invention also arises from the experimental identification of certain preferred species from among the genus of F-series prostaglandins for the purposes of the invention.

(19) Prior to this work, it was envisioned that bimatoprost, when non-systemically and locally administered topically, subcutaneously, intramuscularly, or intralesionally at certain concentrations, e.g., 0.003%, 0.03%, or 0.3%, would locally reduce fat in a subject at the site of administration. See, e.g., the Examples of U.S. Pat. No. 7,666,912, incorporated herein by reference. In a human, an overall dose of 30 mg/m.sup.2/d (about 57 mg) using 0.3% ointment would involve application of about 20 g of ointment daily. The inventor has now discovered that while 0.3% topical bimatoprost (at an overall dose of about 30 mg/m.sup.2/d) locally reduces subcutaneous fat in a subject, the isopropyl ester and free acid of bimatoprost are significantly more effective in reducing subcutaneous fat. The inventor has further observed that while topical administration of bimatoprost locally reduces fat, topical administration of the isopropyl ester and free acid of bimatoprost reduces fat not only locally but also throughout the body, indicative of a systemic effect. In fact, topical administration of 0.3% bimatoprost isopropyl ester (at an overall dose of about 30 mg/m.sup.2/d) shows a significant systemic effect in reduction of serum lipids in the bloodstream of a subject, while topical administration of bimatoprost shows no systemic effect. See Example 1 below. The findings and observations disclosed herein are indeed surprising and unexpected, especially considering U.S. Pat. No. 7,666,912 dissuades from systemically administering such compounds.

(20) Furthermore, the inventor discovered that, unlike transdermal administration of bimatoprost ester or the free acid, neither subcutaneous nor intraperitoneal administration of bimatoprost ester or free acid had any significant effect on fat reduction. Without wishing to be bound by any particular theory, the inventor postulates that even if the compound is eliminated rapidly from the bloodstream (e.g., latanoprost has a serum elimination half-life of about 17 minutes), transdermal administration may provide a depot effect whereby a compound applied to the skin may result in slow release of the active ingredient into the bloodstream, and thereby result in a more sustained therapeutically effective concentration in the bloodstream. Furthermore, without wishing to be bound by theory, a similar effect can be obtained, for example, with a time release formulation, such as a controlled, extended, or sustained release formulation for oral, subcutaneous, intraperitoneal administration, or a continuous intravenous infusion, and the like.

(21) Without wishing to be bound by any particular theory, reduction in fat as a function of administration of the compounds disclosed herein may include reducing the number of fat cells (adipocytes), reducing the volume of one or more fat cells (adipocytes), reducing maturation of one or more fat cells (adipocytes), and/or dedifferentiating one or more fat cells (adipocytes). Such effects may be mediated through prostaglandin or prostaglandin-like receptors, and compounds according to the invention may exert their effects as herein disclosed by acting as agonists at these receptors. Because adipocytes have been specifically implicated in a wide array of human diseases, the present invention suggests a means for treating and/or preventing adipocyte-related diseases, such as, but not limited to, metabolic syndrome, diabetes (e.g., type 2 diabetes), liver disease, atherosclerosis, fatty liver, hepatic fibrosis, inflammation or inflammatory disease, depression, and dementia. The invention can be used to reduce adipocytes by administration of one or more of the compounds described herein, e.g., one or more compounds of the Formula (I) or (II).

(22) Thus, in one aspect, the present invention is directed to the use of certain prostaglandins, e.g., one or more compounds of the Formula (I) or (II), for treating and/or preventing metabolic syndrome or a disorder associated with metabolic syndrome in the body of a subject, by systemically administering the compound to the subject, e.g., at a concentration sufficient to produce a systemic effect in the bloodstream of a subject. More specifically a condition such as obesity, dyslipidemia, and/or a diabetic condition may be treated and/or prevented by administering to a subject a compound described herein. Furthermore, diseases and/or medical outcomes associated with the metabolic syndrome, obesity, dyslipidemia, and/or a diabetic condition may be treated and/or prevented by administering to a subject a compound described herein.

(23) The F-series prostaglandins disclosed herein are considered to be members of the class of prostaglandin F2 receptor agonists, which are known to be in vitro inhibitors of adipocyte differentiation and survival. See, e.g., Serrero et al. (1992) Biochem. Biophys. Res. Commun. 183:438-442; Lepak et al. (1993) Prostaglandins 46:511-517; Serrero et al. (1995) Biochem. Biophys. Res. Commun. 212:1125-1132; and Lepak et al. (1995) Endocrinology 136:3222-3229. Accordingly, without wishing to be bound by any particular theory, the fat-reducing properties of these compounds may relate to its agonism of prostaglandin or prostaglandin-like receptors, in particular the prostaglandin FP receptor (PTGFR).

(24) Compounds for Use in the Present Invention

(25) The present invention relates to uses of a compound of Formula (I) or (II), or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(26) In certain embodiments, the compound useful in the present invention is of Formula (I) or (II):

(27) ##STR00020##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof;
wherein:

(28) L is a group of the formula

(29) ##STR00021##

(30) each instance of independently represents a single bond or a double bond which can be in the cis or trans configuration;

(31) A is optionally substituted C.sub.1-10alkylene, optionally substituted C.sub.2-10alkenylene, or optionally substituted C.sub.2-10 alkynylene, wherein the alkylene, alkenylene, or alkynylene group is optionally interrupted by one or more O or S groups;

(32) B is hydrogen, optionally substituted C.sub.3-7carbocyclyl, optionally substituted 3-8-membered-heterocyclyl, optionally substituted 5-14-membered-heteroaryl, optionally substituted C.sub.6-10aryl, optionally substituted C.sub.1-30alkyl, optionally substituted C.sub.2-30alkenyl, or optionally substituted C.sub.2-30alkynyl;

(33) X is OR.sub.4, SR.sub.4, or N(R.sub.4).sub.2, wherein each instance of R.sub.4 is independently hydrogen, optionally substituted C.sub.1-30alkyl, optionally substituted C.sub.2-30alkenyl, optionally substituted C.sub.2-30alkynyl, C(O)R.sub.5, or C(O)OR.sub.5, wherein R.sub.5 is optionally substituted C.sub.1-30alkyl, optionally substituted C.sub.2-30alkenyl, or optionally substituted C.sub.2-30alkynyl, or two R.sub.4 groups are joined to form an optionally substituted 3-8-membered-heterocyclyl or optionally substituted 5-14-membered-heteroaryl ring;

(34) Z is O, S, or NR.sub.Z, wherein R.sub.Z is selected from hydrogen, an amino protecting group, OH, substituted hydroxyl, optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl, optionally substituted C.sub.3-7carbocyclyl, optionally substituted 3-8-membered-heterocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl, or Z represents two hydrogen atoms;

(35) with regard to the compound of Formula (I), one of R.sub.1 and R.sub.2 is O, OH, or a O(CO)R.sub.6 group and the other one is OH or O(CO)R.sub.6, or R.sub.1 is O and R.sub.2 is H, wherein R.sub.6 is a an optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20 alkynyl, or (CH.sub.2).sub.mR.sub.7 wherein m is 0 or an integer of between 1-10, inclusive, and R.sub.7 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted 3-8-membered-heterocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl; and

(36) with regard to the compound of Formula (II), R.sub.1 is O, OH, or O(CO)R.sub.6, wherein R.sub.6 is a an optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20 alkynyl, or (CH.sub.2).sub.mR.sub.7 wherein m is 0 or an integer of between 1-10, inclusive, and R.sub.7 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted 3-8-membered-heterocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl.

(37) In certain embodiments, the compound is not bimatoprost. In certain embodiments, the compound is not latanoprost. In certain embodiments, the compound is not travoprost.

(38) In certain embodiments, the endocyclic dotted lines of Formula (I) (i.e., depicted in the 5-membered ring) each represent a single bond.

(39) For example, in certain embodiments, wherein the endocyclic dotted lines of Formula (I) each represent a single bond, provided is a compound having any one of the following stereochemistry:

(40) ##STR00022## ##STR00023##
pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof, wherein , R.sub.1, R.sub.2, A, B, Z and X are as defined herein.

(41) In certain embodiments, the exocyclic dotted line (i.e., depicted outside of the 5-membered ring) of Formula (I) or (II) or a subset thereof represents a double bond in the cis or trans configuration. In certain embodiments, the exocyclic dotted line represents a double bond in the cis configuration.

(42) In certain embodiments, each instance of independently represents a single bond or a double bond which can be in the cis or trans configuration.

(43) As generally defined above, one of R.sub.1 and R.sub.2 is O, OH, or a O(CO)R.sub.6 group and the other one is OH or O(CO)R.sub.6, or R.sub.1 is O and R.sub.2 is H, wherein R.sub.6 is an optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20 alkynyl, or or (CH.sub.2).sub.mR.sub.7 wherein m is 0 or an integer of between 1-10, inclusive, and R.sub.7 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted 3-8-membered-heterocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl.

(44) In certain embodiments, R.sub.1 is O and R.sub.2 is H.

(45) In certain embodiments, one of R.sub.1 and R.sub.2 is OH, substituted hydroxyl, or O(CO)R.sub.3, and the other one is OH, substituted hydroxyl, or O(CO)R.sub.6.

(46) In certain embodiments, both R.sub.1 and R.sub.2 are OH.

(47) As generally defined above, A is optionally substituted C.sub.1-10alkylene, optionally substituted C.sub.2-10alkenylene or optionally substituted C.sub.2-10alkynylene, wherein the alkylene, alkenylene, or alkynylene group is optionally interrupted by one or more O or S groups. As used herein, interrupted by refers to an alkylene, alkenylene, or alkynylene which may optionally be flanked by an O or S group and/or an O or S group is included within the carbon chain.

(48) In certain embodiments, A is optionally substituted C.sub.1-10alkylene, optionally substituted C.sub.2-10alkenylene or optionally substituted C.sub.2-10alkynylene, wherein the alkylene, alkenylene, or alkynylene group is optionally interrupted by one O group.

(49) In certain embodiments, A is optionally substituted C.sub.4-6alkylene, optionally substituted C.sub.4-6alkenylene or optionally substituted C.sub.4-6alkynylene, wherein the alkylene, alkenylene, or alkynylene group is optionally interrupted by one O group.

(50) In certain embodiments, A is optionally substituted C.sub.4-6alkylene optionally interrupted by one O group. In certain embodiments, A is optionally substituted C.sub.4-6alkenylene optionally interrupted by one O group. In certain embodiments, A is optionally substituted C.sub.4-6alkynylene optionally interrupted by one O group.

(51) In certain embodiments, A is optionally substituted C.sub.1-10alkylene, optionally substituted C.sub.2-10alkenylene or optionally substituted C.sub.2-10alkynylene, wherein the alkylene, alkenylene, or alkynylene group is optionally interrupted by one S group.

(52) In certain embodiments, A is optionally substituted C.sub.4-6alkylene, optionally substituted C.sub.4-6alkenylene or optionally substituted C.sub.4-6alkynylene, wherein the alkylene, alkenylene, or alkynylene group is optionally interrupted by one S group.

(53) In certain embodiments, A is optionally substituted C.sub.4-6alkylene optionally interrupted by one S group. In certain embodiments, A is optionally substituted C.sub.4-6alkenylene optionally interrupted by one S group. In certain embodiments, A is optionally substituted C.sub.4-6alkynylene optionally interrupted by one S group.

(54) In certain embodiments, A is substituted with one or more groups selected from the group consisting of halogen, OH, substituted hydroxyl, or O(CO)R.sub.8, wherein R.sub.8 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20alkynyl, or (CH.sub.2).sub.mR.sub.9 wherein m is 0 or an integer between 1-10, inclusive, and R.sub.9 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted C.sub.6-10aryl, and optionally substituted 5-14-membered-heteroaryl.

(55) In certain embodiments, A is substituted with O.

(56) In certain embodiments, A is substituted with OC(O)R.sub.8, wherein R.sub.8 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20alkynyl, or (CH.sub.2).sub.mR.sub.9, wherein m is 0 or an integer between 1-10, inclusive, and R.sub.9 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl.

(57) In certain embodiments, A is substituted with OH or substituted hydroxyl.

(58) In certain embodiments, A is substituted with substituted hydroxyl.

(59) In certain embodiments, A is substituted with OH.

(60) In certain embodiments, A is substituted with halogen, e.g., F.

(61) In certain embodiments, A is a group of the formula (i), (ii), (iii), (iv), (v), or (vi):

(62) ##STR00024##
wherein each instance of independently represents a single bond or a double bond which can be in the cis or trans configuration;

(63) each instance of R.sub.3 and R.sub.3 is hydrogen, halogen, OH, substituted hydroxyl, or O(CO)R.sub.8, wherein R.sub.8 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20alkynyl, or (CH.sub.2).sub.mR.sub.9 wherein m is 0 or an integer between 1-10, inclusive, and R.sub.9 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl, or R.sub.3 and R.sub.3 are joined to form O;

(64) G is O or S;

(65) y is 0, 1, or 2; and

(66) x is 0 or 1.

(67) In certain embodiments, G is O. In certain embodiments, G is S.

(68) In certain embodiments, of formula (i), (ii), or (iii) represents a double bond in the cis configuration.

(69) In certain embodiments, of formula (i), (ii), or (iii) represents a double bond in the trans configuration.

(70) In certain embodiments, the group of the formula (i) is of the formula:

(71) ##STR00025##

(72) In certain embodiments, the group of the formula (ii) is of the formula:

(73) ##STR00026##

(74) In certain embodiments, of formula (i), (ii), or (iii) represents a single bond.

(75) In certain embodiments, the group of the formula (i) is of the formula:

(76) ##STR00027##

(77) In certain embodiments, the group of the formula (ii) is of the formula:

(78) ##STR00028##

(79) As generally defined above, each instance of R.sub.3 and R.sub.3 is independently hydrogen, halogen, OH, substituted hydroxyl, or O(CO)R.sub.8, wherein R.sub.8 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20alkynyl, or (CH.sub.2).sub.mR.sub.9 wherein m is 0 or an integer between 1-10, inclusive, and R.sub.9 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl; or R.sub.3 and R.sub.3 are joined to form O.

(80) In certain embodiments, R.sub.3 is hydrogen. In certain embodiments, R.sub.3 is hydrogen. In certain embodiments, R.sub.3 is hydrogen and R.sub.3 is a non-hydrogen group. In certain embodiments, R.sub.3 is hydrogen and R.sub.3 is a non-hydrogen group. In certain embodiments, however, neither R.sub.3 nor R.sub.3 is hydrogen.

(81) In certain embodiments, R.sub.3 and R.sub.3 are joined to form O.

(82) In certain embodiments, R.sub.3 and R.sub.3 are the same group. In certain embodiments, R.sub.3 and R.sub.3 are different groups.

(83) In certain embodiments, R.sub.3 is OH, substituted hydroxyl, or O(CO)R.sub.8, wherein R.sub.8 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20alkynyl, or (CH.sub.2).sub.mR.sub.9 wherein m is 0 or an integer between 1-10, inclusive, and R.sub.9 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl. In certain embodiments, R.sub.3 is O(CO)R.sub.8. In certain embodiments, R.sub.3 is OH or substituted hydroxyl. In certain embodiments, R.sub.3 is substituted hydroxyl. In certain embodiments, R.sub.3 is OH.

(84) In certain embodiments, R.sub.3 is OH, substituted hydroxyl, or O(CO)R.sub.8, wherein R.sub.8 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20alkynyl, or (CH.sub.2).sub.mR.sub.9 wherein m is 0 or an integer between 1-10, inclusive, and R.sub.9 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl. In certain embodiments, R.sub.3 is O(CO)R.sub.8. In certain embodiments, R.sub.3 is OH or substituted hydroxyl. In certain embodiments, R.sub.3 is substituted hydroxyl. In certain embodiments, R.sub.3 is OH.

(85) In certain embodiments, R.sub.3 is halogen, e.g., selected from fluoro, chloro, bromo, and iodo. In certain embodiments, R.sub.3 is halogen, e.g., selected from fluoro, chloro, bromo, and iodo. In certain embodiments, R.sub.3 is halogen and R.sub.3 is halogen, e.g., each independently selected from fluoro, chloro, bromo, and iodo. In certain embodiments, both R.sub.3 and R.sub.3 are fluoro.

(86) In certain embodiments, y is 0 and x is 1. In certain embodiments, y is 0 and x is 0. In certain embodiments, y is 1 and x is 1. In certain embodiments, y is 1 and x is 0. In certain embodiments, y is 2 and x is 0. In certain embodiments, y is 2 and x is 1.

(87) As defined generally above, B is hydrogen, optionally substituted C.sub.3-7carbocyclyl, optionally substituted 3-8-membered-heterocyclyl, optionally substituted 5-14-membered-heteroaryl, optionally substituted C.sub.6-10aryl, optionally substituted C.sub.1-30alkyl, optionally substituted C.sub.2-30alkenyl, or optionally substituted C.sub.2-30alkynyl.

(88) In certain embodiments, B is hydrogen.

(89) In certain embodiments, B is optionally substituted C.sub.1-30alkyl. In certain embodiments, B is optionally substituted C.sub.2-30alkenyl. In certain embodiments, B is optionally substituted C.sub.2-30alkynyl.

(90) In certain embodiments, B is optionally substituted C.sub.3-7carbocyclyl, e.g., optionally substituted cyclohexyl. In certain embodiments, B is optionally substituted 3-8-membered-heterocyclyl. In certain embodiments, B is optionally substituted 5-14-membered-heteroaryl. In certain embodiments, B is optionally substituted C.sub.6-10aryl. In certain embodiments, B is optionally substituted C.sub.6aryl (i.e., phenyl). In certain embodiments, B is optionally substituted C.sub.10aryl (i.e., napthyl).

(91) For example, in certain embodiments, B is an optionally substituted phenyl of the formula (viii):

(92) ##STR00029##
wherein:

(93) Y is selected from the group consisting of optionally substituted C.sub.1-10alkyl, C.sub.1-10perhaloalkyl, optionally substituted C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl, halo, nitro, cyano, thiol, substituted thiol, hydroxyl, substituted hydroxyl, amino, monosubstituted amino, and disubstituted amino; and n is 0 or an integer of from 1 to 5, inclusive.

(94) In certain embodiments, n is 0 or an integer from 1 to 3, inclusive. In certain embodiments, n is 0 or an integer from 1 to 2, inclusive. In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.

(95) For example, in certain embodiments, wherein n is 1, the group of the formula (viii) is of the formula:

(96) ##STR00030##

(97) In certain embodiments, wherein n is 2, the group of the formula (viii) is of the formula:

(98) ##STR00031##

(99) In certain embodiments, Y is halo, i.e. selected from fluoro, iodo, bromo, or chloro. In certain embodiments Y is chloro. In certain embodiments Y is fluoro.

(100) In certain embodiments, Y is optionally substituted C.sub.1-10alkyl or C.sub.1-10perhaloalkyl.

(101) In certain embodiments, Y is optionally substituted C.sub.1-10alkyl. In certain embodiments, Y is optionally substituted C.sub.1-6alkyl. In certain embodiments, Y is optionally substituted C.sub.1-4alkyl. In certain embodiments, Y is optionally substituted C.sub.1-3alkyl. In certain embodiments, Y is optionally substituted C.sub.1-2alkyl. In certain embodiments, Y is CH.sub.3, CH.sub.2F, or CHF.sub.2.

(102) In certain embodiments, Y is C.sub.1-10perhaloalkyl. In certain embodiments, Y is C.sub.1-6perhaloalkyl. In certain embodiments, Y is C.sub.1-4perhaloalkyl. In certain embodiments, Y is C.sub.1-3perhaloalkyl. In certain embodiments, Y is C.sub.1-2perhaloalkyl. In certain embodiments, Y is CF.sub.3, CF.sub.2Cl, or CFCl.sub.2.

(103) As generally defined above, Z is O, S, or NR.sub.Z, wherein R.sub.Z is selected from hydrogen, an amino protecting group, OH, substituted hydroxyl, optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl, optionally substituted C.sub.3-7carbocyclyl, optionally substituted 3-8-membered-heterocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl, or Z represents two hydrogen atoms.

(104) In certain embodiments, Z is O.

(105) In certain embodiments, Z is S.

(106) In certain embodiments, Z is NR.sub.Z, wherein R.sub.Z is selected from hydrogen, an amino protecting group, OH, substituted hydroxyl, optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl, optionally substituted C.sub.3-7carbocyclyl, optionally substituted 3-8-membered-heterocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl. In certain embodiments, Z is NR.sub.Z and R.sub.Z is hydrogen.

(107) In certain embodiments, Z represents two hydrogen atoms.

(108) As generally defined above, X is OR.sub.4, SR.sub.4, or N(R.sub.4).sub.2, wherein each instance of R.sub.4 is independently hydrogen, optionally substituted C.sub.1-30alkyl, optionally substituted C.sub.2-30alkenyl, optionally substituted C.sub.2-30alkynyl, C(O)R.sub.5, or C(O)OR.sub.5, wherein R.sub.5 is optionally substituted C.sub.1-30alkyl, optionally substituted C.sub.2-30alkenyl, or optionally substituted C.sub.2-30alkynyl, or two R.sub.4 groups are joined to form an optionally substituted 3-8-membered-heterocyclyl or optionally substituted 5-14-membered-heteroaryl ring.

(109) In certain embodiments, X is OR.sub.4. In certain embodiments, X is OR.sub.4, and R.sub.4 is hydrogen. In certain embodiments, X is OR.sub.4, and R.sub.4 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, R.sub.4 is optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, R.sub.4 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl. In certain embodiments, R.sub.4 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4alkenyl, or C.sub.4-6alkenyl. In certain embodiments, R.sub.4 is optionally substituted C.sub.2-6alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl.

(110) In certain embodiments, X is OR.sub.4, wherein R.sub.4 is C(O)R.sub.5, or C(O)OR.sub.5.

(111) In certain embodiments, X is OR.sub.4, and R.sub.4 is C(O)R.sub.5, and R.sub.5 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4-alkenyl, or C.sub.4-6alkenyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl.

(112) In certain embodiments, X is OR.sub.4, and R.sub.4 is C(O)OR.sub.5 and R.sub.5 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1alkyl, optionally substituted C.sub.2-10alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4alkenyl, or C.sub.4-6alkenyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl.

(113) In certain embodiments, X is SR.sub.4. In certain embodiments, X is SR.sub.4, and R.sub.4 is hydrogen. In certain embodiments, X is SR.sub.4, and R.sub.4 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, R.sub.4 is optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, R.sub.4 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl. In certain embodiments, R.sub.4 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4alkenyl, or C.sub.4-6alkenyl. In certain embodiments, R.sub.4 is optionally substituted C.sub.2-6alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl.

(114) In certain embodiments, X is SR.sub.4, wherein R.sub.4 is C(O)R.sub.5, or C(O)OR.sub.5.

(115) In certain embodiments, X is SR.sub.4, and R.sub.4 is C(O)R.sub.5, and R.sub.5 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4alkenyl, or C.sub.4-6alkenyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6-alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl.

(116) In certain embodiments, X is SR.sub.4, and R.sub.4 is C(O)OR.sub.5 and R.sub.5 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4alkenyl, or C.sub.4-6alkenyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl.

(117) In certain embodiments, X is N(R.sub.4).sub.2. In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 group is hydrogen. In certain embodiments, X is N(R.sub.4).sub.2 and neither of the two R.sub.4 groups are hydrogen. In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 is optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4alkenyl, or C.sub.4-6alkenyl. In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 is optionally substituted C.sub.2-6alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl. However, in certain embodiments, X is not NH(iPr).

(118) In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 is C(O)R.sub.5, or C(O)OR.sub.5.

(119) In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 is C(O)R.sub.5, and R.sub.5 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4alkenyl, or C.sub.4-6alkenyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl.

(120) In certain embodiments, X is N(R.sub.4).sub.2 and at least one R.sub.4 is C(O)OR.sub.5 and R.sub.5 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, or optionally substituted C.sub.2-20alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-10alkyl, optionally substituted C.sub.2-10alkenyl, or optionally substituted C.sub.2-10alkynyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.1-6alkyl, e.g., C.sub.1-3alkyl, C.sub.3-4alkyl, or C.sub.4-6alkyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkenyl, e.g., C.sub.2-3alkenyl, C.sub.3-4alkenyl, or C.sub.4-6alkenyl. In certain embodiments, R.sub.5 is optionally substituted C.sub.2-6alkynyl, e.g., C.sub.2-3alkynyl, C.sub.3-4alkynyl, or C.sub.4-6alkynyl.

(121) In other embodiments, X is N(R.sub.4).sub.2 and the two R.sub.4 groups are joined to form an optionally substituted 3-8-membered-heterocyclyl or optionally substituted 5-14-membered-heteroaryl ring.

(122) In certain embodiments, wherein X is OR.sub.4, SR.sub.4, or N(R.sub.4).sub.2, any one of R.sub.4 or R.sub.5 is optionally substituted C.sub.1-30alkyl (e.g., C.sub.1-10alkyl, C.sub.1-6alkyl, C.sub.1-3alkyl, C.sub.7-30alkyl, C.sub.10-30alkyl, C.sub.7-25alkyl, C.sub.10-25alkyl, C.sub.15-25alkyl). In certain embodiments, any one of R.sub.4 or R.sub.5 is optionally substituted C.sub.2-30alkenyl (e.g., C.sub.2-10alkenyl, C.sub.2-6alkenyl, C.sub.1-3alkenyl, C.sub.7-30alkenyl, C.sub.10-30alkenyl, C.sub.7-25alkenyl, C.sub.10-25alkenyl, C.sub.15-25alkenyl). In certain embodiments, any one of R.sub.4 or R.sub.5 is optionally substituted C.sub.2-30alkynyl (e.g., C.sub.2-10alkynyl, C.sub.2-6alkynyl, C.sub.1-3alkynyl, C.sub.7-30alkynyl, C.sub.10-30alkynyl, C.sub.7-25alkynyl, C.sub.10-25alkynyl, C.sub.15-25alkynyl).

(123) In any of the above embodiments, when R.sub.4 or R.sub.5 are defined as a C.sub.7-30alkyl or C.sub.7-30alkenyl groups, such groups may also be referred to as lipid tails. Lipid tails present in these lipid groups can be saturated and unsaturated, depending on whether or not the lipid tail comprises double bonds. The lipid tail can also comprise different lengths, often categorized as medium (i.e., with tails between 7-12 carbons, e.g., C.sub.7-12 alkyl or C.sub.7-12 alkenyl), long (i.e., with tails greater than 12 carbons and up to 22 carbons, e.g., C.sub.13-22 alkyl or C.sub.13-22 alkenyl), or very long (i.e., with tails greater than 22 carbons, e.g., C.sub.23-30 alkyl or C.sub.23-30 alkenyl).

(124) Exemplary unsaturated lipid tails include, but are not limited to:

(125) TABLE-US-00001 Myristoleic (CH.sub.2).sub.7CHCH(CH.sub.2).sub.3CH.sub.3, Palmitoliec (CH.sub.2).sub.7CHCH(CH.sub.2).sub.5CH.sub.3, Sapienic (CH.sub.2).sub.4CHCH(CH.sub.2).sub.8CH.sub.3, Oleic (CH.sub.2).sub.7CHCH(CH.sub.2).sub.7CH.sub.3, Linoleic (CH.sub.2).sub.7CHCHCH.sub.2CHCH(CH.sub.2).sub.4CH.sub.3, -Linolenic (CH.sub.2).sub.7CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CH.sub.3, Arachinodonic (CH.sub.2).sub.3CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCH(CH.sub.2).sub.4CH.sub.3, Eicosapentaenoic (CH.sub.2).sub.3CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CH.sub.3, Erucic (CH.sub.2).sub.11CHCH(CH.sub.2).sub.7CH.sub.3, and Docosahexaenoic (CH.sub.2).sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CHCHCH.sub.2CH.sub.3.

(126) Exemplary saturated lipid tails include, but are not limited to:

(127) TABLE-US-00002 Lauric (CH.sub.2).sub.10CH.sub.3, Myristic (CH.sub.2).sub.12CH.sub.3, Palmitic (CH.sub.2).sub.14CH.sub.3, Stearic (CH.sub.2).sub.16CH.sub.3, Arachidic (CH.sub.2).sub.18CH.sub.3, Behenic (CH.sub.2).sub.20CH.sub.3, Lignoceric (CH.sub.2).sub.22CH.sub.3, and Cerotic (CH.sub.2).sub.24CH.sub.3.

(128) In certain embodiments of Formula (I), the compound is of Formula (I-a):

(129) ##STR00032##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein R.sub.1, R.sub.2, Z, and X are as defined herein;

(130) each instance of independently represents a single bond or a double bond which can be in the cis or trans configuration;

(131) each instance of R.sub.3 and R.sub.3 is independently hydrogen, halogen, OH, substituted hydroxyl, or O(CO)R.sub.8, wherein R.sub.8 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20alkynyl, or (CH.sub.2).sub.mR.sub.9 wherein m is 0 or an integer between 1-10, inclusive, and R.sub.9 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl, or R.sub.3 and R.sub.3 are joined to form O;

(132) Y is selected from the group consisting of optionally substituted C.sub.1-10alkyl, C.sub.1-10perhaloalkyl, optionally substituted C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl, halo, nitro, cyano, thiol, substituted thiol, hydroxyl, substituted hydroxyl, amino, monosubstituted amino, and disubstituted amino;

(133) G is O or S;

(134) y is 0, 1, or 2;

(135) x is 0 or 1; and

(136) n is 0 or an integer of from 1 to 5, inclusive.

(137) In certain embodiments of Formula (I-a), wherein R.sub.3 is hydrogen, the compound is of Formula (I-b):

(138) ##STR00033##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, G, y, x, and n are as defined herein.

(139) In certain embodiments of Formula (I-a), wherein R.sub.3 is hydrogen, the compound is of Formula (I-c):

(140) ##STR00034##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, G, y, x, and n are as defined herein.

(141) In certain embodiments, G is O. In certain embodiments, G is S.

(142) In certain embodiments of Formula (I-a), wherein G is O, provided is a compound of Formula (I-a1):

(143) ##STR00035##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative or prodrug thereof; wherein R.sub.1, R.sub.2, Z, and X are as defined herein; wherein , R.sub.1, R.sub.2, R.sub.3, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(144) In certain embodiments of Formula (I-b), wherein G is O, the compound is of Formula (I-b1):

(145) ##STR00036##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(146) In certain embodiments of Formula (I-c), wherein G is O, the compound is of Formula (I-c1):

(147) ##STR00037##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(148) In certain embodiments of Formula (I-a), wherein G is S, provided is a compound of Formula (I-a2):

(149) ##STR00038##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(150) In certain embodiments of Formula (I-b), wherein G is S, the compound is of Formula (I-b2):

(151) ##STR00039##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(152) In certain embodiments of Formula (I-c), wherein G is S, the compound is of Formula (I-c2):

(153) ##STR00040##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(154) In certain embodiments, the compound of Formula (I-a) has the following stereochemistry, also referred to herein as a compound of Formula (I-d):

(155) ##STR00041##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, R.sub.3, Z, Y, G, X, y, x, and n are as defined herein.

(156) In certain embodiments of Formula (I-d), wherein R.sub.3 is hydrogen, the compound is of Formula (I-e):

(157) ##STR00042##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, G, y, x, and n are as defined herein.

(158) In certain embodiments of Formula (I-d), wherein R.sub.3 is hydrogen, the compound is of Formula (I-f):

(159) ##STR00043##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3 Z, X, Y, G, y, x, and n are as defined herein.

(160) In certain embodiments, G is O. In certain embodiments, G is S.

(161) In certain embodiments of Formula (I-d), wherein G is O, the compound is of Formula (I-d1):

(162) ##STR00044##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, R.sub.3, Z, Y, X, y, x, and n are as defined herein.

(163) In certain embodiments of Formula (I-e), wherein G is O, the compound is of Formula (I-e1):

(164) ##STR00045##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(165) In certain embodiments of Formula (I-f), wherein G is O, the compound is of Formula (I-f1):

(166) ##STR00046##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(167) In certain embodiments of Formula (I-d), wherein G is S, the compound is of Formula (I-d2):

(168) ##STR00047##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, R.sub.3, Z, Y, X, y, x, and n are as defined herein.

(169) In certain embodiments of Formula (I-e), wherein G is S, the compound is of Formula (I-e2):

(170) ##STR00048##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(171) In certain embodiments of Formula (I-f), wherein G is S, the compound is of Formula (I-f2):

(172) ##STR00049##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(173) In certain embodiments, Z is O.

(174) In certain embodiments, each represents a single bond.

(175) In certain embodiments, each instance of R.sub.1 and R.sub.2 is OH.

(176) In certain embodiments of Formula (I-d2), wherein Z is O and each represents a single bond, provided is a compound of Formula (I-g):

(177) ##STR00050##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein X, Y, y, x, and n are as defined herein.

(178) In certain embodiments, the compound for use in the present invention is

(179) ##STR00051##
also referred to herein as CAY10509, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(180) In certain embodiments, the compound for use in the present invention is

(181) ##STR00052##
also referred to herein as CAY10509 free acid, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(182) In certain embodiments at least one exocyclic represents a cis-double bond.

(183) For example, in certain embodiments of Formula (I-d1), wherein each instance of R.sub.1 and R.sub.2 is OH, and Z is O, provided is a compound of Formula (I-e):

(184) ##STR00053##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.3, R.sub.3, Y, X, y, x, and n are as defined herein.

(185) In certain embodiments of Formula (I-h), wherein R.sub.3 is hydrogen, provided is a compound of Formula (I-i):

(186) ##STR00054##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.3, Y, X, y, x, and n are as defined herein.

(187) In certain embodiments of Formula (I-i), wherein R.sub.3 is OH, the compound for use in the present invention is of Formula (I-j):

(188) ##STR00055##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein Y, X, y, x, and n are as defined herein.

(189) In certain embodiments, the compound of Formula (I-j), wherein is a trans double bond, X is NHCH.sub.2CH.sub.3, y is 1, x is 0, and n is 0, is the compound:

(190) ##STR00056##
also referred to herein as 17-phenyl trinor prostaglandin F2 ethyl amide, or bimatoprost; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(191) In certain embodiments, the compound of Formula (I-j), wherein is a trans double bond, X is OCH(CH.sub.3).sub.2, y is 1, x is 0, and n is 0, is the compound:

(192) ##STR00057##
also referred to herein as 17-phenyl trinor prostaglandin F2 a isopropyl ester, or bimatoprost isopropyl ester; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(193) In certain embodiments, the compound of Formula (I-j), wherein is a trans double bond, X is OH, y is 1, x is 0, and n is 0, is the compound:

(194) ##STR00058##
also referred to herein as 17-phenyl trinor prostaglandin F2, or bimatoprost free acid; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(195) In certain embodiments, the compound of Formula (I-j), wherein is a trans double bond, X is OCH(CH.sub.3).sub.2, y is 0, x is 1, and n is 1, is the compound:

(196) ##STR00059##
also referred to herein as fluprostenol isopropyl ester, or travoprost; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(197) In certain embodiments, the compound of Formula (I-j), wherein is a trans double bond, X is OH, y is 0, x is 1, and n is 1, is the compound:

(198) ##STR00060##
also referred to herein as travoprost free acid; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(199) In certain embodiments, the compound of Formula (I-j), wherein is a single bond, X is OCH(CH.sub.3).sub.2, y is 1, x is 0, and n is 0, is the compound:

(200) ##STR00061##
also referred to herein as 17-phenyl-13,14-dihydro trinor prostaglandin F2 isopropyl ester, or latanoprost; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(201) In certain embodiments, the compound of Formula (I-j), wherein is a single bond, X is OH, y is 1, x is 0, and n is 0, is the compound:

(202) ##STR00062##
also referred to herein as latanoprost free acid; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(203) In certain embodiments of Formula (I-h), wherein R.sub.3 is F and R.sub.3 is F, the compound for use in the present invention is of Formula (I-k):

(204) ##STR00063##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , Y, X, y, x, and n are as defined herein.

(205) In certain embodiments, the compound of Formula (I-k), wherein is a trans double bond, X is OCH(CH.sub.3).sub.2, y is 1, x is 1, and n is 0, is the compound:

(206) ##STR00064##
also referred to herein as tafluprost; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(207) In certain embodiments, the compound of Formula (I-k), wherein is a trans double bond, X is OH, y is 1, x is 1, and n is 0, is the compound:

(208) ##STR00065##
also referred to herein as tafluprost free acid; or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof.

(209) In certain embodiments of Formula (I), the compound of Formula (I-l):

(210) ##STR00066##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein R.sub.1, R.sub.2, Z, and X are as defined herein;

(211) each instance of independently represents a single bond or a double bond which can be in the cis or trans configuration;

(212) each instance of R.sub.3 and R.sub.3 is independently hydrogen, halogen, OH, substituted hydroxyl, or O(CO)R.sub.8, wherein R.sub.8 is optionally substituted C.sub.1-20alkyl, optionally substituted C.sub.2-20alkenyl, optionally substituted C.sub.2-20alkynyl, or (CH.sub.2).sub.mR.sub.9 wherein m is 0 or an integer between 1-10, inclusive, and R.sub.9 is optionally substituted C.sub.3-7carbocyclyl, optionally substituted C.sub.6-10aryl, or optionally substituted 5-14-membered-heteroaryl, or R.sub.3 and R.sub.3 are joined to form O;

(213) Y is selected from the group consisting of optionally substituted C.sub.1-10alkyl, C.sub.1-10perhaloalkyl, optionally substituted C.sub.2-10alkenyl, optionally substituted C.sub.2-10alkynyl, halo, nitro, cyano, thiol, substituted thiol, hydroxyl, substituted hydroxyl, amino, monosubstituted amino, and disubstituted amino;

(214) G is O or S;

(215) y is 0, 1, or 2;

(216) x is 0 or 1; and

(217) n is 0 or an integer of from 1 to 5, inclusive.

(218) In certain embodiments of Formula (I-l), wherein Z is O, and R.sub.1 and R.sub.2 are each OH, provided is a compound of Formula (I-m):

(219) ##STR00067##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein R.sub.1, R.sub.2, Z, and X are as defined herein.

(220) In certain embodiments of Formula (I-m), wherein R.sub.3 is hydrogen, y is 2 and x is 0, provided is a compound of Formula (I-n):

(221) ##STR00068##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein R.sub.1, R.sub.2, Z, and X are as defined herein.

(222) In certain embodiments, the compound of Formula (I-n), wherein R.sub.3 is OH, and X is OH, is the compound:

(223) ##STR00069##
also referred to as AL-16082, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein R.sub.1, R.sub.2, Z, and X are as defined herein. See, e.g., Feng et al, supra, incorporated herein by reference.

(224) In certain embodiments, the compound useful in the present invention is of Formula (I):

(225) ##STR00070##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof;

(226) wherein each instance of independently represents a single bond or a double bond which can be in the cis or trans configuration;

(227) A is alkylene or alkenylene having from two to six carbon atoms, wherein the alkylene or alkenylene group is optionally interrupted by one or more O groups and optionally substituted with one or more halogen, hydroxy, oxo, alkyloxy or alkylcarboxy groups, wherein each instance of alkyl alone or part of another group independently comprises from one to six carbon atoms;

(228) B is cycloalkyl having from three to seven carbon atoms, aryl having from six to ten carbon atoms, or heteroaryl having from four to ten carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur;

(229) X is OR.sub.4 or N(R.sub.4).sub.2, wherein R.sub.4 is selected from the group consisting of hydrogen, alkyl having from one to six carbon atoms, C(O)R.sub.5, or C(O)OR.sub.5, wherein R.sub.5 is alkyl having from one to six carbon atoms;

(230) Z is O or represents two hydrogen atoms; and

(231) one of R.sub.1 and R.sub.2 is O, OH, or a O(CO)R.sub.6 group and the other one is OH or O(CO)R.sub.6, or R.sub.1 is O and R.sub.2 is H, wherein R.sub.6 is a saturated or unsaturated acyclic hydrocarbon group having from 1 to about 20 carbon atoms or (CH.sub.2).sub.mR.sub.7 wherein m is 0-10, and R.sub.7 is cycloalkyl having from three to seven carbon atoms, aryl having from six to ten carbon atoms, or heteroaryl having from four to ten carbon atoms and one to four heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur.

(232) As generally defined above, in certain embodiments, the compound useful in the present invention is of Formula (II):

(233) ##STR00071##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof;
wherein A, B, X, Z, L, and R.sub.1 are as defined herein. are as defined herein.

(234) In certain embodiments, L is a group of the formula

(235) ##STR00072##
wherein represents a single bond.

(236) In certain embodiments, L is a group of the formula

(237) ##STR00073##
wherein represents a double bond which can be in the cis or trans configuration. In certain embodiments, the double bond is in the cis configuration. In certain embodiments, the double bond is in the trans configuration

(238) In certain embodiments, L is a group of the formula

(239) ##STR00074##
wherein represents a single bond.

(240) In certain embodiments, L is a group of the formula

(241) ##STR00075##
wherein represents a double bond which can be in the cis or trans configuration. In certain embodiments, the double bond is in the cis configuration. In certain embodiments, the double bond is in the trans configuration

(242) In certain embodiments of Formula (II), the compound of Formula (II-a):

(243) ##STR00076##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein R.sub.1, Z, and X are as defined herein; wherein , R.sub.1, Z, X, Y, G, R.sub.3, R.sub.3, y, x, and n are as defined herein.

(244) In certain embodiments of Formula (II-a), wherein R.sub.3 is hydrogen, the compound is of Formula (II-b):

(245) ##STR00077##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.3, Z, X, Y, G, y, x, and n are as defined herein.

(246) In certain embodiments of Formula (II-a), wherein R.sub.3 is hydrogen, the compound is of Formula (II-c):

(247) ##STR00078##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.2, R.sub.3, Z, X, Y, G, y, x, and n are as defined herein.

(248) In certain embodiments, G is O. In certain embodiments, G is S.

(249) In certain embodiments of Formula (II-a), wherein G is O, provided is a compound of Formula (II-a1):

(250) ##STR00079##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein R.sub.1, R.sub.2, Z, and X are as defined herein; wherein , R.sub.1, R.sub.2, R.sub.3, R.sub.3, Z, X, Y, y, x, and n are as defined herein.

(251) In certain embodiments, Z is O.

(252) In certain embodiments at least one exocyclic represents a cis-double bond.

(253) For example, in certain embodiments of Formula (II-a1), wherein Z is O, provided is a compound of Formula (II-d):

(254) ##STR00080##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , R.sub.1, R.sub.3, R.sub.3, Y, X, y, x, and n are as defined herein.

(255) In certain embodiments of Formula (II-d), wherein R.sub.1 is OH, R.sub.3 is hydrogen, R.sub.3 is OH, y is 0, and x is 1, provided is a compound of Formula (II-e):

(256) ##STR00081##
or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , Y, X, and n are as defined herein.

(257) In certain embodiments of Formula (II-e), wherein X is OCH(CH.sub.3).sub.2, the compound is:

(258) ##STR00082##
also referred to as AL-12182, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , Y, X, and n are as defined herein.

(259) In certain embodiments of Formula (II-e), wherein X is OH, the compound is:

(260) ##STR00083##
also referred to as AL-12182 free acid, or a pharmaceutically acceptable salt, hydrate, solvate, stereoisomer, polymorph, tautomer, isotopically enriched derivative, or prodrug thereof; wherein , Y, X, and n are as defined herein.

(261) Other compounds of Formula (II) for use in the present invention are contemplated herein; See, e.g., Selliah et al, supra, incorporated herein by reference.

(262) In certain embodiments, the compound of Formula (I) or (II) is a prodrug of any one of the compounds described herein. Exemplary prodrugs include esters, amides, and/or thioamides of the parent free acid and acyl groups present on the pentacyclic hydroxyl groups. Without being bound by any particular theory, the invention envisions that the free acid of compounds described herein (e.g. for example, wherein Z is O, and X is OH, such as, but not limited to bimatoprost free acid, travoprost free acid, latanoprost free acid, tafluprost free acid, or salts thereof) represents the principal pharmacologically active compound (active metabolite) for the purposes of this invention. It is also envisioned that certain compounds of the present invention will serve as substrates for hydrolases in the body (e.g., esterases such as lipases, amidases), which will in turn produce the corresponding free acid in vitro or in vivo.

(263) Pharmaceutical Compositions and Formulations

(264) In certain embodiments, the present invention provides pharmaceutical compositions and formulations for use in any of the inventive methods, described herein, comprising one or more compounds of the Formula (I) or (II) described herein (the active ingredient) and a pharmaceutically acceptable excipient.

(265) Pharmaceutically acceptable excipients include any and all solvents, diluents or other liquid vehicles, dispersion or suspension aids, surface active agents, isotonic agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like, as suited to the particular dosage form desired. General considerations in the formulation and/or manufacture of pharmaceutical compositions agents can be found, for example, in Remington's Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980), and Remington: The Science and Practice of Pharmacy, 21.sup.st Edition (Lippincott Williams & Wilkins, 2005).

(266) Pharmaceutical compositions described herein can be prepared by any method known in the art of pharmacology. In general, such preparatory methods include the steps of bringing the active ingredient into association with a carrier and/or one or more other accessory ingredients, and then, if necessary and/or desirable, shaping and/or packaging the product into a desired single- or multi-dose unit.

(267) In certain embodiment, the pharmaceutical composition is formulated as a time relase formulation, e.g., a sustained-release (SR), sustained-action (SA), extended-release (ER, XR, or XL), timed-release (TR), controlled-release (CR), modified release (MR), and continuous-release (CR) formulations, refer to dosage forms useful in releasing an active ingredient at a predetermined rate by maintaining a constant level of the active ingredient or active metabolite thereof in the bloodstream for a specific period of time with minimum side effect. Time release formulations may comprise imbedding the active ingredient in a matrix of insoluble particles, micro-encapsulation, use of liposomes and/or use of gels (e.g., hydrogels).

(268) Pharmaceutical compositions can be prepared, packaged, and/or sold in bulk, as a single unit dose, and/or as a plurality of single unit doses. As used herein, a unit dose is discrete amount of the pharmaceutical composition comprising a predetermined amount of the active ingredient. The amount of the active ingredient is generally equal to the dosage of the active ingredient which would be administered to a subject and/or a convenient fraction of such a dosage such as, for example, one-half or one-third of such a dosage.

(269) Relative amounts of the active ingredient, the pharmaceutically acceptable carrier, and/or any additional ingredients in a pharmaceutical composition of the invention will vary, depending upon the identity, size, and/or condition of the subject treated and further depending upon the route by which the composition is to be administered.

(270) Pharmaceutically acceptable excipients used in the manufacture of provided pharmaceutical compositions include inert diluents, dispersing and/or granulating agents, surface active agents and/or emulsifiers, disintegrating agents, binding agents, preservatives, buffering agents, lubricating agents, and/or oils. Excipients such as cocoa butter and suppository waxes, coloring agents, coating agents, sweetening, flavoring, and perfuming agents may also be present in the composition.

(271) Exemplary diluents include calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, calcium hydrogen phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, cornstarch, powdered sugar, etc., and combinations thereof.

(272) Exemplary granulating and/or dispersing agents include potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponge, cation-exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked poly(vinyl-pyrrolidone) (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (croscarmellose), methylcellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum), sodium lauryl sulfate, quaternary ammonium compounds, etc., and combinations thereof.

(273) Exemplary surface active agents and/or emulsifiers include lipids/natural emulsifiers (e.g. acacia, agar, alginic acid, sodium alginate, tragacanth, chondrux, cholesterol, xanthan, pectin, gelatin, egg yolk, casein, wool fat, cholesterol, wax, and lecithin), colloidal clays (e.g. bentonite [aluminum silicate] and Veegum [magnesium aluminum silicate]), long chain amino acid derivatives, high molecular weight alcohols (e.g. stearyl alcohol, cetyl alcohol, oleyl alcohol, triacetin monostearate, ethylene glycol distearate, glyceryl monostearate, and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g. carboxy polymethylene, polyacrylic acid, acrylic acid polymer, and carboxyvinyl polymer), carrageenan, cellulosic derivatives (e.g. carboxymethylcellulose sodium, powdered cellulose, hydroxymethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose), sorbitan fatty acid esters (e.g. polyoxyethylene sorbitan monolaurate [Tween 20], polyoxyethylene sorbitan [Tween 60], polyoxyethylene sorbitan monooleate [Tween 80], sorbitan monopalmitate [Span 40], sorbitan monostearate [Span 60], sorbitan tristearate [Span 65], glyceryl monooleate, sorbitan monooleate [Span 80]), polyoxyethylene esters (e.g. polyoxyethylene monostearate [Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxymethylene stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g. Cremophor), polyoxyethylene ethers, (e.g. polyoxyethylene lauryl ether [Brij 30]), poly(vinyl-pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F 68, Poloxamer 188, cetrimonium bromide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, etc. and/or combinations thereof.

(274) Exemplary binding agents include starch (e.g. cornstarch and starch paste), gelatin, sugars (e.g. sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol, etc.), natural and synthetic gums (e.g. acacia, sodium alginate, extract of Irish moss, panwar gum, ghatti gum, mucilage of isapol husks, carboxymethylcellulose, methylcellulose, ethylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, cellulose acetate, poly(vinyl-pyrrolidone), magnesium aluminum silicate (Veegum), and larch arabogalactan), alginates, polyethylene oxide, polyethylene glycol, inorganic calcium salts, silicic acid, polymethacrylates, waxes, water, alcohol, etc., and/or combinations thereof.

(275) Exemplary preservatives include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcohol preservatives, acidic preservatives, and other preservatives.

(276) Exemplary antioxidants include alpha tocopherol, ascorbic acid, acorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite.

(277) Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA) and salts and hydrates thereof (e.g., sodium edetate, disodium edetate, trisodium edetate, calcium disodium edetate, dipotassium edetate, and the like), citric acid and salts and hydrates thereof (e.g., citric acid monohydrate), fumaric acid and salts and hydrates thereof, malic acid and salts and hydrates thereof, phosphoric acid and salts and hydrates thereof, and tartaric acid and salts and hydrates thereof. Exemplary antimicrobial preservatives include benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethyl alcohol, glycerin, hexetidine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal.

(278) Exemplary antifungal preservatives include butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid.

(279) Exemplary alcohol preservatives include ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol.

(280) Exemplary acidic preservatives include vitamin A, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid.

(281) Other preservatives include tocopherol, tocopherol acetate, deteroxime mesylate, cetrimide, butylated hydroxyanisol (BHA), butylated hydroxytoluened (BHT), ethylenediamine, sodium lauryl sulfate (SLS), sodium lauryl ether sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, Glydant Plus, Phenonip, methylparaben, Germall 115, Germaben II, Neolone, Kathon, and Euxyl. In certain embodiments, the preservative is an anti-oxidant. In other embodiments, the preservative is a chelating agent.

(282) Exemplary buffering agents include citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium gluceptate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propanoic acid, calcium levulinate, pentanoic acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, calcium hydroxide phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dibasic potassium phosphate, monobasic potassium phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, dibasic sodium phosphate, monobasic sodium phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, Ringer's solution, ethyl alcohol, etc., and combinations thereof.

(283) Exemplary lubricating agents include magnesium stearate, calcium stearate, stearic acid, silica, talc, malt, glyceryl behanate, hydrogenated vegetable oils, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, etc., and combinations thereof.

(284) Exemplary oils include almond, apricot kernel, avocado, babassu, bergamot, black current seed, borage, cade, camomile, canola, caraway, carnauba, castor, cinnamon, cocoa butter, coconut, cod liver, coffee, corn, cotton seed, emu, eucalyptus, evening primrose, fish, flaxseed, geraniol, gourd, grape seed, hazel nut, hyssop, isopropyl myristate, jojoba, kukui nut, lavandin, lavender, lemon, litsea cubeba, macademia nut, mallow, mango seed, meadowfoam seed, mink, nutmeg, olive, orange, orange roughy, palm, palm kernel, peach kernel, peanut, poppy seed, pumpkin seed, rapeseed, rice bran, rosemary, safflower, sandalwood, sasquana, savoury, sea buckthorn, sesame, shea butter, silicone, soybean, sunflower, tea tree, thistle, tsubaki, vetiver, walnut, and wheat germ oils. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

(285) A pharmaceutical formulation may comprise excipients that cause the active pharmaceutical ingredient(s) to be transported, trafficked, deposited, concentrated, and/or retained in adipose tissue or more specifically, in or near an adipocyte. For example, a lipophilic excipient (e.g., selected from the group consisting of an liposomes, oil, a surface active agent, an emulsifier, or a mixture thereof, as defined above and herein) may be used in an enteral (e.g., oral) formulation, whereby the active ingredient is administered with a lipophilic excipient, which together are absorbed by enterocytes of the small intestine and formed into chylomicrons, which are in turn preferentially transported by the bloodstream to adipose tissue. As an alternative example, liposomes may be used as a lipophilic excipient for enteral, parenteral, or topical formulation.

(286) Liquid dosage forms for oral and parenteral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active ingredient, the liquid dosage forms may comprise inert diluents commonly used in the art such as, for example, water or other solvents (e.g., ethyl carbonate, ethyl acetate, benzyl benzoate, dimethylformamide), fatty acid esters of sorbitan, polysorbates, solubilizing agents such as alcohols (e.g., ethyl alcohol, isopropyl alcohol, tetrahydrofurfuryl alcohol, benzyl alcohol, glycerol and glycols (e.g., 1,3-butylene glycol, propylene glycol, polyethylene glycols)), oils (e.g., cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), Cremophor, cyclodextrins, polymers) and mixtures thereof. Besides inert diluents, the oral compositions can include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments, for parenteral administration, the active ingredient is mixed with solubilizing agents such as Cremophor, alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof.

(287) Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions can be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution, U.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

(288) The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

(289) Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active ingredient is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may comprise buffering agents.

(290) Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes. Solid compositions of a similar type can be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polethylene glycols and the like.

(291) The active ingredient can be provided in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active ingredient can be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may comprise buffering agents. They may optionally comprise opacifying agents and can be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions which can be used include polymeric substances and waxes.

(292) Compositions for rectal or vaginal administration are typically suppositories which can be prepared by mixing the active ingredient with a suitable non-irritating excipient or carrier such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active ingredient.

(293) In certain embodiments, the pharmaceutical composition further comprises one or more excipients adapted for transdermal administration. Dosage forms for topical and/or transdermal administration of an active ingredient may include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants and/or patches. Generally, the active ingredient is admixed under sterile conditions with a pharmaceutically acceptable carrier and/or any needed preservatives and/or buffers as can be required. Additionally, the present invention contemplates the use of transdermal patches, which often have the added advantage of providing controlled delivery of an active ingredient to the body. Such dosage forms can be prepared, for example, by dissolving and/or dispensing the active ingredient in the proper medium. Alternatively or additionally, the rate can be controlled by either providing a rate controlling membrane and/or by dispersing the active ingredient in a polymer matrix and/or gel. Exemplary carriers for transdermal administration include dimethyl sulfoxide, HRT (hormone replacement therapy) base, Pluronic lecithin organogel, Lipoderm, Vanpen, Aladerm, and anhydrous gels.

(294) Suitable devices for use in delivering intradermal pharmaceutical compositions described herein include short needle devices such as those described in U.S. Pat. Nos. 4,886,499; 5,190,521; 5,328,483; 5,527,288; 4,270,537; 5,015,235; 5,141,496; and 5,417,662. Intradermal compositions can be administered by devices that limit the effective penetration length of a needle into the skin, such as those described in PCT publication WO 99/34850 and functional equivalents thereof. Jet injection devices that deliver liquid vaccines to the dermis via a liquid jet injector and/or via a needle that pierces the stratum corneum and produces a jet that reaches the dermis are suitable. Jet injection devices are described, for example, in U.S. Pat. Nos. 5,480,381; 5,599,302; 5,334,144; 5,993,412; 5,649,912; 5,569,189; 5,704,911; 5,383,851; 5,893,397; 5,466,220; 5,339,163; 5,312,335; 5,503,627; 5,064,413; 5,520,639; 4,596,556; 4,790,824; 4,941,880; 4,940,460; and PCT publications WO 97/37705 and WO 97/13537. Ballistic powder/particle delivery devices that use compressed gas to accelerate vaccine in powder form through the outer layers of the skin to the dermis are suitable. Alternatively or additionally, conventional syringes can be used in the classical mantoux method of intradermal administration.

(295) Formulations suitable for topical administration include, but are not limited to, liquid and/or semi liquid preparations such as liniments, lotions, oil in water and/or water in oil emulsions such as creams, ointments and/or pastes, and/or solutions and/or suspensions. Topically-administrable formulations may, for example, comprise from about 0.3% to about 10% (w/w) or (w/v) of the active ingredient, although the concentration of the active ingredient can be as high as the solubility limit of the active ingredient in the solvent. Formulations for topical administration may further comprise one or more of the additional ingredients described herein.

(296) A pharmaceutical composition can be prepared, packaged, and/or sold in a formulation suitable for pulmonary administration via the buccal cavity. Such a formulation may comprise dry particles which comprise the active ingredient and which have a diameter in the range from about 0.5 to about 7 nanometers or from about 1 to about 6 nanometers. Such compositions are conveniently in the form of dry powders for administration using a device comprising a dry powder reservoir to which a stream of propellant can be directed to disperse the powder and/or using a self propelling solvent/powder dispensing container such as a device comprising the active ingredient dissolved and/or suspended in a low-boiling propellant in a sealed container. Such powders comprise particles wherein at least 98% of the particles by weight have a diameter greater than 0.5 nanometers and at least 95% of the particles by number have a diameter less than 7 nanometers. Alternatively, at least 95% of the particles by weight have a diameter greater than 1 nanometer and at least 90% of the particles by number have a diameter less than 6 nanometers. Dry powder compositions may include a solid fine powder diluent such as sugar and are conveniently provided in a unit dose form.

(297) Low boiling propellants generally include liquid propellants having a boiling point of below 65 F. at atmospheric pressure. Generally the propellant may constitute 50 to 99.9% (w/w) of the composition, and the active ingredient may constitute 0.1 to 20% (w/w) of the composition. The propellant may further comprise additional ingredients such as a liquid non-ionic and/or solid anionic surfactant and/or a solid diluent (which may have a particle size of the same order as particles comprising the active ingredient).

(298) Pharmaceutical compositions formulated for pulmonary delivery may provide the active ingredient in the form of droplets of a solution and/or suspension. Such formulations can be prepared, packaged, and/or sold as aqueous and/or dilute alcoholic solutions and/or suspensions, optionally sterile, comprising the active ingredient, and may conveniently be administered using any nebulization and/or atomization device. Such formulations may further comprise one or more additional ingredients including, but not limited to, a flavoring agent such as saccharin sodium, a volatile oil, a buffering agent, a surface active agent, and/or a preservative such as methylhydroxybenzoate. The droplets provided by this route of administration may have an average diameter in the range from about 0.1 to about 200 nanometers.

(299) The formulations described herein as being useful for pulmonary delivery are useful for intranasal delivery of a pharmaceutical composition of the invention. Another formulation suitable for intranasal administration is a coarse powder comprising the active ingredient and having an average particle from about 0.2 to 500 micrometers. Such a formulation is administered, by rapid inhalation through the nasal passage from a container of the powder held close to the s suitable for nasal administration may, for example, comprise from about as little as 0.1% (w/w) and as much as 100% (w/w) of the active ingredient, and may comprise one or more of the additional ingredients described herein. A pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for buccal administration. Such formulations may, for example, be in the form of tablets and/or lozenges made using conventional methods, and may contain, for example, 0.1 to 20% (w/w) active ingredient, the balance comprising an orally dissolvable and/or degradable composition and, optionally, one or more of the additional ingredients described herein. Alternately, formulations suitable for buccal administration may comprise a powder and/or an aerosolized and/or atomized solution and/or suspension comprising the active ingredient. Such powdered, aerosolized, and/or aerosolized formulations, when dispersed, may have an average particle and/or droplet size in the range from about 0.1 to about 200 nanometers, and may further comprise one or more of the additional ingredients described herein.

(300) A pharmaceutical composition of the invention can be prepared, packaged, and/or sold in a formulation suitable for ophthalmic administration. Such formulations may, for example, be in the form of eye drops including, for example, a 0.1/1.0% (w/w) solution and/or suspension of the active ingredient in an aqueous or oily liquid carrier. Such drops may further comprise buffering agents, salts, and/or one or more other of the additional ingredients described herein. Other ophthalmically-administrable formulations which are useful include those which comprise the active ingredient in microcrystalline form and/or in a liposomal preparation. Ear drops and/or eye drops are contemplated as being within the scope of this invention.

(301) Although the descriptions of pharmaceutical compositions provided herein are principally directed to pharmaceutical compositions that are suitable for administration to humans, it will be understood by the skilled artisan that such compositions are generally suitable for administration to animals of all sorts. Modification of pharmaceutical compositions suitable for administration to humans in order to render the compositions suitable for administration to various animals is well understood, and the ordinarily skilled veterinary pharmacologist can design and/or perform such modification with ordinary experimentation. General considerations in the formulation and/or manufacture of pharmaceutical compositions can be found, for example, in Remington: The Science and Practice of Pharmacy 21st ed., Lippincott Williams & Wilkins, 2005.

(302) Still further encompassed by the invention are kits comprising a compound as described herein and instructions for use. Kits provided may comprise a provided composition and a container (e.g., a vial, ampoule, bottle, syringe, and/or dispenser package, or other suitable container). In some embodiments, provided kits may optionally further include a second container comprising a suitable aqueous carrier for dilution or suspension of the provided composition for preparation of administration to a subject. In some embodiments, contents of provided formulation container and solvent container combine to form at least one unit dosage form.

(303) The active ingredient can be administered using any amount and any route of administration effective for treatment. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular composition, its mode of administration, its mode of activity, and the like.

(304) The active ingredient is typically formulated in dosage unit form for ease of administration and uniformity of dosage. It will be understood, however, that the total daily usage of the compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment. The specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the condition being treated and the severity of the condition; the activity of the specific active ingredient employed; the specific composition employed; the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific active ingredient employed; the duration of the treatment; drugs used in combination or coincidental with the specific active ingredient employed; and like factors well known in the medical arts.

(305) The active ingredient can be administered by any route, including enteral (e.g., oral, rectal), parenteral (e.g., intravenous, intramuscular, intra-arterial, intramedullary, intrathecal, subcutaneous, intraventricular, interdermal), and topical administration (e.g., transdermal, transmucosal).

(306) In certain embodiments, the active ingredient is administered systemically. As used herein, systemic administration or administering systemically or systemic effect means administration to the subject by enteral, parenteral, or topical (e.g., transdermal) administration, whereby the active ingredient or active metabolite thereof reaches and maintains a therapeutically effective concentration in the bloodstream for a period of time. A systemic effect is distinguishable from a local effect in a variety of ways, e.g., for example, as demonstrated in Example 1, a systemic effect is indicative of fat reduction in both treated and untreated areas of a subject's body.

(307) In certain embodiments, systemic administration or administering systemically or systemic effect refers to the administration of an active ingredient to the subject, whereby the active ingredient or active metabolite thereof reaches and maintains a therapeutically effective concentration in the bloodstream for at least 4 hours, at least 8 hours, at least 10 hours, at least 12 hours, at least 15 hours, at least 24 hours, between 4 hours and 24 hours, between 8 hours and 24 hours, between 10 hours and 24 hours, or between 15 hours and 24 hours. In certain embodiments, the administration is transdermal administration. Without wishing to be bound by any particular theory, even if the active ingredient is eliminated rapidly from the bloodstream (e.g., latanoprost has a serum elimination half-life of about 17 minutes), transdermal administration can provide a depot effect whereby a single application to the skin can result in slow release of the active ingredient into the bloodstream, and thereby result in a more sustained therapeutically effective concentration in the bloodstream. Other formulations or techniques, such as time release formulations or continuous IV infusion, may enable this desired slow release of the active ingredient via other routes of administration.

(308) In certain embodiments, the active ingredient is administered to the subject twice daily, daily, every 3 days, or weekly for at least 1 week, at least 2 weeks, at least one month, at least 2 months, at least 3 months, at least 4 months, at least 5 months, at least 6 months, between 1 week to 6 months, between 2 weeks to 6 months, between 1 month to 6 months, between 2 months to 6 months, between 3 months to 6 months, between 4 months to 6 months or between 5 months to 6 months. In certain embodiments, the administration is transdermal administration. In certain embodiments, the active ingredient is administered transdermally once daily.

(309) The exact amount of the active ingredient required to achieve a therapeutically effective amount will vary from subject to subject, depending, for example, on species, age, and general condition of a subject, severity of the side effects or disorder, identity of the particular compound(s), mode of administration, and the like. The desired dosage can be delivered three times a day, two times a day, once a day, every other day, every third day, every week, every two weeks, every three weeks, or every four weeks. In certain embodiments, the desired dosage can be delivered using multiple administrations (e.g., two, three, four, five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, or more administrations). As demonstrated in the accompanying Examples, daily administration to the subject can be adequate (but not necessarily preferable) to achieve the desired effect. A daily administration schedule is considered convenient for human use. The active ingredient may be administered by the subject to himself or herself repeatedly and without special equipment or training, although a medical professional also can also administer the active ingredient to the subject.

(310) It will be appreciated that dose ranges as described herein provide guidance for the administration of provided pharmaceutical compositions to an adult. The amount to be administered to, for example, a child or an adolescent can be determined by a medical practitioner or person skilled in the art and can be lower or the same as that administered to an adult.

(311) In certain embodiments, a therapeutically effective concentration of the compound is in the range of about 50 pg/ml and 1000 pg/ml, inclusive, e.g., greater than 50 pg/ml, greater than 60 pg/ml, greater than 70 pg/ml, greater than 80 pg/ml, greater than 90 pg/ml, greater than 100 pg/ml, greater than 150 pg/ml, greater than 200 pg/ml, greater than 250 pg/ml, greater than 300 pg/ml, greater than 350 pg/ml, greater than 400 pg/ml, greater than 450 pg/ml, greater than 500 pg/ml, greater than 550 pg/ml, greater than 600 pg/ml, greater than 650 pg/ml, greater than 700 pg/ml, greater than 750 pg/ml, greater than 800 pg/ml, greater than 850 pg/ml, greater than 900 pg/ml, greater than 950 pg/ml. The present invention contemplates a significant amount of compound or active metabolite thereof, e.g., the free acid, to appear systemically, i.e., in the blood. However, the concentration is not necessarily maintained within this range throughout the entire dosing interval, and may fluctuate during the dosing interval.

(312) In certain embodiments, the compound is administered, e.g., orally, subcutaneously, or intravenously, at a dose of between about 0.5 mg in a 24-hour period and about 50 mg in a 24-hour period, inclusive, e.g., between about 0.5 mg to about 40 mg, between about 0.5 mg to about 30 mg, between about 0.5 mg to about 20 mg, between about 0.5 mg to about 10 mg, between about 0.5 mg to about 5 mg, between about 1 mg to about 50 mg, between about 10 mg to about 50 mg, between about 15 mg to about 50 mg, between about 20 mg to about 50 mg, between about 30 mg to about 50 mg, between about 40 mg to about 50 mg, in a 24-hour period, inclusive.

(313) In certain embodiments, the compound is administered, e.g., to the skin, at a dose of between about 3 mg in a 24-hour period and about 50 mg in a 24-hour period, inclusive, e.g., between about 3 mg to about 40 mg, between about 3 mg to about 30 mg, between about 3 mg to about 20 mg, between about 3 mg to about 10 mg, between about 3 mg to about 5 mg, between about 5 mg to about 50 mg, between about 10 mg to about 50 mg, between about 20 mg to about 50 mg, between about 30 mg to about 50 mg, or between about 40 mg to about 50 mg, in a 24-hour period, inclusive.

(314) In certain embodiments, the compound is administered, e.g., to the skin, and delivered to bloodstream of a subject a dose between about 0.05 mg and about 2 mg per hour, inclusive, e.g., between about 0.1 mg and about 2 mg, between about 0.5 mg and about 2 mg, between about 1 mg and about 2 mg, per hour, inclusive.

(315) In certain embodiments, the compound is administered to the skin by a transdermal patch or gel.

(316) In certain embodiments, a composition comprises greater than or equal to about 0.3% (w/v) of the active ingredient in order to achieve a systemic effect. In certain embodiments, the composition comprises greater than 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10.0% (w/v) of the active ingredient. In certain embodiments, the composition comprises between about 0.4% and about 10%, weight per volume, inclusive. In certain embodiments, the composition comprises between about 0.4% and about 2%, weight per volume, inclusive.

(317) In a particular embodiment, a composition for application to the skin comprises at or greater than or equal to about 0.3% (w/v) of the active ingredient in order to achieve a systemic effect. In certain embodiments, the composition comprises greater than 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1.0%, 2.0%, 3.0%, 4.0%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10.0% (w/v) of the active ingredient. In certain embodiments, the composition comprises between about 0.4% and about 10%, weight per volume, inclusive. In certain embodiments, the composition comprises between about 0.4% and about 2%, weight per volume, inclusive.

(318) In a particular embodiment, a composition for subcutaneous injection comprises at or greater than or equal to 0.05% (w/v) of the active ingredient in order to achieve a systemic effect. In certain embodiments, the composition comprises greater than 0.1%, 0.3%, 0.5%, 1%, 2%, 3%, 4%, 5.0%, 6.0%, 7.0%, 8.0%, 9.0%, or 10.0% (w/v) of the active ingredient. In certain embodiments, the composition comprises between about 0.4% and about 10%, weight per volume, inclusive. In certain embodiments, the composition comprises between about 0.4% and about 2%, weight per volume, inclusive.

(319) In certain embodiments, the compound is administered at a dose of about 0.5 mg/m.sup.2/d to about 50 mg/m.sup.2/d, e.g., between about 0.5 mg/m.sup.2/d to about 40 mg/m.sup.2/d, between about 0.5 mg/m.sup.2/d to about 30 mg/m.sup.2/d, between about 0.5 mg/m.sup.2/d to about 20 mg/m.sup.2/d, between about 0.5 mg/m.sup.2/d to about 10 mg/m.sup.2/d, between about 0.5 mg/m.sup.2/d to about 5 mg/m.sup.2/d, between about 0.5 mg/m.sup.2/d to about 4 mg/m.sup.2/d, between about 1 mg/m.sup.2/d to about 5 mg/m.sup.2/d, between about 2 mg/m.sup.2/d to about 5 mg/m.sup.2/d, between about 3 mg/m.sup.2/d to about 5 mg/m.sup.2/d, between about 3 mg/m.sup.2/d to about 4 mg/m.sup.2/d, between about 5 mg/m.sup.2/d to about 50 mg/m.sup.2/d, between about 10 mg/m.sup.2/d to about 50 mg/m.sup.2/d, between about 20 mg/m.sup.2/d to about 50 mg/m.sup.2/d, between about 30 mg/m.sup.2/d to about 50 mg/m.sup.2/d, or between about 40 mg/m.sup.2/d to about 50 mg/m.sup.2/d, in a 24-hour period, inclusive.

(320) It is appreciated that more potent compounds may be administered at lower dosages than less potent compounds. For example, as shown in Example 3, a latanoprost dose of about 3.7 mg/m.sup.2/d may be acceptable for systemic therapy, but for more potent compounds the systemic dose could be lower.

(321) It will be also appreciated that the active ingredient can be administered in combination with one or more additional therapeutically active agents (agents or active agents). The compound or composition can be administered concurrently with, prior to, or subsequent to, one or more additional agents. In general, the active ingredient and each additional active agent will be administered at a dose and/or on a time schedule determined for the ingredient and agent. In will further be appreciated that the active ingredient and active agent utilized in this combination can be administered together in a single composition or administered separately in different compositions. The particular combination to employ in a regimen will take into account compatibility of the active ingredient with the active agent and/or the desired therapeutic effect to be achieved. In general, it is expected that additional active agents utilized in combination be utilized at levels that do not exceed the levels at which they are utilized individually. In some embodiments, the levels utilized in combination will be lower than those utilized individually.

(322) The active ingredient can be administered in combination with active agents that improve their bioavailability, reduce and/or modify their metabolism, inhibit their excretion, and/or modify their distribution within the body. It will also be appreciated that therapy employed may achieve a desired effect for the same disorder (for example, an active ingredient can be administered in combination with an anti-inflammatory and/or anti-depressive agent, etc.), and/or it may achieve different effects (e.g., control of adverse side-effects).

(323) Exemplary active agents include, but are not limited to, anti-obesity agents, steroidal agents, steroidal anti-inflammatory agent, non-steroidal anti-inflammatory agents, hormones, prostaglandins, progestational agents, anti-glaucoma agents, ophthalmic agents, diuretics, cardiovascular active agents, vasoactive agents, vasodilating agents, anti-hypertensive agents, angiogenic agents, or modulators of cell-extracellular matrix interactions (e.g. cell growth inhibitors and anti-adhesion molecules). Active agents include small organic molecules such as drug compounds (e.g., compounds approved by the Food and Drugs Administration as provided in the Code of Federal Regulations (CFR)), peptides, proteins, carbohydrates, monosaccharides, oligosaccharides, polysaccharides, nucleoproteins, mucoproteins, lipoproteins, synthetic polypeptides or proteins, small molecules linked to proteins, glycoproteins, steroids, nucleic acids, DNAs, RNAs, nucleotides, nucleosides, oligonucleotides, antisense oligonucleotides, lipids, hormones, vitamins and cells.

(324) Methods for Treating a Disorder associated with metabolic syndrome

(325) In one aspect, the invention provides a method of treating and/or preventing a metabolic syndrome or a disorder associated with metabolic syndrome in a subject in need thereof, comprising administering to a subject a compound of Formula (I) or (II).

(326) The method encompasses administering one or more compounds of Formula (I) or (II) to a subject by any contemplated systemic route in an amount sufficient to treat and/or prevent metabolic syndrome or a disorder associated with metabolic syndrome in the subject. In certain embodiments, the compound is systemically administered to a subject transdermally. In certain embodiments, the compound is systemically administered to a subject orally. In certain embodiments, the compound is systemically administered to a subject parenterally.

(327) In some embodiments, the disorder associated with metabolic syndrome is selected from the group consisting of obesity, dyslipidemia, and a diabetic condition, as described herein.

(328) Methods for Treating Obesity

(329) In this aspect, the present invention provides a method of treating and/or preventing obesity in a subject, comprising administering to a subject in need thereof one or more compounds of Formula (I) or (II).

(330) The method encompasses administering one or more compounds of Formula (I) or (II) to a subject by any contemplated systemic route in an amount sufficient to treat and/or prevent obesity in the subject. In certain embodiments, the compound is systemically administered to a subject transdermally. In certain embodiments, the compound is systemically administered to a subject orally. In certain embodiments, the compound is systemically administered to a subject parenterally.

(331) In certain embodiments, the present invention provides a method of reducing adipocytes in a subject, comprising administering systemically to a subject in need thereof one or more compounds as described herein. Reducing adipocytes in a subject includes, but is not limited to, reducing fat cell amount (e.g., for example, fat cell number), reducing fat cell volume, reducing fat cell formation, reducing fat cell maturation, dedifferentiating a fat cell, and/or inducing the death of a fat cell (e.g., for example, by apoptosis) as measured by at least one of volume, size, mass, bulk, density, amount, and/or quantity. In certain embodiments, the method of reducing adipocytes comprises reducing the fat cell amount, reducing fat cell volume, reducing fat cell formation, or reducing fat cell maturation, in a subject by greater than or equal to 75%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 25%, greater than or equal to 20%, greater than or equal to 15%, greater than or equal to 10%, or greater than or equal to 5%. Treating obesity can include reducing body weight or reducing body mass index (BMI). The present invention is expected to reduce body weight by greater than or equal to 75%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 25%, greater than or equal to 20%, greater than or equal to 15%, greater than or equal to 10%, or greater than or equal to 5%.

(332) Treating obesity can include reducing body fat, as measured by at least one of volume, size, mass, bulk, density, amount, and/or quantity. Body fat can be measured by skin calipers, dual energy x-ray Absorptiometry (DEXA), computed tomography (CT), magnetic resonance imaging (MRI), or any other suitable method known in the art, The measurement can be of total body fat, or only body fat on a particular part of the body. Fat reduction can also include reducing fat cell amount (for example, fat cell number), reducing fat cell volume, reducing fat cell maturation, and/or dedifferentiating a fat cell. These phenomena can be seen and measured, for example, by histologic examination of body fat.

(333) The present invention is expected to reduce fat by greater than or equal to 75%, greater than or equal to 70%, greater than or equal to 60%, greater than or equal to 50%, greater than or equal to 40%, greater than or equal to 30%, greater than or equal to 25%, greater than or equal to 20%, greater than or equal to 15%, greater than or equal to 10%, or greater than or equal to 5%.

(334) In certain embodiments, the subject is overweight. Overweight is a medical condition, and is defined by the subject's BMI. Any subject with a BMI of greater than or equal to 25 is considered overweight. An overweight subject encompasses pre-obese subjects (e.g., having a BMI of between 25 and 30) and obese subjects (e.g., having a BMI of greater than or equal to 30). In some embodiments of the invention, methods or compositions used to treat or prevent obesity can likewise be used to treat or prevent overweight or pre-obesity.

(335) In certain embodiments, the overweight subject is obese and suffers from obesity. Any subject with a BMI of between 35 and 40, inclusive, is considered severely obese and suffers from severe obesity. Any subject with a BMI between 40 and 45 is considered morbidly obese and suffers from morbid obesity. Any subject with a BMI greater than or equal to 45 is considered super obese and suffers from super obesity.

(336) In certain embodiments, the subject has obesity as a side effect of medication (e.g., for example, cortisol and analogs, corticosteroids, megace, sulfonylureas, anti-retrovirals, antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors, oral contraceptives, insulin or a form of insulin, risperidone, clozapine, and thiazolidinediones).

(337) In certain embodiments, the subject has obesity due to changes in hormonal status (e.g., as a result of physiologic changes such as pregnancy or menopause).

(338) In certain embodiments, the subject with obesity is undergoing or has recently undergone smoking cessation.

(339) In certain embodiments, the subject with obesity is also suffering or likely to suffer from diabetes, hypertension, hyperlipidemia, coronary artery disease, stroke, sleep apnea, gallbladder disease, gastroesophogeal reflux disease, fatty liver disease, gout, thromboembolism, elevated blood pressure, elevated blood sugar, elevated serum cholesterol, elevated serum uric acid, cancer (e.g., breast cancer, colon cancer, lipomas, fatty tumors, particularly if there are multiple fatty tumors), or a genetic disorder or medical condition characterized at least in part by excess body fat (e.g., Cushing syndrome, pseudo-Cushing syndrome, drug-induced obesity, HIV-related lipodystrophy, partical lipodystrophy, benign symmetric lipomatosis, Madelung's disease, hypothyroidism, pseudohypoparathyroidism, hypothalamic obesity, polycystic ovarian disease, depression, binge eating, Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, Down syndrome, Turner syndrome, growth hormone deficiency, growth hormone resistance, and leptin deficiency or resistance). The present invention contemplates treating any such disease, disorder, or condition using any of the described inventive methods.

(340) In certain embodiments, the subject is not overweight. For example, the method of reducing body fat in a subject is contemplated useful for not only treating obesity in a subject, but also useful in treating subjects who are not overweight, but still desire to increase the proportion of lean body mass to total body mass.

(341) In certain embodiments, the subject does not suffer from metabolic syndrome.

(342) In certain embodiments, the methods of the present invention are useful for treating or preventing an adipocyte-related disease. As used herein, adipocyte-related disease means a disease: (i) wherein reduction of adipocytes treats the disease, disorder, or condition from which the subject is suffering; or (ii) whose mechanism comprises an adipocyte and/or its molecular products, e.g., secreted proteins, e.g., adiponectin, resistin, tumor necrosis factor alpha (TNF-), interleukin-6 (IL-6), C-reactive protein (CRP), fibrinogen, plasminogen activator inhibitor-1 (PAI-1), and/or C-terminal binding protein (CtBP). Exemplary adipocyte-related diseases include, but are not limited to, metabolic syndrome, excess body fat (e.g., being overweight, obesity), dyslipidemia, hypercholesterolemia, hypertriglyceridemia, diabetes (e.g., type 2 diabetes), atherosclerosis, vascular disease, coronary artery disease, stroke, cerebrovascular disease, peripheral vascular disease, fatty liver, pancreatitis, inflammation or inflammatory disease, depression, and dementia. In certain embodiments, the adipocyte-related disease is selected from the group consisting of metabolic syndrome, diabetes (e.g., type 2 diabetes), liver disease, atherosclerosis, fatty liver disease, inflammation or inflammatory disease, depression, and dementia. In certain embodiments, treatment of an adipocyte-related disease can be accomplished by reduction of adipocytes that is microscopic rather than macroscopic, or diffuse rather than focal.

(343) Methods for Treating Dyslipidemia

(344) In another aspect, provided is a method for treating and/or preventing dyslipidemia a subject in need thereof, comprising administering one or more compounds of Formula (I) or (II) to the subject.

(345) The method encompasses administering one or more compounds Formula (I) or (II) to a subject by any contempated route in an amount sufficient to treat and/or prevent dyslipidemia in the subject. In certain embodiments, the compound is systemically administered to a subject transdermally. In certain embodiments, the compound is systemically administered to a subject orally. In certain embodiments, the compound is systemically administered to a subject parenterally.

(346) In certain embodiments, wherein the concentration of a lipid or lipoprotein in the blood is abnormally elevated, e.g., elevated serum triglycerides or elevated LDL, the method reduces the concentration by greater than or equal to 50%, by greater than or equal to 40%, by greater than or equal to 30%, by greater than or equal to 25%, by greater than or equal to 20%, by greater than or equal to 15%, by greater than or equal to 10%, and/or by greater than or equal to 5%.

(347) In certain embodiments, wherein the concentration of a lipid or lipoprotein in the blood is abnormally low, e.g., low HDL, the method increases the concentration by greater than or equal to 50%, by greater than or equal to 40%, by greater than or equal to 30%, by greater than or equal to 25%, by greater than or equal to 20%, by greater than or equal to 15%, by greater than or equal to 10%, and/or by greater than or equal to 5%.

(348) In certain embodiments, treating dyslipidemia comprises one or more of: reducing serum triglycerides, reducing serum total cholesterol, reducing serum LDL, and/or increasing serum HDL. In certain embodiments, the subject suffers from or is likely to suffer from a disease, disorder, or condition associated with dyslipidemia. In certain embodiments, the subject suffers from or is likely to suffer from a disease, disorder or condition selected from the group consisting of dyslipidemia, hypercholesterolemia, hypertriglyceridemia, a heritable disorder characterized at least in part by one or more abnormal serum lipid levels (e.g., familial hypercholesterolemia, familial hypertriglyceridemia), excess body fat (e.g., overweight, obesity), metabolic syndrome, vascular disease, atherosclerosis, coronary artery disease, stroke, cerebrovascular disease, peripheral vascular disease, diabetes (e.g., type 2 diabetes), fatty liver disease, hepatic fibrosis, pancreatitis, inflammation or inflammatory disease, depression, and dementia.

(349) In certain embodiments, the subject does not suffer from metabolic syndrome.

(350) Methods for Treating a Diabetic Condition

(351) In another aspect, provided is a method for treating and/or preventing a diabetic condition in a subject in need thereof, comprising administering one or more compounds of Formula (I) or (II) to the subject.

(352) The method encompasses administering one or more compounds of Formula (I) or (II) to a subject by any contemplated systemic route in an amount sufficient to treat and/or prevent a diabetic condition in the subject. In certain embodiments, the compound is systemically administered to a subject transdermally. In certain embodiments, the compound is systemically administered to a subject orally. In certain embodiments, the compound is systemically administered to a subject parenterally.

(353) In certain embodiments, treating a diabetic condition comprises one or more of: reducing serum glucose, reducing glycated hemoglobin levels, reducing serum insulin, increasing insulin sensitivity, improving glucose tolerance (e.g., reducing the glucose levels measured during a glucose tolerance test), reducing a subject's need for another medication (e.g., insulin) to maintain normal blood sugar levels, and/or treating or preventing a diabetic complication.

(354) In certain embodiments, the method reduces a serum glucose concentration, a glycated hemoglobin concentration, a serum insulin concentration, a medication requirement (e.g., insulin requirement), and/or incidence or severity of a diabetic complication by greater than or equal to 50%, by greater than or equal to 40%, by greater than or equal to 30%, by greater than or equal to 25%, by greater than or equal to 20%, by greater than or equal to 15%, by greater than or equal to 10%, and/or by greater than or equal to 5%.

(355) In certain embodiments, the subject suffers from or is likely to suffer from a disease, disorder or condition selected from the group consisting of type 2 diabetes mellitus, type 1 diabetes mellitus, prediabetes, hyperglycemia, insulin resistance, hyperinsulinemia, diabetic nephropathy, diabetic retinopathy, diabetic neuropathy, atherosclerosis, coronary artery disease, stroke, myocardial ischemia, myocardial infarction, diabetic myocardial small vessel disease, diabetic gastroparesis, diabetic hearing loss, a diabetic skin disease, a diabetes-related infection, diabetic oral disease (e.g., gingivitis), diabetic acidosis (e.g., diabetic ketoacidosis), nonketotic hypersosmolar state, coma, and diabetic foot ulcer.

(356) In certain embodiments, the subject does not suffer from metabolic syndrome.

(357) Other Uses of the Compositions and Compounds

(358) Given the ability of the compounds disclosed herein to reduce fat, adipocytes, and lipid concentrations, and the association of these species with metabolic pathways and disease (e.g., as part of the metabolic syndrome), it is further envisioned that the compounds, compositions, and methods described herein may be used to lower one or more of the following clinical parameters in a body: serum glucose concentration, glycated hemoglobin concentration (i.e., hemoglobin A1C, HbA1c), circulating insulin concentration, serum urate concentration, concentration(s) of hepatic serum biomarkers, e.g. transaminases, and concentrations of pancreas-related serum biomarkers, e.g. amylase and lipase. As used herein, the term serum glucose concentration is intended to encompass any suitable measure of the concentration of glucose in the blood.

(359) It is further envisioned that compounds, compositions, and methods described herein may be used to improve an individual's response to insulin (i.e., treat insulin resistance) or to leptin (i.e., treat leptin deficiency).

EXAMPLES

(360) Throughout the description, where laboratory assays, e.g. for glucose or lipid concentrations, refer to a particular matrix, e.g. serum, it is to be understood that such assays may, depending on the analyte, be conducted on other matrices or sample types, e.g. plasma, or with other technologies, e.g., noninvasive methods, that yield comparable measurements.

(361) Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes are described as having, including, or comprising specific process steps, it is contemplated that compositions of the present invention may also consist essentially of, or consist of, the recited components, and that the processes of the present invention may also consist essentially of, or consist of, the recited processing steps. Further, it should be understood that the order of steps or order for performing certain actions are immaterial so long as the invention remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

(362) In light of the foregoing description, the specific non-limiting examples presented below are for illustrative purposes and not intended to limit the scope of the invention in any way.

Example 1

(363) A randomized, controlled, repeat-dose, 4-week trial was conducted on (db/db) mice, which are defective for the leptin receptor (Jackson Laboratories). These mice are genetically obese, dyslipidemic, and diabetic.

(364) Methods: Mice were obtained from Jackson Laboratories and acclimated to the facility. At about 5 weeks of age, mice were prospectively randomized into groups and assigned to the treatment conditions shown in FIG. 1. Topical treatments were applied in a thin film to the right flank skin without occlusive dressings; subcutaneous injections were also administered to the right flank. Mice were observed for condition and weighed daily. They were housed in the same room, in 11 cages according to group, and fed ad libitum. Skin tissue was sampled and serum lipids tested on day 28. Tissue was fixed in formalin and stained with hematoxylin and eosin.

(365) Results: Animals fed and behaved normally throughout the study. Skin condition remained normal. Mean weight gain for days 0 to 28, by group, is shown in FIG. 2. Animals treated with vehicle only (Groups 1 and 2) showed an expected amount of weight gain for the strain (normative data, Jackson Laboratories). Transdermal bimatoprost isopropyl ester (BIE) and bimatoprost free acid (BFA) reduced weight gain significantly and in a dose-dependent manner, but topical bimatoprost did not. Subcutaneous BIE, subcutaneous BFA, and intraperitoneal BFA had no significant effect on weight gain.

(366) FIG. 3 shows representative histologic sections of skin and subcutaneous fat from untreated (left) and treated (right) flanks of animals assigned to vehicle only (Group 1), topical bimatoprost 0.3% (Group 4), and topical BIE 0.3% (Group 11). All sections are shown at the same magnification (scale bar at top right=640 microns). The surface of the skin is oriented toward the top and left of each panel. Arrows in each section denote the panniculus carnosus, an anatomic layer that separates the first layer of subdermal fat from deeper, subpannicular fat (separation artifact is commonly seen deep to the panniculus and is not an in vivo process).

(367) In vehicle-only treated animals (Group 1), the adipose layer between skin and panniculus was thick, with approximately 10 pseudo-layers of plump adipocytes.

(368) In animals treated with topical bimatoprost 0.3%, smaller adipocytes and a thinner adipose layer were seen on the right (treated) flank but not on the left (untreated) flank. The untreated flank resembled that of a vehicle-treated animal, with a thick adipose layer and plump adipocytes. This observation is consistent with a local effect, but not a systemic effect, from topical bimatoprost at a concentration up to 0.3%.

(369) In animals treated with topical BIE 0.3%, smaller adipocytes and thinner adipocyte layers were seen on both treated and untreated flanks. The effects were symmetric, indicative of a systemic effect. In contrast to animals treated with vehicle or bimatoprost 0.3%, animals treated with BIE 0.3% also showed profound shrinkage of adipocytes deep to the panniculus (toward bottom of each panel), closer to vasculature, and again indicative of a systemic effect.

(370) FIG. 4 shows mean, unfasted, serum lipid concentrations for each group (day 28), expressed as a percent reduction, relative to control (Group 1). FIG. 5 charts the triglyceride and total cholesterol results (mg/dl) for the topical treatment conditions as follows: Group 1=C, 3=D, 4=E, 5=F, 6=G, 10=H, 11=I.

(371) Triglycerides were significantly reduced in animals treated with transdermal BFA (0.1% or 0.3%), and even more so in those treated with transdermal BIE (0.1% or 0.3%). Total cholesterol was significantly lower in animals treated with transdermal BIE 0.1%. Topical bimatoprost had no significant effect on serum lipids. Subcutaneous BIE, subcutaneous BFA, and intraperitoneal BFA had no significant effect on serum lipids.

(372) Thus, in a mouse model of obesity and dyslipidemia, the foregoing results show reduced weight gain and serum lipids following transdermal administration of BIE and BFA, but not bimatoprost. Histology pointed to a systemic effect of BIE at concentrations tested, which was not seen with bimatoprost at the same concentrations. Thus, although adipose tissue was reduced by locally active treatment (e.g. by topical bimatoprost 0.3%), significant reductions in serum lipids and overall body weight appeared to occur only with systemically active treatment (e.g. topical BIE 0.3%).

(373) For each of the above effects, transdermal BIE was more potent that transdermal BFA. Neither subcutaneous nor intraperitoneal administration of any compound had any significant effect due to the compound being quickly metabolized and extruded from the system. Transdermal administration appears to allow for a more slow exposure of the compound over a more lengthy period of time, e.g., over the dosing interval. Time-release formulations for subcutaneous and intraperitoneal administration of these compounds are contemplated as conferring a systemic effect similar to transdermal administration.

Example 2

(374) A controlled, repeat-dose, 4-week, dose-ranging study of latanoprost transdermal cream was conducted in Zucker Diabetic Fatty (ZDF) rats (ZDF-Lepr.sup.fa/Crl), which are defective for the leptin receptor, obese, hyperlipidemic, and diabetic.

(375) Methods: Male ZDF rats, approximately 8 weeks old, were obtained from Jackson Laboratories and acclimated to the facility. They were prospectively assigned to treatment conditions shown in FIG. 6. There were 3 animals per treatment arm. Test articles were applied in a thin film to the right flank without occlusive dressings, at 0.3 ml daily for 28 days. Rats were fed ad libitum and housed in the same room in 4 cages according to group. They were observed for condition and weighed daily. Food consumption was measured by residual weight of chow. Animals were fasted overnight prior to day 29, and Oral Glucose Tolerance Tests were conducted on day 29 (1 g glucose per kg body weight). Skin tissue and serum chemistries were collected at day 29.

(376) Results: Daily observations and skin condition were unremarkable. There were no differences in food consumption between treatment conditions. FIG. 7 shows mean weight gain, by group, for days 0 to 29. Compared to vehicle, topical latanoprost 0.5%, 0.05%, 0.005% caused a dose-dependent reductions in weight gain, which were statistically significant for the 0.5% and 0.05% concentrations.

(377) FIG. 8 shows representative histologic sections of skin and subcutaneous fat from untreated (left) and treated (right) flanks of animals assigned to vehicle only (Group 1), latanoprost 0.005% (Group 2), and latanoprost 0.5% (Group 4). All sections are shown at the same magnification (scale bar at top right=500 microns). The surface of the skin is oriented toward the top of each panel.

(378) In vehicle-only treated animals (Group 1), subcutaneous adipose tissue consisted of several pseudolayers of plump adipocytes, which extended into the reticular dermis and were occasionally seen interspersed with panniculus muscle. The dermis was thick.

(379) In animals treated with latanoprost 0.005%, the right (treated) flank fewer and smaller adipocytes, and a thinner adipose layer. Adipocytes were not interspersed with dermis, and the dermis was thinner than in vehicle-only animals. The untreated (left) flank resembled that of a vehicle-treated animal, with a thick adipose layer and full adipocytes. This observation is consistent with a local effect, but not a systemic effect, from topical latanoprost at a concentration of 0.005%.

(380) In animals treated with topical latanoprost 0.5%, fewer and smaller adipocytes, and thinner adipose layer and dermis were seen on both treated and untreated flanks. The effects were symmetric, indicative of a systemic effect.

(381) FIG. 9 summarizes serum lipid levels by group, as measured on day 29. Compared to vehicle-treated control animals, latanoprost was associated with dose-dependent reductions in triglycerides and LDL, and dose-dependent increases in HDL and HDL:LDL ratio. These benefits were seen at the 0.5% and 0.05% concentrations, and were absent at the 0.005% concentration. Because of the small sample size, these differences did not reach statistical significance, except for the HDL:LDL ratio of Latanoprost 0.5% vs. vehicle (one-sided p<0.05).

(382) FIG. 10 shows the results of oral glucose tolerance testing on day 29. Latanoprost caused dose-dependent improvements in oral glucose tolerance, seen at the 0.5% and 0.05% concentrations (results for the 0.005% concentration [not shown] were similar to control). As summarized in FIG. 11, the serum glucose Area Under the Curve from 15 to 120 minutes post-glucose load (AUC.sub.15-120) was 12% and 26% lower in animals treated with latanoprost 0.05% and 0.5%, respectively, compared to vehicle-treated animals. There was no effect on oral glucose tolerance with latanoprost 0.005%.

(383) Thus, in a rat model of obesity, dyslipidemia, and diabetes, the foregoing results show reduced weight gain, improved serum lipids, and improved glucose tolerance following transdermal administration of latanoprost at concentrations of 0.5% and 0.05%, but not 0.005%. These effects were dose-dependent, and the minimum effective dose for these effects was deemed to be the 0.05% concentration.

(384) Histology pointed to a systemic effect of latanoprost 0.5%, which was not seen with latanoprost 0.005%. Thus, although adipose tissue was reduced by locally active treatment (e.g. by topical latanoprost 0.005%), significant reductions in serum lipids and overall body weight appeared to occur only in response systemically active treatment (e.g. topical latanoprost 0.05% or 0.5%).

Example 3

(385) FIG. 12 compares various topical doses of latanoprost in mouse, rat, and human, with respect to projected systemic dose. All calculations assume once-daily dosing and 100% serum bioavailability. The derivation of each dose is set forth based on the animal body weight, drug concentration, and drug volume. Finally, doses are scaled allometrically for body surface area (mg/m.sup.2/d), as is appropriate for most low-molecular-weight molecules.

(386) In the rat, the minimum effective dose of topical latanoprost for lipid, diabetes, and obesity reduction, which was 0.05%, equivalent to 0.5 mg/ml (Example 2), corresponds to a systemic dose of 3.6 mg/m.sup.2/d. This is corroborated in the mouse (Example 1), where serum lipids and obesity responded to BIE, a close analog of latanoprost, at systemic doses of 10 mg/m.sup.2/d; a minimum effective dose of BIE was not determined in the mouse.

(387) In humans, administration of a latanoprost eye drop (Xalatan), which is sufficient to reduce adipose tissue locally around the human eye, nonetheless involves a very low systemic dose of 0.008 mg/m.sup.2/d, or 0.016 mg/m.sup.2/d if both eyes are treated. Thus, the recommended human ophthalmic dose, if both eyes are treated, is 450-fold lower than the minimum effective dose for lipid and obesity reduction in the rat.

(388) Without any wish to be bound by theory, by comparison to the minimum effective dose of latanoprost in the rat, it is therefore predicted that a human transdermal dose of about 7 mg latanoprost per day would be sufficient to achieve a systemic benefit for serum lipids, a diabetic condition, and/or obesity. This could be delivered, for example, as a daily dose of 1 ml transdermal gel with a concentration 0.7% (w/v) or 7 mg/ml latanoprost.

Example 4

(389) The following description exemplifies preparation of a pharmaceutical composition of latanoprost gel for transdermal administration to a human.

(390) 700 mg of pure latanoprost powder, made under Good Manufacturing Practice, is fully dissolved in 20 ml of an organic phase consisting of lecithin (about 10 ml), and isopropyl palmitate (about 10 ml). Into the organic phase is slowly mixed 80 ml of an aqueous phase, previously cooled to 4 degrees centrigrade, consisting of poloxamer 407 (about 16-24 ml) and water (q.s.). Suitable preservatives (e.g., sorbic acid, potassium sorbate) are included in the formulation. The mixture is mixed well at room temperature until a gel forms, and the mixture is then processed through an ointment mill. About 100 ml of latanoprost transdermal gel is obtained, at a 7 mg/ml or 0.7% concentration.

Example 5

(391) The following description exemplifies preparation of a pharmaceutical composition of latanoprost cream for transdermal administration to a human.

(392) 500 mg of pure latanoprost powder, made under Good Manufacturing Practice, is mixed in a mortar with 5 ml of ethoxy diglycol to form a paste. 100 ml of Lipoderm Base (PCCA, Houston, Tex.) is added geometrically to the mortar. A suitable preservative such as potassium sorbate is added. The mixture is transferred to an electric mortar and pestle and mixed at 2 rpm for 2 minutes. Optionally, the mixture is then run through an ointment mill on setting #2, then setting #1. About 100 ml of latanoprost transdermal cream is obtained, at a 5 mg/ml or 0.5% concentration.

Example 6

(393) The following description exemplifies preparation of a pharmaceutical composition of latanoprost anhydrous liquid for transdermal administration to a human.

(394) 630 mg of pure latanoprost powder, made under Good Manufacturing Practice, is mixed with 8.4 ml of benzyl alcohol, 33.6 ml of acetone, and isopropyl alcohol q.s. to 84 ml. The liquid is thoroughly mixed. About 84 ml of latanoprost transdermal liquid is obtained, at a 7.5 mg/ml or 0.75% concentration.

Example 7

(395) The following description exemplifies a clinical application of the invention to treat obesity, dyslipidemia, and type 2 diabetes mellitus in a man with metabolic syndrome.

(396) A 52-year-old man is suffers from obesity, dyslipidemia, and type 2 diabetes. Medical evaluation reveals that his height is 5 feet 8 inches and a weight of 240 pounds, corresponding to a body mass index (BMI) of 36.5 (clinically obese). His waist circumference is 42 inches. His noninvasive blood pressure is 184/98. His fasting serum glucose is 137 g/dL and his glycated hemoglobin (hemoglobin A1C) is 8.1. Fasting serum lipids are as follows: triglycerides, 220 mg/dL; total cholesterol, 310 mg/dL, LDL 240 mg/dL, HDL, 35 mg/dL. His physical exam is notable for prominent central (abdominal) obesity. In addition to medical therapy, the man's physician recommends a regimen of diet and exercise. After six months the man's weight, hemoglobin A1C, serum glucose, and serum lipids are unimproved. The physician prescribes systemic therapy with latanoprost, for example, a transdermal 0.7% gel in a metered-dose dispenser, with instructions to apply 2 ml metered dose once daily to the skin of the shoulders. After a period of time, for example from 1 to 6 months, the man's weight is reduced. Serum glucose, hemoglobin A1C, fasting serum LDL, and fasting serum triglycerides also diminish. Fasting serum HDL rises.

Example 8

(397) The following description exemplifies a clinical application of the invention to reduce lipid concentrations in a patient with dyslipidemia and a history of coronary artery disease and myocardial infarction.

(398) A 67-year-old woman with a history of obesity, hyperlipidemia, coronary artery disease, and myocardial infarction is found to have elevated serum triglycerides, total cholesterol, and low density lipoprotein, despite use of a statin. The woman's physician prescribes an oral, extended-release formulation of tafluprost, for example, an extended-release tablet comprising 5 mg tafluprost, with instructions to take one capsule by mouth daily. After a period of time, for example from 1 to 6 months, the woman's serum triglycerides, total cholesterol, and low density lipoprotein concentrations are reduced. Body weight is also seen to improve.

Other Embodiments

(399) All patents, patent applications, and literature references cited herein are incorporated herein by reference.

(400) The foregoing has been a description of certain non-limiting embodiments of the invention. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present invention, as defined in the following claims.