DETAILED DESCRIPTION OF THE INVENTION

[0027] Recently, it was surprisingly found that the treatment of MCH-1R knock out mice with MT-II, a melanocortin receptor agonist, decreases overnight food intake by greater than 80%. This finding is supported by data showing that there was a significantly greater decrease in food intake in MCH-1R knock out mice treated with MT-II than in wild type mice treated with MT-II (See FIG. 1 ). This study also showed that there is a greater overnight decrease in bodyweight in MCH-1R knock out mice treated with MT-II than in wild type mice treated with MT-II (See FIG. 2 ). The study findings also surprisingly showed that MCH1R knock out mice eat more than the wild type mice and that treating MCH1R knock out mice with MT-II, a melanocortin agonist, still results in food intake inhibition. These studies suggest that a melanocortin receptor agonist will be efficacious in the presence of a MCH receptor antagonist. As a result, a combination of a melanocortin receptor agonist and a MCH receptor antagonist is surprisingly more efficacious, in the treatment of obesity, and obesity-related disorders, than treatment with either agent alone. These studies further suggest that combinations of two agents that operate based on parallel biological mechanisms are more efficacious than combinations of two agents that operate based on sequential biological mechanisms.

[0028] Another study showed that AM251, a CB1R inverse agonist, significantly inhibits the overnight food intake in wild type mice, in AGRP-NPY (agouti protein, neuropeptide Y) double knock out mice and in NPY knock out mice (See FIG. 3 ). AGRP is an endogenous Mc4r antagonist that enhances food intake; and NPY is also known to enhance food intake. This study suggests that a CB-1 inverse agonist/antagonist will be efficacious even in the presence of a NPY antagonist, and that a CB-1 inverse agonist/antagonist will be efficacious in the presence of both a NPY antagonist and Mc4r agonist. The combination of a CB-1 inverse agonist/antagonist and a NPY antagonist has enhanced efficacy in the treatment of obesity and obesity-related diseases. Furthermore, the combination of a CB-1 inverse agonist/antagonist, a NPY antagonist and a Mc4r agonist also has enhanced efficacy in the treatment of obesity and obesity related diseases.

[0029] A further study showed that treatment of wild type mice and MCH1R knock out mice with AM251, a CB1 inverse agonist, inhibits the overnight food intake in both wild type and MCH-1R knock out mice (see FIG. 4 ). This study suggests that a CB-1 inverse agonist/antagonist will be efficacious even in the presence of a MCH-1 receptor antagonist. This study further suggests that the combination of a CB-1 inverse agonist/antagonist and a MCH receptor antagonist has enhanced efficacy in the treatment of obesity and obesity-related disorders.

[0030] Based on these studies, a combination treatment with two agents, that work via different biological mechanisms is expected to result in greater decrease in food intake, and greater weight loss, than treatment with either agent alone.

[0031] These studies also show that agents that work through one specific physiological mode of action, or via one specific pathway, are still efficacious when a different physiological pathway, which is known to be involved in energy homeostasis in rodents, is absent.

[0032] Based on these findings, the combination therapy with two agents that affect energy homeostasis via different biological mechanisms of action is surprisingly more efficacious, in the treatment of obesity, and obesity-related disorders, than the treatment with two agents that work through the same mechanistic pathway, or the treatment with the individual agents alone. More particularly, combining appetite suppressants and/or metabolic rate enhancers and/or nutrient absorption inhibitors, whose biological mechanism of action differs, is advantageous in the treatment of obesity over the treatment of two agents that work through the same biological mechanism of action. Combining two agents with different biological mechanisms of action at clinical or sub-clinical doses will produce clinical efficacy without the side-effects of treatment with either agent alone at the monotherapy clinical dose.

[0033] The present invention provides compositions comprising at least one appetite suppressant and/or at least one metabolic rate enhancer and/or at least one nutrient absorption inhibitors useful in the treatment or prevention of obesity, and obesity-related disorders.

[0034] The methods and compositions of the present invention comprise an appetite suppressant. The appetite suppressant useful in the compositions of the present invention may be any agent useful to decrease food intake known in the art. The appetite suppressant may be peptidal or non-peptidal in nature; however, the use of a non-peptidal agent is preferred. For convenience, the use of an orally active appetite suppressant is also preferred. The appetite suppressant useful in the compositions of the present invention is selected from the group consisting of:

[0035] (1) a 5HT transporter inhibitor,

[0036] (2) a NE transporter inhibitor,

[0037] (3) a CB-1 antagonist/inverse agonist,

[0038] (4) a ghrelin antagonist,

[0039] (5) a H3 antagonist/inverse agonist,

[0040] (6) a MCH1R antagonist,

[0041] (7) a MCH2R agonist/antagonist,

[0042] (8) a NPY1 antagonist,

[0043] (9) a NPY5 antagonist,

[0044] (10) a NPY2 agonist,

[0045] (11) a NPY4 agonist,

[0046] (12) a mGluR5 antagonist,

[0047] (13) leptin,

[0048] (14) a leptin agonist/modulator,

[0049] (15) a leptin derivative,

[0050] (16) an opioid antagonist,

[0051] (17) an orexin antagonist,

[0052] (18) a BRS3 agonist,

[0053] (19) a CCK-A agonist,

[0054] (20) CNTF,

[0055] (21) a CNTF derivative,

[0056] (22) a CNTF agonist/modulator,

[0057] (23) 5HT2c agonist,

[0058] (24) a Mc4r agonist,

[0059] (25) a monoamine reuptake inhibitor,

[0060] (26) a serotonin reuptake inhibitor,

[0061] (27) a GLP-1 agonist,

[0062] (28) axokine,

[0063] (29) fenfluramine,

[0064] (30) nalmafene,

[0065] (31) phentermine,

[0066] (32) rimonabant,

[0067] (33) sibutramine,

[0068] (34) topiramate, and

[0069] (35) phytopharm compound 57;

[0070] and pharmaceutically acceptable salts and esters thereof.

[0071] In one embodiment of the present invention, the appetite suppressant is selected from the group consisting of:

[0072] (1) a 5HT transporter inhibitor,

[0073] (2) a NE transporter inhibitor,

[0074] (3) a CB-1 antagonist/inverse agonist,

[0075] (4) a ghrelin antagonist,

[0076] (5) a H3 antagonist/inverse agonist,

[0077] (6) a MCH1R antagonist,

[0078] (7) a MCH2R agonist/antagonist,

[0079] (8) a NPY1 antagonist,

[0080] (9) a NPY2 agonist,

[0081] (10) a NPY4 agonist,

[0082] (11) a mGluR5 antagonist,

[0083] (12) leptin,

[0084] (13) a leptin agonist/modulator,

[0085] (14) a leptin derivative,

[0086] (15) an opioid antagonist,

[0087] (16) an orexin antagonist,

[0088] (17) a BRS3 agonist,

[0089] (18) a CCK-A agonist,

[0090] (19) CNTF,

[0091] (20) a CNTF agonist/modulator,

[0092] (21) a CNTF derivative,

[0093] (22) a 5HT2c agonist,

[0094] (23) a Mc4r agonist,

[0095] (24) a monoamine reuptake inhibitor,

[0096] (25) a serotonin reuptake inhibitor,

[0097] (26) a GLP-1 agonist,

[0098] (27) axokine,

[0099] (28) fenfluramine,

[0100] (29) nalmafene,

[0101] (30) phentermine,

[0102] (31) rimonabant,

[0103] (32) sibutramine,

[0104] (33) topiramate, and

[0105] (34) phytopharm compound 57;

[0106] and pharmaceutically acceptable salts and esters thereof.

[0107] In a class of this embodiment, the appetite suppressant is selected from the group consisting of:

[0108] (1) a 5HT transporter inhibitor,

[0109] (2) a NE transporter inhibitor,

[0110] (3) a CB-1 antagonist/inverse agonist,

[0111] (4) a ghrelin antagonist,

[0112] (5) a H3 antagonist/inverse agonist,

[0113] (6) a MCH1R antagonist,

[0114] (7) a MCH2R agonist/antagonist,

[0115] (8) a NPY1 antagonist,

[0116] (9) a NPY2 agonist,

[0117] (10) a NPY4 agonist,

[0118] (11) a mGluR5 antagonist,

[0119] (12) an opioid antagonist,

[0120] (13) an orexin antagonist,

[0121] (14) a BRS3 agonist,

[0122] (15) a CCK-A agonist,

[0123] (16) CNTF,

[0124] (17) a CNTF agonist/modulator,

[0125] (18) a CNTF derivative,

[0126] (19) a 5HT2c agonist,

[0127] (20) a Mc4r agonist,

[0128] (21) a monoamine reuptake inhibitor,

[0129] (22) a serotonin reuptake inhibitor,

[0130] (23) a GLP-1 agonist,

[0131] (24) axokine,

[0132] (25) fenfluramine,

[0133] (26) nalmafene,

[0134] (27) phentermine,

[0135] (28) rimonabant,

[0136] (29) sibutramine, and

[0137] (30) topiramate;

[0138] and pharmaceutically acceptable salts and esters thereof.

[0139] In another class of this embodiment, the appetite suppressant is selected from the group consisting of:

[0140] (1) a 5HT transporter inhibitor,

[0141] (2) a NE transporter inhibitor,

[0142] (3) a ghrelin antagonist,

[0143] (4) a H3 antagonist/inverse agonist,

[0144] (5) a MCH1R antagonist,

[0145] (6) a MCH2R agonist/antagonist,

[0146] (7) an opioid antagonist,

[0147] (8) an orexin antagonist,

[0148] (9) a BRS3 agonist,

[0149] (10) a CCK-A agonist,

[0150] (1 1) CNTF,

[0151] (12) a CNTF agonist/modulator,

[0152] (13) a CNTF derivative,

[0153] (14) a 5HT2c agonist,

[0154] (15) a Mc4r agonist,

[0155] (16) a monoamine reuptake inhibitor,

[0156] (17) a serotonin reuptake inhibitor,

[0157] (18) a GLP-1 agonist,

[0158] (19) axokine,

[0159] (20) fenfluramine,

[0160] (21) nalmafene,

[0161] (22) phentermine,

[0162] (23) rimonabant,

[0163] (24) sibutramine,

[0164] (25) topiramate, and

[0165] (26) phytopharm compound 57;

[0166] and pharmaceutically acceptable salts and esters thereof.

[0167] In a subclass of this class, the appetite suppressant is selected from the group consisting of:

[0168] (1) a 5HT transporter inhibitor,

[0169] (2) a NE transporter inhibitor,

[0170] (3) a ghrelin antagonist,

[0171] (4) a H3 antagonist/inverse agonist,

[0172] (5) a MCH1R antagonist,

[0173] (6) a MCH2R agonist/antagonist,

[0174] (7) an opioid antagonist,

[0175] (8) an orexin antagonist,

[0176] (9) a BRS3 agonist,

[0177] (10) a CCK-A agonist,

[0178] (11) CNTF,

[0179] (12) a CNTF derivative,

[0180] (13) a Mc4r agonist,

[0181] (14) a monoamine reuptake inhibitor, and

[0182] (15) a serotonin reuptake inhibitor;

[0183] and pharmaceutically acceptable salts and esters thereof.

[0184] In another subclass of this class, the appetite suppressant is selected from the group consisting of:

[0185] (1) a 5HT transporter inhibitor,

[0186] (2) a NE transporter inhibitor,

[0187] (3) a ghrelin antagonist,

[0188] (4) a H3 antagonist/inverse agonist,

[0189] (5) a MCH2R agonist,

[0190] (6) an opioid antagonist,

[0191] (7) an orexin antagonist,

[0192] (8) a BRS3 agonist,

[0193] (9) a CCK-A agonist,

[0194] (10) CNTF, and

[0195] (11) a CNTF derivative,

[0196] and pharmaceutically acceptable salts and esters thereof.

[0197] In another class of this embodiment, the appetite suppressant is a 5HT transporter inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a NE transporter inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a CB-1 antagonist/inverse agonist, and pharmaceutically acceptable salts or esters thereof. In a subclass of this class, the CB-1 antagonist/inverse agonist is selected from rimonabant, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a ghrelin antagonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a H3 antagonist/inverse agonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a MCH1R antagonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a MCH2R agonist/antagonist, and pharmaceutically acceptable salts or esters thereof.

[0198] In another class of this embodiment, the appetite suppressant is a NPY1 antagonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is leptin, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a leptin derivative, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is an opioid antagonist, and pharmaceutically acceptable salts or esters thereof. In a subclass of this class, the opioid antagonist is selected from nalmefene, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is an orexin antagonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a BRS3 agonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a CCK-A agonist, and pharmaceutically acceptable salts or esters thereof.

[0199] In another class of this embodiment, the appetite suppressant is CNTF, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a CNTF derivative, and pharmaceutically acceptable salts or esters thereof. In subclass of this class, the CNTF derivative is selected from axokine, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a 5HT2c agonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a Mc4r agonist, and pharmaceutically acceptable salts or esters thereof.

[0200] In another class of this embodiment, the appetite suppressant is a monoamine reuptake inhibitor, and pharmaceutically acceptable salts or esters thereof. In a subclass of this class, the monoamine reuptake inhibitor is selected from sibutramine, and pharmaceutically acceptable salts and esters thereof. In another class of this embodiment, the appetite suppressant is a serotonin reuptake inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is a GLP-1 agonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is topiramate, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the appetite suppressant is phytopharm compound 57, and pharmaceutically acceptable salts or esters thereof.

[0201] The methods and compositions of the present invention comprise a metabolic rate enhancer. The metabolic rate enhancer useful in the compositions of the present invention may be any agent useful to enhance metabolic rate known in the art. The metabolic rate enhancer may be peptidal or non-peptidal in nature; however, the use of a non-peptidal agent is preferred. For convenience, the use of an orally active metabolic rate enhancer is also preferred. The metabolic rate enhancer useful in the compositions of the present invention is selected from the group consisting of:

[0202] (1) an ACC2 inhibitor,

[0203] (2) a β3 agonist,

[0204] (3) a DGAT1 inhibitor,

[0205] (4) a DGAT2 inhibitor,

[0206] (5) a FAS inhibitor,

[0207] (6) a PDE inhibitor,

[0208] (7) a thyroid hormone β agonist,

[0209] (8) an UCP-1, 2, or 3 activator,

[0210] (9) an acyl-estrogen,

[0211] (10) a glucocorticoid antagonist,

[0212] (11) an 11β HSD-1 inhibitor;

[0213] (12) a Mc3r agonist;

[0214] (13) a SCD-1; and

[0215] (14) oleoyl-estrone,

[0216] and pharmaceutically acceptable salts and esters thereof.

[0217] In one embodiment of the present invention, the metabolic rate enhancer is selected from the group consisting of:

[0218] (1) an ACC2 inhibitor,

[0219] (2) a DGAT1 inhibitor,

[0220] (3) a DGAT2 inhibitor,

[0221] (4) a FAS inhibitor,

[0222] (5) a PDE inhibitor,

[0223] (6) a thyroid hormone β agonist,

[0224] (7) an UCP-1, 2, or 3 activator,

[0225] (8) an acyl-estrogen,

[0226] (9) a glucocorticoid antagonist,

[0227] (10) an 11β HSD-1 inhibitor; and

[0228] (11) oleoyl-estrone;

[0229] and pharmaceutically acceptable salts and esters thereof.

[0230] In another class of this embodiment, the metabolic rate enhancer is an ACC2 inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the metabolic rate enhancer is a DGAT1 inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the metabolic rate enhancer is a DGAT2 inhibitor, and pharmaceutically acceptable salts or esters thereof.

[0231] In another class of this embodiment, the metabolic rate enhancer is a FAS inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the metabolic rate enhancer is a PDE inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the metabolic rate enhancer is a thyroid hormone β agonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the metabolic rate enhancer is an UCP-1, 2, or 3 activator, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the metabolic rate enhancer is a glucocorticoid antagonist, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the metabolic rate enhancer is an acyl-estrogen, and pharmaceutically acceptable salts or esters thereof. In a subclass of this class, the acyl-estrogen, is selected from oleoyl-estrone, and pharmaceutically acceptable salts or esters thereof.

[0232] In another class of this embodiment, the metabolic rate enhancer is an 11β HSD-1 inhibitor, and pharmaceutically acceptable salts or esters thereof. In a subclass of this class, the 11β HSD-1 inhibitor is selected from the group consisting of

[0233] (1) 3-[(3,5,7-trimethyl-1-adamantyl)methyl]-6,7,8,9-tetrahydro-5 H-[1,2,4]triazolo[4,3-a]azepine,

[0234] (2) 3-(1-adamantyl)-4-ethyl-5-(ethylthio)-4H-1,2,4-triazole,

[0235] (3) 3-adamantanyl-4,5,6,7,8,9,10,11,12,3a-decahydro-1,2,4-triazo lo[4,3-a][11]annulene, and

[0236] (4) 3-(1-adamantyl)-5-(3,4,5-trimethoxyphenyl)-4-methyl-4H-1,2,4 -triazole;

[0237] and pharmaceutically acceptable salts and esters thereof.

[0238] In another class of this embodiment, the metabolic rate enhancer is a Mc3r agonist, and pharmaceutically acceptable salts or esters thereof. In yet another class of this embodiment, the metabolic rate enhancer is a SCD-1, and pharmaceutically acceptable salts or esters thereof.

[0239] The methods and compositions of the present invention comprise a nutrient absorption inhibitor. The nutrient absorption inhibitor useful in the compositions of the present invention may be any nutrient absorption inhibitor known in the art. The nutrient absorption inhibitor may be peptidal or non-peptidal in nature, however, the use of a non-peptidal agent is preferred. For convenience, the use of an orally active nutrient absorption inhibitor is also preferred. The nutrient absorption inhibitor useful in the compositions of the present invention is selected from the group consisting of:

[0240] (1) a lipase inhibitor,

[0241] (2) a fatty acid transporter inhibitor,

[0242] (3) a dicarboxylate transporter inhibitor,

[0243] (4) a glucose transporter inhibitor,

[0244] (5) a phosphate transporter inhibitor, and

[0245] (6) orlistat,

[0246] and pharmaceutically acceptable salts and esters thereof.

[0247] In one embodiment of the present invention, the nutrient absorption inhibitor is selected from the group consisting of:

[0248] (1) a lipase inhibitor,

[0249] (2) a fatty acid transporter inhibitor,

[0250] (3) a dicarboxylate transporter inhibitor,

[0251] (4) a glucose transporter inhibitor, and

[0252] (5) orlistat,

[0253] and pharmaceutically acceptable salts and esters thereof.

[0254] In a class of this embodiment, the nutrient absorption inhibitor is a lipase inhibitor, and pharmaceutically acceptable salts or esters thereof. In a subclass of this embodiment, the lipase inhibitor is orlistat, and the pharmaceutically acceptable salts thereof. In another class of this embodiment, the nutrient absorption inhibitor is a fatty acid transporter inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the nutrient absorption inhibitor is a dicarboxylate transporter inhibitor, and pharmaceutically acceptable salts or esters thereof. In another class of this embodiment, the nutrient absorption inhibitor is a glucose transporter inhibitor, and pharmaceutically acceptable salts or esters thereof.

[0255] In another embodiment of this invention, the nutrient absorption inhibitor is a phosphate transporter inhibitor, and pharmaceutically acceptable salts or esters thereof.

[0256] In another embodiment of the present invention, the composition comprises two appetite suppressants, and pharmaceutically acceptable salts and esters thereof, provided that the appetite suppressants have different biological mechanisms of action.

[0257] In class of this embodiment, the composition comprises two appetite suppressants, wherein each appetite suppressant is selected from the group consisting of:

[0258] (1) a 5HT transporter inhibitor,

[0259] (2) a NE transporter inhibitor,

[0260] (3) a CB-1 antagonist/inverse agonist,

[0261] (4) a ghrelin antagonist,

[0262] (5) a H3 antagonist/inverse agonist,

[0263] (6) a MCH1R antagonist,

[0264] (7) a MCH2R agonist/antagonist,

[0265] (8) a NPY1 antagonist,

[0266] (9) a NPY5 antagonist,

[0267] (10) a NPY2 agonist,

[0268] (11) a NPY4 agonist,

[0269] (12) a mGluR5 antagonist,

[0270] (13) leptin,

[0271] (14) a leptin agonist/modulator,

[0272] (15) a leptin derivative,

[0273] (16) an opioid antagonist,

[0274] (17) an orexin antagonist,

[0275] (18) a BRS3 agonist,

[0276] (19) a CCK-A agonist,

[0277] (20) CNTF,

[0278] (21) a CNTF agonist/modulator,

[0279] (22) a CNTF derivative,

[0280] (23) a 5HT2c agonist,

[0281] (24) a Mc4r agonist,

[0282] (25) a monoamine reuptake inhibitor,

[0283] (26) a serotonin reuptake inhibitor,

[0284] (27) a GLP-1 agonist,

[0285] (28) axokine,

[0286] (29) fenfluramine,

[0287] (30) nalmafene,

[0288] (31) phentermine,

[0289] (32) rimonabant,

[0290] (33) sibutramine,

[0291] (34) topiramate, and

[0292] (35) phytopharm compound 57;

[0293] and pharmaceutically acceptable salts and esters thereof;

[0294] provided that when the first appetite suppressant is a NPY1 antagonist, then the second appetite suppressant is not selected from the group consisting of: a MCH1R antagonist, a MCH2R antagonist, a NPY5 antagonist, leptin, a leptin derivative, 5HT2c agonist, a Mc4r agonist, a serotonin reuptake inhibitor, and a GLP-1 agonist;

[0295] provided that when the first appetite suppressant is leptin, then the second appetite suppressant is not selected from the group consisting of: a MCH-1R antagonist, a MCH-2R antagonist, a NPY1 antagonist, a NPY5 antagonist, a leptin derivative, 5HT2c agonist, a Mc4r agonist, a serotonin reuptake inhibitor, a GLP-1 agonist, a CCK-A agonist, an opioid antagonist, and a monoamine reuptake inhibitor;

[0296] provided that when the first appetite suppressant is a CB-1 antagonist/inverse agonist, then the second appetite suppressant is not selected from the group consisting of an opioid antagonist, a serotonin reuptake inhibitor, and a monoamine reuptake inhibitor;

[0297] provided that when the first appetite suppressant is an opioid antagonist, then the second appetite suppressant is not a serotonin reuptake inhibitor; and

[0298] provided that the appetite suppressants have different biological mechanisms of action.

[0299] In a subclass of this class, the appetite suppressant is selected from the group consisting of

[0300] (1) a 5HT transporter inhibitor,

[0301] (2) a NE transporter inhibitor,

[0302] (3) a CB-1 antagonist/inverse agonist,

[0303] (4) a ghrelin antagonist,

[0304] (5) a H3 antagonist/inverse agonist,

[0305] (6) a MCH1R antagonist,

[0306] (7) a MCH2R agonist/antagonist,

[0307] (8) a NPY1 antagonist,

[0308] (9) a NPY2 agonist,

[0309] (10) a NPY4 agonist,

[0310] (11) a mGluR5 antagonist,

[0311] (12) leptin,

[0312] (13) a leptin agonist/modulator,

[0313] (14) a leptin derivative,

[0314] (15) an opioid antagonist,

[0315] (16) an orexin antagonist,

[0316] (17) a BRS3 agonist,

[0317] (18) a CCK-A agonist,

[0318] (19) CNTF,

[0319] (20) a CNTF agonist/modulator,

[0320] (21) a CNTF derivative,

[0321] (22) a 5HT2c agonist,

[0322] (23) a Mc4r agonist,

[0323] (24) a monoamine reuptake inhibitor,

[0324] (25) a serotonin reuptake inhibitor,

[0325] (26) a GLP-1 agonist,

[0326] (27) axokine,

[0327] (28) fenfluramine,

[0328] (29) nalmafene,

[0329] (30) phentermine,

[0330] (31) rimonabant,

[0331] (32) sibutramine,

[0332] (33) topiramate, and

[0333] (34) phytopharm compound 57;

[0334] and pharmaceutically acceptable salts and esters thereof;

[0335] provided that when the first appetite suppressant is a NPY1 antagonist, then the second appetite suppressant is not selected from the group consisting of: a MCH1R antagonist, a MCH2R antagonist, leptin, a leptin derivative, 5HT2c agonist, a Mc4r agonist, a serotonin reuptake inhibitor, and a GLP-1 agonist;

[0336] provided that when the first appetite suppressant is leptin, then the second appetite suppressant is not selected from the group consisting of: a MCH-1R antagonist, a MCH-2R antagonist, a NPY1 antagonist, a leptin derivative, 5HT2c agonist, a Mc4r agonist, a serotonin reuptake inhibitor, a GLP-1 agonist, a CCK-A agonist, an opioid antagonist, and a monoamine reuptake inhibitor; provided that when the first appetite suppressant is a CB-1 antagonist/inverse agonist, then the second appetite suppressant is not selected from the group consisting of an opioid antagonist, a serotonin reuptake inhibitor, and a monoamine reuptake inhibitor;

[0337] provided that when the first appetite suppressant is an opioid antagonist, then the second appetite suppressant is not a serotonin reuptake inhibitor; and

[0338] provided that the appetite suppressants have different biological mechanisms of action.

[0339] In another subclass of this class, the appetite suppressant is selected from the group consisting of

[0340] (1) a 5HT transporter inhibitor,

[0341] (2) a NE transporter inhibitor,

[0342] (3) a CB-1 antagonist/inverse agonist,

[0343] (4) a ghrelin antagonist,

[0344] (5) a H3 antagonist/inverse agonist,

[0345] (6) a MCH1R antagonist,.

[0346] (7) a MCH2R agonist/antagonist,

[0347] (8) a NPY1 antagonist,

[0348] (9) a NPY2 agonist,

[0349] (10) a NPY4 agonist,

[0350] (11) a mGluR5 antagonist,

[0351] (12) an opioid antagonist,

[0352] (13) an orexin antagonist,

[0353] (14) a BRS3 agonist,

[0354] (15) a CCK-A agonist,

[0355] (16) CNTF,

[0356] (17) a CNTF agonist/modulator,

[0357] (18) a CNTF derivative,

[0358] (19) a 5HT2c agonist,

[0359] (20) a Mc4r agonist,

[0360] (21) a monoamine reuptake inhibitor,

[0361] (22) a serotonin reuptake inhibitor,

[0362] (23) a GLP-1 agonist,

[0363] (24) axokine,

[0364] (25) fenfluramine,

[0365] (26) nalmafene,

[0366] (27) phentermine,

[0367] (28) rimonabant,

[0368] (29) sibutramine, and

[0369] (30) topiramate;

[0370] and pharmaceutically acceptable salts and esters thereof;

[0371] provided that when the first appetite suppressant is a NPY1 antagonist, then the second appetite suppressant is not selected from the group consisting of: a MCH1R antagonist, a MCH2R antagonist, 5HT2c agonist, a Mc4r agonist, a serotonin reuptake inhibitor, and a GLP-1 agonist; provided that when the first appetite suppressant is a CB-1 antagonist/inverse agonist, then the second appetite suppressant is not selected from the group consisting of an opioid antagonist, a serotonin reuptake inhibitor, and a monoamine reuptake inhibitor;

[0372] provided that when the first appetite suppressant is an opioid antagonist, then the second appetite suppressant is not a serotonin reuptake inhibitor; and

[0373] provided that the appetite suppressants have different biological mechanisms of action.

[0374] In another subclass of this class, the first appetite suppressant is a Mc4r agonist, and pharmaceutically acceptable salts and esters thereof, and the second appetite suppressant is selected from the group consisting of

[0375] (1) a MCH1R antagonist, and

[0376] (2) a MCH2R agonist/antagonist,

[0377] and pharmaceutically acceptable salts and esters thereof.

[0378] In another subclass of this class, the first appetite suppressant is a CB-1 antagonist/inverse agonist, and pharmaceutically acceptable salts and esters thereof, and the second appetite suppressant is selected from the group consisting of

[0379] (1) a NPY1 antagonist,

[0380] (2) a NPY2 agonist,

[0381] (3) a NPY4 agonist,

[0382] (4) a MCH1R antagonist,

[0383] (5) a MCH2R agonist/antagonist, and

[0384] (6) a Mc4r agonist;

[0385] and pharmaceutically acceptable salts and esters thereof.

[0386] In another subclass of this class, the first appetite suppressant is a CB-1 antagonist/inverse agonist, and pharmaceutically acceptable salts and esters thereof, and the second appetite suppressant is a Mc4r agonist, and pharmaceutically acceptable salts and esters thereof.

[0387] In yet another subclass of this class, the second appetite suppressant is selected from the group consisting of

[0388] (1) a 5HT transporter inhibitor,

[0389] (2) a NE transporter inhibitor,

[0390] (3) a ghrelin antagonist,

[0391] (4) a H3 antagonist/inverse agonist,

[0392] (5) a MCH1R antagonist,

[0393] (6) a MCH2R agonist/antagonist,

[0394] (7) an orexin antagonist,

[0395] (8) a BRS3 agonist,

[0396] (9) a CCK-A agonist,

[0397] (10) CNTF,

[0398] (11) a CNTF agonist/modulator,

[0399] (12) a CNTF derivative,

[0400] (13) a 5HT2c agonist,

[0401] (14) a Mc4r agonist,

[0402] (15) a monoamine reuptake inhibitor,

[0403] (16) a serotonin reuptake inhibitor, and

[0404] (17) a GLP-1 agonist;

[0405] and pharmaceutically acceptable salts and esters thereof;

[0406] provided that the appetite suppressant have different biological mechanisms of action.

[0407] In another embodiment of the present invention, the compositions comprise an appetite suppressant, and pharmaceutically acceptable salts and esters thereof, and a metabolic rate enhancer, and pharmaceutically acceptable salts and esters thereof.

[0408] In a class of this embodiment of this invention, the composition comprises

[0409] (a) an appetite suppressant selected from the group consisting of

[0410] (1) a 5HT transporter inhibitor,

[0411] (2) a NE transporter inhibitor,

[0412] (3) a CB-1 antagonist/inverse agonist,

[0413] (4) a ghrelin antagonist,

[0414] (5) a H3 antagonist/inverse agonist,

[0415] (6) a MCH1R antagonist,

[0416] (7) a MCH2R agonist/antagonist,

[0417] (8) a NPY1 antagonist,

[0418] (9) a NPY5 antagonist,

[0419] (10) a NPY2 agonist,

[0420] (11) a NPY4 agonist,

[0421] (12) a mGluR5 antagonist,

[0422] (13) leptin,

[0423] (14) leptin agonist/modulator,

[0424] (15) a leptin derivative,

[0425] (16) an opioid antagonist,

[0426] (17) an orexin antagonist,

[0427] (18) a BRS3 agonist,

[0428] (19) a CCK-A agonist,

[0429] (20) CNTF,

[0430] (21) a CNTF agonist/modulator,

[0431] (22) a CNTF derivative,

[0432] (23) 5HT2c agonist,

[0433] (24) a Mc4r agonist,

[0434] (25) a monoamine reuptake inhibitor,

[0435] (26) a serotonin reuptake inhibitor,

[0436] (27) a GLP-1 agonist,

[0437] (28) axokine,

[0438] (29) fenfluramine,

[0439] (30) nalmafene,

[0440] (31) phentermine,

[0441] (32) rimonabant,

[0442] (33) sibutramine,

[0443] (34) topiramate, and

[0444] (35) phytopharm compound 57;

[0445] and pharmaceutically acceptable salts and esters thereof, and

[0446] (b) a metabolic rate enhancer selected from the group consisting of

[0447] (1) an ACC2 inhibitor,

[0448] (2) a β3 agonist,

[0449] (3) a DGAT1 inhibitor,

[0450] (4) a DGAT2 inhibitor,

[0451] (5) a FAS inhibitor,

[0452] (6) a PDE inhibitor,

[0453] (7) a thyroid hormone β agonist,

[0454] (8) an UCP-1, 2, or 3 activator,

[0455] (9) an acyl-estrogen,

[0456] (10) a glucocorticoid antagonist,

[0457] (11) an 11β HSD-1 inhibitor,

[0458] (12) a Mc3r agonist,

[0459] (12) a SCD-1, and

[0460] (13) oleoyl-estrone;

[0461] and pharmaceutically acceptable salts and esters thereof;

[0462] provided that when the metabolic rate enhancer is a β3 agonist, then the appetite suppressant is not selected from the group consisting of a CB-1 antagonist/inverse agonist, a MCH1R antagonist, a MCH2R antagonist, a NPY5 antagonist, leptin, a leptin derivative, a CCK-A agonist, a 5HT2c agonist, a Mc4r agonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, and a GLP-1 agonist;

[0463] provided that when the metabolic rate enhancer is a UCP-1, 2 or 3 activator, then the appetite suppressant is not selected from the group consisting of leptin and a leptin derivative; provided that when the metabolic rate enhancer is an 11β HSD-1 inhibitor, then the appetite suppressant is not selected from the group consisting of: a CB-1 antagonist/inverse agonist, a NPY5 antagonist, a Mc4r agonist,

[0464] a monoamine reuptake inhibitor, and a serotonin reuptake inhibitor; and

[0465] provided that when the appetite suppressant is a monoamine reuptake inhibitor, then the metabolic rate enhancer is not a PDE inhibitor.

[0466] In a subclass of this class, the appetite suppressant is selected from the group consisting of

[0467] (1) a 5HT transporter inhibitor,

[0468] (2) a NE transporter inhibitor,

[0469] (3) a CB-1 antagonist/inverse agonist,

[0470] (4) a ghrelin antagonist,

[0471] (5) a H3 antagonist/inverse agonist,

[0472] (6) a MCH1R antagonist,

[0473] (7) a MCH2R agonist/antagonist,

[0474] (8) a NPY1 antagonist,

[0475] (9) a NPY2 agonist,

[0476] (10) a NPY4 agonist,

[0477] (11) a mGluR5 antagonist,

[0478] (12) leptin,

[0479] (13) a leptin derivative,

[0480] (14) an opioid antagonist,

[0481] (15) an orexin antagonist,

[0482] (16) a BRS3 agonist,

[0483] (17) a CCK-A agonist,

[0484] (18) CNTF,

[0485] (19) a CNTF agonist/modulator,

[0486] (20) a CNTF derivative,

[0487] (21) 5HT2c agonist,

[0488] (22) a Mc4r agonist,

[0489] (23) a monoamine reuptake inhibitor,

[0490] (24) a serotonin reuptake inhibitor,

[0491] (25) a GLP-1 agonist,

[0492] (26) axokine,

[0493] (27) fenfluramine,

[0494] (28) nalmafene,

[0495] (29) phentermine,

[0496] (30) rimonabant,

[0497] (31) sibutramine,

[0498] (32) topiramate, and

[0499] (33) phytopharm compound 57;

[0500] and pharmaceutically acceptable salts and esters thereof; and

[0501] (b) a metabolic rate enhancer selected from the group consisting of

[0502] (1) an ACC2 inhibitor,

[0503] (2) a β3 agonist,

[0504] (3) a DGAT1 inhibitor,

[0505] (4) a DGAT2 inhibitor,

[0506] (5) a FAS inhibitor,

[0507] (6) a PDE inhibitor,

[0508] (7) a thyroid hormone β agonist,

[0509] (8) an UCP-1, 2, or 3 activator,

[0510] (9) an acyl-estrogen,

[0511] (10) a glucocorticoid antagonist,

[0512] (11) an 11β HSD-1 inhibitor,

[0513] (12) a Mc3r agonist,

[0514] (13) a SCD-1, and

[0515] (14) oleoyl-estrone;

[0516] and pharmaceutically acceptable salts and esters thereof; and

[0517] provided that when the metabolic rate enhancer is a β3 agonist, then the appetite suppressant is not selected from the group consisting of a CB-1 antagonist/inverse agonist, a MCH1R antagonist, a MCH2R antagonist, leptin, a leptin derivative, a CCK-A agonist, a 5HT2c agonist, a Mc4r agonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, and a GLP-1 agonist;

[0518] provided that when the metabolic rate enhancer is a UCP-1, 2 or 3 activator, then the appetite suppressant is not selected from the group consisting of leptin and a leptin derivative;

[0519] provided that when the metabolic rate enhancer is an 11β HSD-1 inhibitor, then the appetite suppressant is not selected from the group consisting of: a CB-1 antagonist/inverse agonist, a Mc4r agonist, a monoamine reuptake inhibitor, and a serotonin reuptake inhibitor; and provided that when the appetite suppressant is a monoamine reuptake inhibitor, then the metabolic rate enhancer is not a PDE inhibitor.

[0520] In another subclass of this class, the composition comprises

[0521] (a) an appetite suppressant selected from the group consisting of

[0522] (1) a 5HT transporter inhibitor,

[0523] (2) a NE transporter inhibitor,

[0524] (3) a CB-1 antagonist/inverse agonist,

[0525] (4) a ghrelin antagonist,

[0526] (5) a H3 antagonist/inverse agonist,

[0527] (6) a MCH1R antagonist,

[0528] (7) a MCH2R agonist/antagonist,

[0529] (8) a NPY1 antagonist,

[0530] (9) a NPY2 agonist,

[0531] (10) a NPY4 agonist,

[0532] (11) a mGluR5 antagonist,

[0533] (12) an opioid antagonist,

[0534] (13) an orexin antagonist,

[0535] (14) a BRS3 agonist,

[0536] (15) a CCK-A agonist,

[0537] (16) CNTF,

[0538] (17) a CNTF agonist/modulator,

[0539] (18) a CNTF derivative,

[0540] (19) a 5HT2c agonist,

[0541] (20) a Mc4r agonist,

[0542] (21) a serotonin reuptake inhibitor, and

[0543] (22) a GLP-1 agonist;

[0544] and pharmaceutically acceptable salts and esters thereof; and

[0545] (b) a metabolic rate enhancer selected from the group consisting of

[0546] (1) an ACC2 inhibitor,

[0547] (2) a FAS inhibitor,

[0548] (3) a thyroid hormone β agonist,

[0549] (4) an UCP-1, 2, or 3 activator,

[0550] (5) an acyl-estrogen,

[0551] (6) a glucocorticoid antagonist, and

[0552] (7) oleoyl-estrone;

[0553] and pharmaceutically acceptable salts and esters thereof.

[0554] In yet another subclass of this class, the composition comprises an appetite suppressant selected from the group consisting of a NPY5 antagonist, and pharmaceutically acceptable salts and esters thereof, and a metabolic rate enhancer selected from the group consisting of an 11β HSD-1 inhibitor, and pharmaceutically acceptable salts and esters thereof.

[0555] In another embodiment of the present invention, the compositions comprise an appetite suppressant, and pharmaceutically acceptable salts and esters thereof, and a nutrient absorption inhibitor, and pharmaceutically acceptable salts and esters thereof.

[0556] In a class of this embodiment, the composition comprises

[0557] (a) an appetite suppressant selected from the group consisting of

[0558] (1) a 5HT transporter inhibitor,

[0559] (2) a NE transporter inhibitor,

[0560] (3) a CB-1 antagonist/inverse agonist,

[0561] (4) a ghrelin antagonist,

[0562] (5) a H3 antagonist/inverse agonist,

[0563] (6) a MCH1R antagonist,

[0564] (7) a MCH2R agonist/antagonist,

[0565] (8) a NPY1 antagonist,

[0566] (9) a NPY5 antagonist,

[0567] (10) a NPY2 agonist,

[0568] (11) a NPY4 agonist,

[0569] (12) a mGluR5 antagonist,

[0570] (13) leptin,

[0571] (14) a leptin agonist/modulator,

[0572] (15) a leptin derivative,

[0573] (16) an opioid antagonist,

[0574] (17) an orexin antagonist,

[0575] (18) a BRS3 agonist,

[0576] (19) a CCK-A agonist,

[0577] (20) CNTF,

[0578] (21) a CNTF agonist/modulator,

[0579] (22) a CNTF derivative,

[0580] (23) a 5HT2c agonist,

[0581] (24) a Mc4r agonist,

[0582] (25) a monoamine reuptake inhibitor,

[0583] (26) a serotonin reuptake inhibitor,

[0584] (27) a GLP-1 agonist,

[0585] (28) axokine,

[0586] (29) fenfluramine,

[0587] (30) nalmafene,

[0588] (31) phentermine,

[0589] (32) rimonabant,

[0590] (33) sibutramine,

[0591] (34) topiramate, and

[0592] (35) phytopharm compound 57;

[0593] and pharmaceutically acceptable salts and esters thereof, and

[0594] (b) a nutrient absorption inhibitor selected from the group consisting of

[0595] (1) a lipase inhibitor,

[0596] (2) a fatty acid transporter inhibitor,

[0597] (3) a dicarboxylate transporter inhibitor,

[0598] (4) a glucose transporter inhibitor,

[0599] (5) a phosphate transporter inhibitor, and

[0600] (6) orlistat;

[0601] and pharmaceutically acceptable salts and esters thereof;

[0602] provided that when the appetite suppressant is a monoamine reuptake inhibitor, then the nutrient absorption inhibitor is not a lipase inhibitor.

[0603] In a subclass of this class, the composition comprises

[0604] (a) an appetite suppressant selected from the group consisting of

[0605] (1) a 5HT transporter inhibitor,

[0606] (2) a NE transporter inhibitor,

[0607] (3) a CB-1 antagonist/inverse agonist,

[0608] (4) a ghrelin antagonist,

[0609] (5) a H3 antagonist/inverse agonist,

[0610] (6) a MCH1R antagonist,

[0611] (7) a MCH2R agonist/antagonist,

[0612] (8) a NPY1 antagonist,

[0613] (9) a NPY2 agonist,

[0614] (10) a NPY4 agonist,

[0615] (11) a mGluR5 antagonist,

[0616] (12) leptin,

[0617] (13) a leptin agonist/modulator,

[0618] (14) a leptin derivative,

[0619] (15) an opioid antagonist,

[0620] (16) an orexin antagonist,

[0621] (17) a BRS3 agonist,

[0622] (18) a CCK-A agonist,

[0623] (19) CNTF,

[0624] (20) a CNTF agonist/modulator,

[0625] (21) a CNTF derivative,

[0626] (22) a 5HT2c agonist,

[0627] (23) a Mc4r agonist,

[0628] (24) a serotonin reuptake inhibitor,

[0629] (25) a GLP-1 agonist,

[0630] (26) axokine,

[0631] (27) fenfluramine,

[0632] (28) nalmafene,

[0633] (29) phentermine,

[0634] (30) rimonabant,

[0635] (31) sibutramine,

[0636] (32) topiramate, and

[0637] (33) phytopharm compound 57;

[0638] and pharmaceutically acceptable salts and esters thereof; and

[0639] (b) a nutrient absorption inhibitor selected from the group consisting of

[0640] (1) a lipase inhibitor,

[0641] (2) a fatty acid transporter inhibitor,

[0642] (3) a dicarboxylate transporter inhibitor,

[0643] (4) a glucose transporter inhibitor,

[0644] (5) a phosphate transporter inhibitor, and

[0645] (6) orlistat;

[0646] and pharmaceutically acceptable salts and esters thereof.

[0647] In another subclass of this class, the composition comprises

[0648] (a) an appetite suppressant selected from the group consisting of

[0649] (1) a 5HT transporter inhibitor,

[0650] (2) a NE transporter inhibitor,

[0651] (3) a CB-1 antagonist/inverse agonist,

[0652] (4) a ghrelin antagonist,

[0653] (5) a H3 antagonist/inverse agonist,

[0654] (6) a MCH1R antagonist,

[0655] (7) a MCH2R agonist/antagonist,

[0656] (8) a NPY1 antagonist,

[0657] (9) a NPY2 agonist,

[0658] (10) a NPY4 agonist,

[0659] (11) a mGluR5 antagonist,

[0660] (12) an opioid antagonist,

[0661] (13) an orexin antagonist,

[0662] (14) a BRS3 agonist,

[0663] (15) a CCK-A agonist,

[0664] (16) CNTF,

[0665] (17) a CNTF agonist/modulator,

[0666] (18) a CNTF derivative,

[0667] (19) a 5HT2c agonist,

[0668] (20) a Mc4r agonist,

[0669] (21) a serotonin reuptake inhibitor,

[0670] (22) a GLP-1 agonist;

[0671] and pharmaceutically acceptable salts and esters thereof; and

[0672] (b) a nutrient absorption inhibitor selected from the group consisting of

[0673] (1) a lipase inhibitor,

[0674] (2) a fatty acid transporter inhibitor,

[0675] (3) a dicarboxylate transporter inhibitor,

[0676] (4) a glucose transporter inhibitor, and

[0677] (5) orlistat;

[0678] and pharmaceutically acceptable salts and esters thereof.

[0679] In another embodiment of the present invention, the composition comprises two metabolic rate enhancers, and pharmaceutically acceptable salts and esters thereof, provided that the metabolic rate enhancers have different biological mechanisms of action.

[0680] In a class of this embodiment, the composition comprises two metabolic rate enhancers, wherein each metabolic rate enhancer is selected from the group consisting of

[0681] (1) an ACC2 inhibitor,

[0682] (2) a β3 agonist,

[0683] (3) a FAS inhibitor,

[0684] (4) a PDE inhibitor,

[0685] (5) a thyroid hormone β agonist,

[0686] (6) an UCP-1, 2, or 3 activator,

[0687] (7) an acyl-estrogen,

[0688] (8) a glucocorticoid antagonist,

[0689] (9) an 11βHSD-1 inhibitor,

[0690] (10) a Mc3r agonist,

[0691] (11) a SCD-1, and

[0692] (12) oleoyl-estrone;

[0693] and pharmaceutically acceptable salts and esters thereof,

[0694] provided that the metabolic rate enhancers have different biological mechanisms of action.

[0695] In another embodiment of the present invention, the composition comprises a metabolic rate enhancer, and pharmaceutically acceptable salts and esters thereof, and a nutrient absorption inhibitor, and pharmaceutically acceptable salts and esters thereof.

[0696] In a class of this embodiment, the composition comprises:

[0697] (a) a metabolic rate enhancer selected from the group consisting of

[0698] (1) an ACC2 inhibitor,

[0699] (2) a β3 agonist,

[0700] (3) a FAS inhibitor,

[0701] (4) a PDE inhibitor,

[0702] (5) a thyroid hormone β agonist,

[0703] (6) an UCP-1, 2, or 3 activator,

[0704] (7) an acyl-estrogen,

[0705] (8) a glucocorticoid antagonist,

[0706] (9) an 11β HSD-1 inhibitor,

[0707] (10) a Mc3r agonist,

[0708] (11) a SCD-1, and

[0709] (12) oleoyl-estrone;

[0710] and pharmaceutically acceptable salts and esters thereof; and

[0711] (b) a nutrient absorption inhibitor selected from the group consisting of

[0712] (1) a lipase inhibitor,

[0713] (2) a fatty acid transporter inhibitor,

[0714] (3) a dicarboxylate transporter inhibitor,

[0715] (4) a glucose transporter inhibitor,

[0716] (5) a phosphate transporter inhibitor, and

[0717] (6) orlistat;

[0718] and pharmaceutically acceptable salts and esters thereof.

[0719] In a subclass of this class, the composition comprises:

[0720] (a) a metabolic rate enhancer selected from the group consisting of

[0721] (1) an ACC2 inhibitor,

[0722] (2) a β3 agonist,

[0723] (3) a FAS inhibitor,

[0724] (4) a PDE inhibitor,

[0725] (5) a thyroid hormone β agonist,

[0726] (6) an UCP-1, 2, or 3 activator,

[0727] (7) an acyl-estrogen,

[0728] (8) a glucocorticoid antagonist,

[0729] (9) an 11β HSD-1 inhibitor, and

[0730] (10) oleoyl-estrone;

[0731] and pharmaceutically acceptable salts and esters thereof; and

[0732] (b) a nutrient absorption inhibitor selected from the group consisting of

[0733] (1) a lipase inhibitor,

[0734] (2) a fatty acid transporter inhibitor,

[0735] (3) a dicarboxylate transporter inhibitor,

[0736] (4) a glucose transporter inhibitor and

[0737] (5) orlistat;

[0738] and pharmaceutically acceptable salts and esters thereof.

[0739] In another embodiment of the present invention, the composition comprises two nutrient absorption inhibitors, and pharmaceutically acceptable salts and esters thereof, provided that the nutrient absorption inhibitors have different biological mechanisms of action.

[0740] In a class of this embodiment, the composition comprises two nutrient absorption inhibitors, wherein each nutrient absorption inhibitor is selected from the group consisting of

[0741] (1) a lipase inhibitor,

[0742] (2) a fatty acid transporter inhibitor,

[0743] (3) a dicarboxylate transporter inhibitor,

[0744] (4) a glucose transporter inhibitor,

[0745] (5) a phosphate transporter inhibitor and

[0746] (6) orlistat;

[0747] and pharmaceutically acceptable salts and esters thereof; provided that the nutrient absorption inhibitors have different biological mechanisms of action.

[0748] In a subclass of this class, the composition comprises two nutrient absorption inhibitors, wherein each nutrient absorption inhibitors is selected from the group consisting of

[0749] (1) a lipase inhibitor,

[0750] (2) a fatty acid transporter inhibitor,

[0751] (3) a dicarboxylate transporter inhibitor,

[0752] (4) a glucose transporter inhibitor, and

[0753] (5) orlistat;

[0754] and pharmaceutically acceptable salts and esters thereof;

[0755] provided that the nutrient absorption inhibitors have different biological mechanisms of action.

[0756] The present invention further relates to methods of treating or preventing obesity in a subject in need thereof by administering an effective amount of an appetite suppressant and/or a metabolic rate enhancer and/or a nutrient absorption inhibitor.

[0757] The present invention relates to a method of treating a subject having a disorder associated with excessive food intake comprising administration of

[0758] (a) a therapeutically effective amount of an appetite suppressant, and pharmaceutically acceptable salts and esters thereof; and

[0759] (b) a therapeutically effective amount of a metabolic rate enhancer, and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment.

[0760] In one embodiment of the present invention, the method of treating a subject having a disorder associated with excessive food intake comprising administration of

[0761] (a) a therapeutically effective amount of an appetite suppressant selected from the group consisting of a 5HT transporter inhibitor, a NE transporter inhibitor, a CB-1 antagonist/inverse agonist, a ghrelin antagonist, a H3 antagonist/inverse agonist, a MCH1R antagonist, a MCH2R agonist/antagonist, a NPY1 antagonist, a NPY2 agonist, NPY4 agonist, a mGluR5 antagonist, leptin, a leptin derivative, an opioid antagonist, an orexin antagonist, a BRS3 agonist, a CCK-A agonist, CNTF, a CNTF derivative, a 5HT2c agonist, a Mc4r agonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, a GLP-1 agonist, topiramate, and phytopharm compound 57; and pharmaceutically acceptable salts and esters thereof; and

[0762] (b) a therapeutically effective amount of a metabolic rate enhancer selected from the group consisting of an ACC2 inhibitor, a β3 agonist, a DGAT1 inhibitor, a DGAT2 inhibitor, a FAS inhibitor, a PDE inhibitor, a thyroid hormone β agonist, an UCP-1, 2, or 3 activator, an acyl-estrogen, a glucocorticoid antagonist, and an 11β HSD-1 inhibitor, a Mc3r agonist, and a SCD-1; and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment; and pharmaceutically acceptable salts and esters thereof; provided that when the metabolic rate enhancer is a β3 agonist, then the appetite suppressant is not selected from the group consisting of a CB-1 antagonist/inverse agonist, a MCH1R antagonist, a MCH2R antagonist, leptin, a leptin derivative, a CCK-A agonist, a 5HT2c agonist, a Mc4r agonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, and a GLP-1 agonist; provided that when the metabolic rate enhancer is a UCP-1, 2 or 3 activator, then the appetite suppressant is not selected from the group consisting of leptin and a leptin derivative; provided that when the metabolic rate enhancer is an 11β HSD-1 inhibitor, then the appetite suppressant is not selected from the group consisting of: a CB-1 antagonist/inverse agonist, a Mc4r agonist, a monoamine reuptake inhibitor, and a serotonin reuptake inhibitor; and provided that when the appetite suppressant is a monoamine reuptake inhibitor, then the metabolic rate enhancer is not a PDE inhibitor.

[0763] The present invention relates to a method of treating a subject having a disorder associated with excessive food intake comprising administration of

[0764] (a) a therapeutically effective amount of an appetite suppressant, and pharmaceutically acceptable salts and esters thereof; and

[0765] (b) a therapeutically effective amount of a nutrient absorption inhibitor, and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment.

[0766] In one embodiment of the present invention, the method of treating a subject having a disorder associated with excessive food intake comprises administration of

[0767] (a) a therapeutically effective amount of an appetite suppressant selected from the group consisting of a 5HT transporter inhibitor, a NE transporter inhibitor, a CB-1 antagonist/inverse agonist, a ghrelin antagonist, a H3 antagonist/inverse agonist, a MCH1R antagonist, a MCH2R agonist/antagonist, a NPY1 antagonist, NPY2 agonist, NPY4 agonist, a mGluR5 antagonist, leptin, a leptin derivative, an opioid antagonist, an orexin antagonist, a BRS3 agonist, a CCK-A agonist, CNTF, a CNTF derivative, a 5HT2c agonist, a Mc4r agonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, a GLP-1 agonist, topiramate, and phytopharm compound 57; and pharmaceutically acceptable salts and esters thereof; and

[0768] (b) a therapeutically effective amount of a nutrient absorption inhibitor selected from the group consisting of a lipase inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, a glucose transporter inhibitor, and a phosphate transporter inhibitor; and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment; provided that when the appetite suppressant is a monoamine reuptake inhibitor, then the nutrient absorption inhibitor is not a lipase inhibitor.

[0769] The present invention relates to a method of treating a subject having a disorder associated with excessive food intake comprising administration of

[0770] (a) a therapeutically effective amount of a metabolic rate enhancer, and pharmaceutically acceptable salts and esters thereof; and

[0771] (b) a therapeutically effective amount of a nutrient absorption inhibitor, and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment.

[0772] In one embodiment of the present invention, the method of treating a subject having a disorder associated with excessive food intake comprises administration of

[0773] (a) a therapeutically effective amount of a metabolic rate enhancer selected from the group consisting of an ACC2 inhibitor, a β3 agonist, a DGAT1 inhibitor, a DGAT2 inhibitor, a FAS inhibitor, a PDE inhibitor, a thyroid hormone β agonist, an UCP-1, 2, or 3 activator, an acyl-estrogen, a glucocorticoid antagonist, an 11β HSD-1 inhibitor, a Mc3r agonist, a SCD-1; and pharmaceutically acceptable salts and esters thereof; and

[0774] (b) a therapeutically effective amount of a nutrient absorption inhibitor selected from the group consisting of a lipase inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, a glucose transporter inhibitor, and a phosphate transporter inhibitor; and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment.

[0775] The present invention also relates to a method of treating a subject having a disorder associated with excessive food intake comprising administration of a therapeutically effective amount of two appetite suppressants, and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment.

[0776] In one embodiment of the present invention, the method of treating a subject having a disorder associated with excessive food intake comprises administration of a therapeutically effective amount of two appetite suppressants selected from the group consisting of: a 5HT transporter inhibitor, a NE transporter inhibitor, a CB-1 antagonist/inverse agonist, a ghrelin antagonist, a H3 antagonist/inverse agonist, a MCH1R antagonist, a MCH2R agonist/antagonist, a NPY1 antagonist, NPY2 agonist, a NPY4 agonist, a mGluR5 antagonist, a leptin, a leptin derivative, an opioid antagonist, an orexin antagonist, a BRS3 agonist, a CCK-A agonist, CNTF, a CNTF derivative, a 5HT2c agonist, a Mc4r agonist, a monoamine reuptake inhibitor, a serotonin reuptake inhibitor, a GLP-1 agonist,topiramate, and phytopharm compound 57; and pharmaceutically acceptable salts and esters thereof;

[0777] to a subject in need of such treatment; provided that when the first appetite suppressant is a NPY1 antagonist, then the second appetite suppressant is not selected from the group consisting of: a MCH1R antagonist, a MCH2R antagonist, leptin, a leptin derivative, 5HT2c agonist, a Mc4r agonist, a serotonin reuptake inhibitor, and a GLP-1 agonist; provided that when the first appetite suppressant is leptin, then the second appetite suppressant is not selected from the group consisting of: a MCH-1R antagonist, a MCH-2R antagonist, a NPY1 antagonist, a leptin derivative, 5HT2c agonist, a Mc4r agonist, a serotonin reuptake inhibitor, a GLP-1 agonist, a CCK-A agonist, an opioid antagonist, and a monoamine reuptake inhibitor; provided that when the first appetite suppressant is a CB-1 antagonist/inverse agonist, then the second appetite suppressant is not selected from the group consisting of an opioid antagonist, a serotonin reuptake inhibitor, and a monoamine reuptake inhibitor; and provided that the appetite suppressants have different biological mechanisms of action.

[0778] The present invention also relates to a method of treating a subject having a disorder associated with excessive food intake comprising administration of a therapeutically effective amount of two metabolic rate enhancers, and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment.

[0779] In one embodiment of the present invention, the method of treating a subject having a disorder associated with excessive food intake comprises administration of a therapeutically effective amount of two metabolic rate enhancers selected from the group consisting of an ACC2 inhibitor, a β3 agonist, a DGAT1 inhibitor, a DGAT2 inhibitor, a FAS inhibitor, a PDE inhibitor, a thyroid hormone β agonist, an UCP-1, 2, or 3 activator, an acyl-estrogen, a glucocorticoid antagonist, an 11β HSD-1 inhibitor, a Mc3r agonist, and a SCD-1; and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment; provided that when the first metabolic rate enhancer is an 11β HSD-1 inhibitor, then the second metabolic rate enhancer is not a β3 agonist; and provided that the metabolic rate enhancers have different biological mechanisms of action.

[0780] The present invention also relates to a method of treating a subject having a disorder associated with excessive food intake comprising administration of a therapeutically effective amount of two nutrient absorption inhibitors, and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment.

[0781] In one embodiment of the present invention, the method of treating a subject having a disorder associated with excessive food intake comprises administration of a therapeutically effective amount of two nutrient absorption inhibitors selected from the group consisting of a lipase inhibitor, a fatty acid transporter inhibitor, a dicarboxylate transporter inhibitor, a glucose transporter inhibitor, and a phosphate transporter inhibitor; and pharmaceutically acceptable salts and esters thereof; to a subject in need of such treatment; provided that the nutrient absorption inhibitors have different biological mechanisms of action.

[0782] The present invention relates to a method of preventing obesity in a subject at risk for obesity comprising administration to said subject

[0783] (a) a prophylactically effective amount of an appetite suppressant, and pharmaceutically acceptable salts and esters thereof,

[0784] (b) a prophylactically effective amount of a metabolic rate enhancer, and pharmaceutically acceptable salts and esters thereof.

[0785] The present invention relates to a method of preventing obesity in a subject at risk for obesity comprising administration to said subject

[0786] (a) a prophylactically effective amount of an appetite suppressant, and pharmaceutically acceptable salts and esters thereof,

[0787] (b) a prophylactically effecti