Organic compounds
The present invention provides heterocyclic derivatives that modulate the activity of stearoyl-CoA desaturase. Methods of using such derivatives to modulate the activity of stearoyl-CoA desaturase and pharmaceutical compositions comprising such derivatives are also encompassed.
1. A compound represented by Formula (III):
or a pharmaceutically acceptable salt thereof, wherein,
V is a direct bond;
W is selected from —N(R 6 )C(O)—, or —C(O)O— wherein the carbonyl(—C(O)—) is directly linked to the thiazole ring;
R 1 is hydrogen, aralkyl, or C 1-9 heteroarylC 1-4 alkyl;
R 2 is C 1-4 alkyl, C 3-6 cycloalkylC 1-4 alkyl, C 6-10 aryl or C 6-10 arC 1-4 alkyl; and
R 6 is hydrogen.
2. The compound according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein
V is a direct bond;
W is —N(R 6 )C(O)—;
R 1 is hydrogen, aralkyl or C 1-9 heteroaryl C 1-4 alkyl;
R 6 is hydrogen; and
R 2 is C 1-4 alkyl, C 3-6 cycloalkylC 1-4 alkyl, or C 6-10 arC 1-4 alkyl,
wherein the C 3-6 cycloalkylC 1-4 alkyl is
wherein the aralkyl is
wherein the C 1-4 alkyl is
3. The compound according to claim 2 , or a pharmaceutically acceptable salt thereof, wherein
W is —N(R 6 )C(O)—,
R 1 is hydrogen,
4. A pharmaceutical composition, comprising:
the compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, and
a pharmaceutically acceptable excipient or carrier.
5. A method of inhibiting human stearoyl-CoA desaturase (hSCD) activity, comprising:
contacting a source of hSCD with a compound of claim 1 , or a pharmaceutically acceptable salt thereof.
6. A method of treating a disease or condition mediated by stearoyl-CoA desaturase (SCD) in a mammal in need thereof, comprising: administering to the mammal in need thereof a therapeutically effective amount of a compound of Formula (I) according to claim 1 , or a pharmaceutically acceptable salt thereof, wherein the disease or condition is metabolic syndrome, Syndrome X, diabetes, insulin resistance, decreased glucose tolerance, non-insulin-dependent diabetes mellitus, Type II diabetes, Type I diabetes, a diabetic complication, a body weight disorder, weight loss, body mass index or a leptin related disease.
7. The method according to claim 6 , wherein the disease or condition is metabolic syndrome and is selected from the group consisting of dyslipidemia, obesity, insulin resistance, hypertension, microalbuminemia, hyperuricaemia, and hypercoagulability.
8. The method according to claim 6 , wherein the disease or condition is a bodyweight disorder and is selected from the group consisting of obesity, overweight, cachexia and anorexia.
9. The method according to claim 6 , where the disease or condition is a skin disorder.
10. The method according to claim 9 , wherein the skin disorder is eczema, acne, psoriasis, or keloid scar formation or prevention.
11. A pharmaceutical composition, comprising:
a compound of claim 1 , or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of insulin, an insulin derivative or mimetic; an insulin secretagogue; an insulinotropic sulfonylurea receptor ligand; a PPAR ligand; an insulin sensitizer; a biguanide; an alpha-glucosidase inhibitor; GLP-1, a GLP-1 analog or mimetic; a DPPIV inhibitor; a HMG-CoA reductase inhibitor; a squalene synthase inhibitor; a FXR or LXR ligand; cholestyramine; a fibrate; nicotinic acid; or aspirin.