TY - JOUR
T1 - Discovery of orally active carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamide as potent diacylglycerol acyltransferase-1 inhibitors for the potential treatment of obesity and diabetes
AU - Qian, Yimin
AU - Wertheimer, Stanley J.
AU - Ahmad, Mushtaq
AU - Cheung, Adrian Wai Hing
AU - Firooznia, Fariborz
AU - Hamilton, Matthew M.
AU - Hayden, Stuart
AU - Li, Shiming
AU - Marcopulos, Nicholas
AU - McDermott, Lee
AU - Tan, Jenny
AU - Yun, Weiya
AU - Guo, Liang
AU - Pamidimukkala, Anjula
AU - Chen, Yingsi
AU - Huang, Kuo Sen
AU - Ramsey, Gwendolyn B.
AU - Whittard, Toni
AU - Conde-Knape, Karin
AU - Taub, Rebecca
AU - Rondinone, Cristina M.
AU - Tilley, Jefferson
AU - Bolin, David
PY - 2011/4/14
Y1 - 2011/4/14
N2 - Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC50 = 57 nM; CHO-K1 cell triglyceride formation assay, EC50 = 0.5 μM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, PO, qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).
AB - Diacylglycerol acyltransferase-1 (DGAT-1) is the enzyme that catalyzes the final and committed step of triglyceride formation, namely, the acylation of diacylglycerol with acyl coenzyme A. DGAT-1 deficient mice demonstrate resistance to weight gain on high fat diet, improved insulin sensitivity, and reduced liver triglyceride content. Inhibition of DGAT-1 thus represents a potential novel approach for the treatment of obesity, dyslipidemia, and metabolic syndrome. In this communication, we report the identification of the lead structure 6 and our lead optimization efforts culminating in the discovery of potent, selective, and orally efficacious carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides. In particular, compound 29 (DGAT-1 enzyme assay, IC50 = 57 nM; CHO-K1 cell triglyceride formation assay, EC50 = 0.5 μM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, PO, qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).
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U2 - 10.1021/jm101580m
DO - 10.1021/jm101580m
M3 - Article
C2 - 21413799
AN - SCOPUS:79953801433
SN - 0022-2623
VL - 54
SP - 2433
EP - 2446
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 7
ER -