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.

Abstract

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, IC(50) = 57 nM; CHO-K1 cell triglyceride formation assay, EC(50) = 0.5 μM) demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats (0.3, 1, and 3 mg/kg, p.o., qd) during a 21-day efficacy study. Furthermore, compound 29 demonstrated improved glucose tolerance determined by an oral glucose tolerance test (OGTT).

DOI: 10.1021/jm101580m

Cite this paper

@article{Qian2011DiscoveryOO, title={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.}, author={Yimin Qian and Stanley J Wertheimer and Mushtaq Ahmad and A. Cheung and Fariborz Firooznia and Matthew M Hamilton and Stuart Hayden and Shiming Li and Nicholas Marcopulos and Lee A. McDermott and Jenny S. Tan and Weiya Yun and Liang Guo and Anjula Pamidimukkala and Yingsi Chen and Kuo-Sen Huang and Gwendolyn B Ramsey and Toni Whittard and Karin Conde-Knape and Rebecca L Taub and Cristina M. Rondinone and Jefferson W Tilley and David R. Bolin}, journal={Journal of medicinal chemistry}, year={2011}, volume={54 7}, pages={2433-46} }