Diacylglycerol acyltransferase-1 (DGAT-1) catalyzes the final step of triglyceride formation by acylation of diacylglycerol with acyl-coenzyme A. DGAT1 (-/-) mice demonstrate resistance to weight gain on high fat diets, enhanced insulin sensitivity and reduced hepatic triglyceride levels and therefore represents a potential approch for the treatment of obesity, dyslipidemia and metabolic syndrome.We report here, the identification of a high-throughput screening hit and the subsequent lead expansion efforts that developed into the discovery of potent class of carboxylic acid derivatives of 2-phenyl-5-trifluoromethyloxazole-4-carboxamides.  Efforts then directed toward improving biopharmaceutical properties, as well as minimizing early in vitro safety issues, resulted in the emergence of RO5131723 as a lead candidate.  In vivo, RO5131723 demonstrated dose dependent inhibition of weight gain in diet induced obese (DIO) rats when dosed for 21 day.  Additionally, this compound demonstrated improved glucose tolerance as measured in an oral glucose tolerance test (OGTT) in rats.

Discovery of a potent, orally efficacious DGAT1 inhibitor that improves glucose tolerance and lowers weight in animal models of obesity

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.