2. Academic Validation
  3. 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

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

  • J Med Chem. 2011 Apr 14;54(7):2433-46. doi: 10.1021/jm101580m.
Yimin Qian 1,  Stanley J Wertheimer,  Mushtaq Ahmad,  Adrian Wai-Hing Cheung,  Fariborz Firooznia,  Matthew M Hamilton,  Stuart Hayden,  Shiming Li,  Nicholas Marcopulos,  Lee McDermott,  Jenny Tan,  Weiya Yun,  Liang Guo,  Anjula Pamidimukkala,  Yingsi Chen,  Kuo-Sen Huang,  Gwendolyn B Ramsey,  Toni Whittard,  Karin Conde-Knape,  Rebecca Taub,  Cristina M Rondinone,  Jefferson Tilley,  David Bolin
Affiliations

Affiliation

  • 1 Department of Discovery Chemistry, Hoffmann-La Roche Inc., 340 Kingsland Street, Nutley, New Jersey 07110, United States. yimin.qian@roche.com
PMID: 21413799 DOI: 10.1021/jm101580m
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).

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