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. Epub 2011 Mar 17.

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).

MeSH terms

  • Administration, Oral
  • Amides / administration & dosage
  • Amides / chemistry*
  • Amides / pharmacokinetics
  • Amides / pharmacology*
  • Animals
  • Carboxylic Acids / chemistry*
  • Cell Line
  • Diabetes Mellitus / drug therapy*
  • Diabetes Mellitus / enzymology
  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Dogs
  • Drug Discovery*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology
  • Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
  • Humans
  • Inhibitory Concentration 50
  • Male
  • Mice
  • Obesity / drug therapy*
  • Obesity / enzymology
  • Oxazoles / administration & dosage
  • Oxazoles / chemistry*
  • Oxazoles / pharmacokinetics
  • Oxazoles / pharmacology*
  • Rats

Substances

  • Amides
  • Carboxylic Acids
  • Enzyme Inhibitors
  • Ether-A-Go-Go Potassium Channels
  • Oxazoles
  • Diacylglycerol O-Acyltransferase