Discovery of a potent, selective, and orally efficacious pyrimidinooxazinyl bicyclooctaneacetic acid diacylglycerol acyltransferase-1 inhibitor

J Med Chem. 2009 Mar 26;52(6):1558-68. doi: 10.1021/jm801507v.


Inhibition of DGAT-1 is increasingly seen as an attractive mechanism with the potential for treatment of obesity and other elements of the metabolic syndrome. We report here a bicyclooctaneacetic acid derivative in the pyrimidinooxazine structural class of DGAT-1 inhibitors that has good potency, selectivity, and pharmacokinetic characteristics across a variety of species. This compound is an effective inhibitor of DGAT-1 in both intestinal and adipose tissue, which results in a reduction in body weight or body weight gain following oral administration in both mouse and rat models of dietary-induced obesity.

MeSH terms

  • Administration, Oral
  • Animals
  • Body Weight / drug effects
  • Diacylglycerol O-Acyltransferase / antagonists & inhibitors*
  • Enzyme Inhibitors / administration & dosage
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Female
  • Humans
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Obesity / drug therapy
  • Oxazines / pharmacology*
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Wistar
  • Spectrometry, Mass, Electrospray Ionization


  • (4-(4-(4-amino-7,7-dimethyl-7H-pyrimido(4,5-b)(1,4)oxazin-6-yl)phenyl)bicyclo(2.2.2)oct-1-yl)acetic acid
  • Enzyme Inhibitors
  • Oxazines
  • Pyrimidines
  • Diacylglycerol O-Acyltransferase