Discovery of 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H-pyrazolo[3,4-f][1,4]oxazepin-8(5H)-one (PF-514273), a novel, bicyclic lactam-based cannabinoid-1 receptor antagonist for the treatment of obesity

J Med Chem. 2009 May 14;52(9):2652-5. doi: 10.1021/jm900255t.

Abstract

We report the design, synthesis, and structure-activity relationships of novel bicyclic lactam-based cannabinoid type 1 (CB(1)) receptor antagonists. Members of these series are potent, selective antagonists in in vitro/in vivo efficacy models of CB(1) antagonism and exhibit robust oral activity in rodent models of food intake. These efforts led to the identification of 19d, which has been advanced to human clinical trials for weight management.

MeSH terms

  • Animals
  • Clinical Trials as Topic
  • Crystallography, X-Ray
  • Drug Discovery*
  • Humans
  • Lactams / chemical synthesis*
  • Lactams / chemistry
  • Lactams / pharmacology*
  • Lactams / therapeutic use
  • Obesity / drug therapy*
  • Oxazepines / chemical synthesis*
  • Oxazepines / chemistry
  • Oxazepines / pharmacology*
  • Oxazepines / therapeutic use
  • Pyrazoles / chemical synthesis
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Rats
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*

Substances

  • 2-(2-chlorophenyl)-3-(4-chlorophenyl)-7-(2,2-difluoropropyl)-6,7-dihydro-2H-pyrazolo(3,4-f)(1,4)oxazepin-8(5H)-one
  • Lactams
  • Oxazepines
  • Pyrazoles
  • Receptor, Cannabinoid, CB1