Methylsulfonylpyrazolyl oxadiazoles and thiadiazoles as potent, orally bioavailable cannabinoid-1 receptor antagonists for the treatment of obesity

Future Med Chem. 2009 Aug;1(5):947-67. doi: 10.4155/fmc.09.64.

Abstract

Background: Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity.

Discussion: In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity.

Results: The structure-activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Oral
  • Animals
  • Anti-Obesity Agents / chemistry*
  • Anti-Obesity Agents / pharmacokinetics
  • Anti-Obesity Agents / therapeutic use
  • Binding Sites
  • Biological Availability
  • Computer Simulation
  • Humans
  • Mice
  • Obesity / drug therapy*
  • Oxadiazoles / chemistry*
  • Oxadiazoles / pharmacokinetics
  • Oxadiazoles / therapeutic use
  • Pyrazoles / chemistry*
  • Pyrazoles / pharmacokinetics
  • Pyrazoles / therapeutic use
  • Rats
  • Receptor, Cannabinoid, CB1 / antagonists & inhibitors*
  • Receptor, Cannabinoid, CB1 / metabolism
  • Structure-Activity Relationship
  • Thiadiazoles / chemistry*
  • Thiadiazoles / pharmacokinetics
  • Thiadiazoles / therapeutic use

Substances

  • 2-(1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-(methylsulfonyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclobutyl)-1,3,4-thiadiazole
  • 2-(5-(4-bromophenyl)-1-(2-chlorophenyl)-4-(methylsulfonyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclobutyl)-1,3,4-thiadiazole
  • Anti-Obesity Agents
  • Oxadiazoles
  • Pyrazoles
  • Receptor, Cannabinoid, CB1
  • Thiadiazoles