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

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.

• Authors: Hee Jeong Seo, Min Ju Kim, Kwang-Seop Song, Sung-Han Lee, Myung Eun Jung, Mi-Soon Kim, Hyun-Ju Park, Jakyung Yoo, Chong-Hwan Chang, Jeongmin Kim, Jinhwa Lee
• Journal: Future medicinal chemistry (Future Med Chem) Vol. 1 Issue 5 Pg. 947-67 (Aug 2009) ISSN: 1756-8927 [Electronic] England
• PMID: 21426091 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 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

Topics

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