☆ 4.7 Article

Biarylpyrazolyl Oxadiazole as Potent, Selective, Orally Bioavailable Cannabinoid-1 Receptor Antagonists for the Treatment of Obesity

JOURNAL OF MEDICINAL CHEMISTRY (2008)

Journal

JOURNAL OF MEDICINAL CHEMISTRY

Volume 51, Issue 22, Pages 7216-7233

Publisher

AMER CHEMICAL SOC

DOI: 10.1021/jm800843r

Keywords

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Categories

Chemistry, Medicinal

Funding

Center for Biological Modulators of the 21st Century Frontier RD Program [CBM32-B2000-01-02-00]
Ministry of Science, Republic of Korea
Korean Government (MOEHRD) [KRF-2007-412-J04001]

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Abstract

Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC50 similar to 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxa- diazole 43c as a promising precandidate for the development as an antiobesity agent.

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