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

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• 作者：Suk Ho Lee ; Hee Jeong Seo ; Sung-Han Lee ; Myung Eun Jung ; Ji-Hyun Park ; Hyun-Ju Park ; Jakyung Yoo ; Hoseop Yun ; Jooran Na ; Suk Youn Kang ; Kwang-Seop Song ; Min-ah Kim ; Chong-Hwan Chang ; Jeongmin Kim ; Jinh
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：November 27, 2008
• 年：2008
• 卷：51
• 期：22
• 页码：7216-7233
• 全文大小：508K
• 年卷期：v.51,no.22(November 27, 2008)
• ISSN：1520-4804

文摘

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 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-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.