Identification of Novel Cannabinoid CB1 Receptor Antagonists by Using Virtual Screening with a Pharmacophore Model

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• 作者：Hongwu Wang ; Ruth A. Duffy ; George C. Boykow ; Samuel Chackalamannil ; Vincent S. Madison
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：April 24, 2008
• 年：2008
• 卷：51
• 期：8
• 页码：2439 - 2446
• 全文大小：446K
• 年卷期：v.51,no.8(April 24, 2008)
• ISSN：1520-4804

文摘

CB1 receptor antagonists have proven to be clinically effective in treating obesity and related disorders. We report here the identification of a novel class of azetidinone CB1 antagonists by using virtual screening methods. For this purpose, we developed a pharmacophore model based on known representative CB1 antagonists and employed it to screen a database of about a half million Schering-Plough compounds. We applied a stepwise filtering protocol based on molecular weight, compound availability, and a modified rule-of-five to reduce the number of hits. We then combined Bayesian modeling and clustering techniques to select a final set of 420 compounds for in vitro testing. Five compounds were found to have >50% inhibition at 100 nM in a CB1 competitive binding assay and were further characterized by using both CB1 and CB2 assays. The most potent compound has a CB1 K_i of 53 nM and >5-fold selectivity against the CB2 receptor.