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J Med Chem. 2008 Apr 24;51(8):2439-46. doi: 10.1021/jm701519h. Epub 2008 Mar 26.

Identification of novel cannabinoid CB1 receptor antagonists by using virtual screening with a pharmacophore model.

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Department of Structural Chemistry, CNS Biological Research, and CNS/CV Chemistry, Schering-Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA.


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.

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