Peripherally Selective Diphenyl Purine Antagonist of the CB1 Receptor

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• 作者：Alan Fulp ; Katherine Bortoff ; Yanan Zhang ; Rodney Snyder ; Tim Fennell ; Julie A. Marusich ; Jenny L. Wiley ; Herbert Seltzman ; Rangan Maitra
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：October 24, 2013
• 年：2013
• 卷：56
• 期：20
• 页码：8066-8072
• 全文大小：258K
• 年卷期：v.56,no.20(October 24, 2013)
• ISSN：1520-4804

文摘

Antagonists of the CB1 receptor can be useful in the treatment of several important disorders. However, to date, the only clinically approved CB1 receptor antagonist, rimonabant, was withdrawn because of adverse central nervous system (CNS)-related side effects. Since rimonabant鈥檚 withdrawal, several groups are pursuing peripherally selective CB1 antagonists. These compounds are expected to be devoid of undesirable CNS-related effects but maintain efficacy through antagonism of peripherally expressed CB1 receptors. Reported here are our latest results toward the development of a peripherally selective analog of the diphenyl purine CB1 antagonist otenabant 1. Compound 9 (N-{1-[8-(2-chlorophenyl)-9-(4-chlorophenyl)-9H-purin-6-yl]piperidin-4-yl}pentanamide) is a potent, orally absorbed antagonist of the CB1 receptor that is >50-fold selective for CB1 over CB2, highly selective for the periphery in a rodent model, and without efficacy in a series of in vivo assays designed to evaluate its ability to mitigate the central effects of 螖⁹-tetrahydrocannabinol through the CB1 receptor.