Novel Vanilloid Receptor-1 Antagonists: 1. Conformationally Restricted Analogues of trans-Cinnamides

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• 作者：Mark H. Norman ; Jiawang Zhu ; Christopher Fotsch ; Yunxin Bo ; Ning Chen ; Partha Chakrabarti ; Elizabeth M. Doherty ; Narender R. Gavva ; Nobuko Nishimura ; Thomas Nixey ; Vassil I. Ognyanov ; Robert M. Rzasa
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：July 26, 2007
• 年：2007
• 卷：50
• 期：15
• 页码：3497 - 3514
• 全文大小：326K
• 年卷期：v.50,no.15(July 26, 2007)
• ISSN：1520-4804

文摘

The vanilloid receptor-1 (VR1 or TRPV1) is a member of the transient receptor potential (TRP) family ofion channels and plays a role as an integrator of multiple pain-producing stimuli. From a high-throughputscreening assay, measuring calcium uptake in TRPV1-expressing cells, we identified an N-aryl trans-cinnamide (AMG9810, compound 9) that acts as a potent TRPV1 antagonist. We have demonstrated theantihyperalgesic properties of 9 in vivo and have also reported the discovery of novel, orally bioavailablecinnamides derived from this lead. Herein, we expand our investigations and describe the synthesis andbiological evaluation of a series of conformationally constrained analogues of the s-cis conformer of compound9. These investigations resulted in the identification of 4-amino- and 4-oxopyrimidine cores as suitableisosteric replacements for the trans-acrylamide moiety. The best examples from this series, pyrimidines 79and 74, were orally bioavailable and exhibited potent antagonism of both rat (IC₅₀ = 4.5 and 0.6 nM,respectively) and human TRPV1 (IC₅₀ = 7.4 and 3.7 nM, respectively). In addition, compound 74 wasshown to be efficacious at blocking a TRPV1-mediated physiological response in vivo in the capsaicin-induced hypothermia model in rats; however, it was ineffective at preventing thermal hyperalgesia inducedby complete Freund's adjuvant in rats.