Novel Vanilloid Receptor-1 Antagonists: 2. Structure-Activity Relationships of 4-Oxopyrimidines Leading to the Selection of a Clinical Candidate

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• 作者：Elizabeth M. Doherty ; Christopher Fotsch ; Anthony W. Bannon ; Yunxin Bo ; Ning Chen ; Celia Dominguez ; James Falsey ; Narender R. Gavva ; Jodie Katon ; Thomas Nixey ; Vassil I. Ognyanov ; Liping Pettus ; Robe
• 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：3515 - 3527
• 全文大小：209K
• 年卷期：v.50,no.15(July 26, 2007)
• ISSN：1520-4804

文摘

A series of novel 4-oxopyrimidine TRPV1 antagonists was evaluated in assays measuring the blockade ofcapsaicin or acid-induced influx of calcium into CHO cells expressing TRPV1. The investigation of thestructure-activity relationships in the heterocyclic A-region revealed the optimum pharmacophoric elementsrequired for activity in this series and resulted in the identification of subnanomolar TRPV1 antagonists.The most potent of these antagonists were thoroughly profiled in pharmacokinetic assays. Optimization ofthe heterocyclic A-region led to the design and synthesis of 23, a compound that potently blocked multiplemodes of TRPV1 activation. Compound 23 was shown to be effective in a rodent "on-target" biochemicalchallenge model (capsaicin-induced flinch, ED₅₀ = 0.33 mg/kg p.o.) and was antihyperalgesic in a modelof inflammatory pain (CFA-induced thermal hyperalgesia, MED = 0.83 mg/kg, p.o.). Based on its in vivoefficacy and pharmacokinetic profile, compound 23 (N-{4-[6-(4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-benzothiazol-2-yl}-acetamide; AMG 517) was selected for further evaluation in human clinical trials.