In Vitro Intrinsic Clearance-Based Optimization of N3-Phenylpyrazinones as Corticotropin-Releasing Factor-1 (CRF1) Receptor Antagonists

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• 作者：Richard A. Hartz ; Vijay T. Ahuja ; Maria Rafalski ; William D. Schmitz ; Allison B. Brenner ; Derek J. Denhart ; Jonathan L. Ditta ; Jeffrey A. Deskus ; Eddy W. Yue ; Argyrios G. Arvanitis ; Snjezana Lelas ; Yu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：July 23, 2009
• 年：2009
• 卷：52
• 期：14
• 页码：4161-4172
• 全文大小：875K
• 年卷期：v.52,no.14(July 23, 2009)
• ISSN：1520-4804

文摘

A series of pyrazinone-based heterocycles was identified as potent and orally active corticotropin-releasing factor-1 (CRF₁) receptor antagonists. Selected compounds proved efficacious in an anxiety model in rats; however, pharmacokinetic properties were not optimal. In this article, we describe an in vitro intrinsic clearance-based approach to the optimization of pyrazinone-based CRF₁ receptor antagonists wherein sites of metabolism were identified by incubation with human liver microsomes. It was found that the rate of metabolism could be decreased by incorporation of appropriate substituents at the primary sites of metabolism. This led to the discovery of compound 12x, a highly potent (IC₅₀ = 1.0 nM) and selective CRF₁ receptor antagonist with good oral bioavailability (F = 52%) in rats and efficacy in the defensive withdrawal anxiety test in rats.