Synthesis and biological evaluation of 1-(2,4,5-trisubstituted phenyl)-3-(5-cyanopyrazin-2-yl)ureas as potent Chk1 kinase inhibitors

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• 作者：Gaoquan Li ; Lisa A. Hasvold ; Zhi-Fu Tao ; Gary T. Wang ; Stephen L. Gwaltney II ; Jyoti Patel ; Peter Kovar ; Robert B. Credo ; Zehan Chen ; Haiying Zhang et al.
• 关键词：Urea ; Chk1 inhibitor
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2006
• 期刊代码：10_0960894x
• 类别：ch
• 出版时间：15 April 2006
• 卷：16
• 期：8
• 页码：2293-2298
• 文件大小：202 K

摘要

Based on the X-ray crystallography of our lead compound 1-(5-chloro-2,4-dimethoxyphenyl)-3-(5-cyanopyrazin-2-yl)urea in the checkpoint kinase 1 (Chk1) enzyme, we modified R⁴, and to a lesser extent, R², and R⁵ of the phenyl ring, and made a variety of N-aryl-N′-pyrazinylurea Chk1 inhibitors. Enzymatic activity less than 20 nM was observed in 15 of 41 compounds. Compound 8i provided the best overall results in the cellular assays as it abrogated doxorubicin-induced cell cycle arrest (IC₅₀ = 1.7 μM) and enhanced doxorubicin cytotoxicity (IC₅₀ = 0.44 μM) while displaying no single agent activity.