Discovery of 4-(Benzylaminomethylene)isoquinoline-1,3-(2H,4H)-diones and 4-[(Pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-diones as Potent and Selective Inhibitors

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• 作者：Hwei-Ru Tsou ; Xiaoxiang Liu ; Gary Birnberg ; Joshua Kaplan ; Mercy Otteng ; Tritin Tran ; Kristina Kutterer ; Zhilian Tang ; Ron Suayan ; Arie Zask ; Malini Ravi ; Angela Bretz ; Mary Grillo ; John P. McGinnis
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2289-2310
• 全文大小：376K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

The series of 4-(benzylaminomethylene)isoquinoline-1,3-(2H,4H)-dione and 4-[(pyridylmethyl)aminomethylene]isoquinoline-1,3-(2H,4H)-dione derivatives reported here represents a novel class of potential antitumor agents, which potently and selectively inhibit CDK4 over CDK2 and CDK1. In the benzylamino headpiece, a 3-OH substituent is required on the phenyl ring for CDK4 inhibitory activity, which is further enhanced when an iodo, aryl, heteroaryl, t-butyl, or cyclopentyl substituent is introduced at the C-6 position of the isoquinoline-1,3-dione core. To circumvent the metabolic liability associated with the phenolic OH group on the 4-substituted 3-OH phenyl headpiece, we take two approaches: first, introduce a nitrogen o- or p- to the 3-OH group in the phenyl ring; second, replace the phenyl headpiece with N-substituted 2-pyridones. We present here the synthesis, SAR data, metabolic stability data, and a CDK4 mimic model that explains the binding, potency, and selectivity of our CDK4 selective inhibitors.