Structure guided design of a series of selective pyrrolopyrimidinone MARK inhibitors

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• 作者：Jason D. Katz^a ; ^{jason_katz2@merck.com} ; Andrew Haidle^a ; Kaleen K. Childers^a ; Anna A. Zabierek^a ; James P. Jewell^a ; Yongquan Hou^a ; Michael D. Altman^b ; Alexander Szewczak^c ; Dapeng Chen^d ; Andreas Harsch^d ; Mansuo Hayashi^e ; Lee Warren^e ; Michael Hutton^e ; Hugh Nuthall^e ; Hua-Poo Su^f ; Sanjeev Munshi^f ; Matt G. Stanton^a ; Ian W. Davies^a ; Ben Munoz^a ; Alan Northrup^a
• 关键词：MARK ; Kinase ; Tau ; Alzheimer&rsquo ; s disease ; Pyrrolopyrimidinone
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2017
• 出版时间：1 January 2017
• 年：2017
• 卷：27
• 期：1
• 页码：114-120
• 全文大小：1433 K
• 卷排序：27

文摘

The initial structure activity relationships around an isoindoline uHTS hit will be described. Information gleaned from ligand co-crystal structures allowed for rapid refinements in both MARK potency and kinase selectivity. These efforts allowed for the identification of a compound with properties suitable for use as an in vitro tool compound for validation studies on MARK as a viable target for Alzheimer’s disease.Figure options