MARK inhibitors: Declaring a No-Go decision on a chemical series based on extensive DMPK experimentation

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• 作者：Andrew M. Haidle^a ; ; Kaleen K. Childers^a ; Anna A. Zabierek^a ; Jason D. Katz^a ; James P. Jewell^a ; Yongquan Hou^a ; Michael D. Altman^a ; Alexander Szewczak^c ; Dapeng Chen^b ; Andreas Harsch^b ; Mansuo Hayashi^d ; Lee Warren^d ; Michael Hutton^d ; Hugh Nuthall^d ; Matt G. Stanton^a ; Ian W. Davies^a ; Ben Munoz^a ; Alan Northrup^a
• 关键词：MARK ; Kinase ; Pharmacokinetics ; Optimization ; Physical properties ; Disposition study ; In vitro&ndash ; in vivo correlation
• 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：109-113
• 全文大小：1396 K
• 卷排序：27

文摘

Attempts to optimize pharmacokinetic properties in a promising series of pyrrolopyrimidinone MARK inhibitors for the treatment of Alzheimer’s disease are described. A focus on physical properties and ligand efficiency while prosecuting this series afforded key tool compounds that revealed a large discrepancy in the rat in vitro–in vivo DMPK (Drug Metabolism/Pharmacokinetics) correlation. These differences prompted an in vivo rat disposition study employing a radiolabeled representative of the series, and the results from this experiment justified the termination of any further optimization efforts.