SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors
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- 作者：Timothy Forsyth ; Patrick C. Kearney ; Byung Gyu Kim ; byunggyu72kim@gmail.com ; Henry W.B. Johnson ; hjohnson@onyx.com ; Naing Aay ; Arlyn Arcalas ; David S. Brown ; Vicky Chan ; Jeff Chen ; Hongwang Du ; Sergey Epshteyn ; Adam A. Galan ; Tai P. Huynh ; Mohamed A. Ibrahim ; Brian Kane ; Elena S. Koltun ; Grace Mann ; Lisa E. Meyr ; Matthew S. Lee ; Gary L. Lewis ; Robin T. Noguchi ; Michael Pack ; Brian H. Ridgway ; Xian Shi ; Craig S. Takeuchi ; Peiwen Zu ; James W. Leahy ; John M. Nuss ; Ron Aoyama ; Stefan Engst ; Steven B. Gendreau ; Robert Kassees ; Jia Li ; Shwu-Hwa Lin ; Jean-Francois Martini ; Thomas Stout ; Philip Tong ; John Woolfrey ; Wentao Zhang ; Peiwen Yu
- 关键词：JAK1 ; JAK2 ; JAK3 ; 4-Aryl-2-aminoalkylpyrimidine
- 刊名：Bioorganic and Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：15 December, 2012
- 年：2012
- 卷：22
- 期：24
- 页码：7653-7658
- 全文大小：1905 K
文摘
We report the discovery of a series of 4-aryl-2-aminoalkylpyrimidine derivatives as potent and selective JAK2 inhibitors. High throughput screening of our in-house compound library led to the identification of hit 1, from which optimization resulted in the discovery of highly potent and selective JAK2 inhibitors. Advanced lead 10d demonstrated a significant dose-dependent pharmacodynamic and antitumor effect in a mouse xenograft model. Based upon the desirable profile of 10d (XL019) it was advanced into clinical trials.