SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors
作者:Timothy Forsyth、Patrick C. Kearney、Byung Gyu Kim、Henry W.B. Johnson、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
DOI:10.1016/j.bmcl.2012.10.007
日期:2012.12
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. (C) 2012 Elsevier Ltd. All rights reserved.