SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines as potent and selective Janus kinase 2 (JAK2) inhibitors

  • Bioorg Med Chem Lett. 2012 Dec 15;22(24):7653-8. doi: 10.1016/j.bmcl.2012.10.007.
Timothy Forsyth  1 ,  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
Affiliations
  • 1. Exelixis, Department of Drug Discovery, 169 Harbor Way, South San Francisco, CA 94083, USA.
PMID: 23127890 DOI: 10.1016/j.bmcl.2012.10.007
Abstract

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.

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