SAR and in vivo evaluation of 4-aryl-2-aminoalkylpyrimidines

Bioorg. Med. Chem. Lett. · Dec 2012

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

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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- 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, and Peiwen Yu.
- Exelixis, Department of Drug Discovery, 169 Harbor Way, South San Francisco, CA 94083, USA.
- Bioorg. Med. Chem. Lett. 2012 Dec 15; 22 (24): 7653-8.
AbstractWe 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.Copyright © 2012 Elsevier Ltd. All rights reserved.

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

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