Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection

被引:287
作者
Flanagan, Mark E. [1 ]
Blumenkopf, Todd A. [2 ]
Brissette, William H. [3 ]
Brown, Matthew F. [1 ]
Casavant, Jeffrey M. [1 ]
Shang-Poa, Chang [4 ]
Doty, Jonathan L.
Elliott, Eileen A. [1 ]
Fisher, Michael B. [5 ]
Hines, Michael [1 ]
Kent, Craig [1 ]
Kudlacz, Elizabeth M. [2 ]
Lillie, Brett M. [1 ]
Magnuson, Kelly S. [2 ]
McCurdy, Sandra P. [1 ]
Munchhof, Michael J. [1 ]
Perry, Bret D. [1 ]
Sawyer, Perry S. [1 ]
Strelevitz, Timothy J. [1 ]
Subramanyam, Chakrapani [1 ]
Sun, Jianmin [1 ]
Whipple, David A. [6 ]
Changelian, Paul S. [7 ]
机构
[1] Pfizer Global Res & Dev, Groton Labs, Groton, CT 06340 USA
[2] Pfizer Global Res & Dev, New London, CT 06320 USA
[3] Yale Univ, New Haven, CT 06520 USA
[4] Univ Connecticut, Dept Stat, Storrs, CT 06269 USA
[5] Boehringer Ingelheim Pharmaceut Inc, Ridgefield, CT 06877 USA
[6] Univ Kansas, Del Shankel Struct Biol Ctr, Lawrence, KS 66047 USA
[7] Lycera Corp, Plymouth, MI 48170 USA
关键词
SEVERE COMBINED IMMUNODEFICIENCY; RHEUMATOID-ARTHRITIS; ALLOGRAFT-REJECTION; GAMMA-CHAIN; CP-690550; IMMUNOSUPPRESSANT; CYTOKINES; MUTATION; SAFETY; IL-2;
D O I
10.1021/jm1004286
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
There is a critical need for safer and more convenient treatments for organ transplant rejection and autoimmune disorders such as rheumatoid arthritis. Janus tyrosine kinases (JAK1, JAK3) are expressed in lymphoid cells and are involved in the signaling of multiple cytokines important for various T cell functions. Blockade of the JAK1/JAK3-STAT pathway with a small molecule was anticipated to provide therapeutic immunosuppression/immunomodulation. The Pfizer compound library was screened against the catalytic domain of JAK3 resulting in the identification of a pyrrolopyrimidine-based series of inhibitors represented by CP-352,664 (2a). Synthetic analogues of 2a were screened against the JAK enzymes and evaluated in an IL-2 induced T cell blast proliferation assay. Select compounds were evaluated in rodent efficacy models of allograft rejection and destructive inflammatory arthritis. Optimization within this chemical series led to identification of CP-690,550 1, a potential first-in-class JAK inhibitor for treatment of autoimmune diseases and organ transplant rejection.
引用
收藏
页码:8468 / 8484
页数:17
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