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

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    Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection
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    † Groton Laboratories, Pfizer Global Research & Development, Eastern Point Road, Groton, Connecticut 06340, United States
    ‡ Pfizer Global Research & Development, 50 Pequot Avenue, New London, Connecticut 06320, United States
    § Yale University, New Haven, Connecticut 06520, United States
    ∥ Department of Statistics, University of Connecticut, 215 Glenbrook Road U-4120, Storrs, Connecticut 06269, United States
    ⊥ Hill Road, East Lyme, Connecticut 06333, United States
    # Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut 06877, United States
    △ Del Shankel Structural Biology Center, University of Kansas, 2034 Becker Drive, Lawrence, Kansas 66047, United States
    ∇ Lycera Corporation, 46701 North Commerce Center Drive, Plymouth, Michigan 48170, United States
    *To whom correspondence should be addressed. Telephone: 860-441-0205. Fax: 860-715-4693. E-mail: [email protected]
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    Journal of Medicinal Chemistry

    Cite this: J. Med. Chem. 2010, 53, 24, 8468–8484
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    https://doi.org/10.1021/jm1004286
    Published November 24, 2010
    Copyright © 2010 American Chemical Society
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    Abstract

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    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.

    Copyright © 2010 American Chemical Society

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    Additional HSA compounds (6c, S1−S63), with initial JAK3% inhibition data. This material is available free of charge via the Internet at http://pubs.acs.org.

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    Cite this: J. Med. Chem. 2010, 53, 24, 8468–8484
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