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

作者：Flanagan Mark E^*; Blumenkopf Todd A; Brissette William H; Brown Matthew F; Casavant Jeffrey M; Shang Poa Chang; Doty Jonathan L; Elliott Eileen A; Fisher Michael B; Hines Michael; Kent Craig; Kudlacz Elizabeth M; Lillie Brett M; Magnuson Kelly S; McCurdy Sandra P; Munchhof Michael J; Perry Bret D; Sawyer Perry S; Strelevitz Timothy J; Subramanyam Chakrapani; Sun Jianmin; Whipple David A; Changelian Paul S

来源：Journal of Medicinal Chemistry, 2010, 53(24): 8468-8484.

DOI：10.1021/jm1004286

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.

• 出版日期2010-12-23