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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Flanagan ME, Blumenkopf TA, Brissette WH, Brown MF, Casavant JM, Shang-Poa C, Doty JL, Elliott EA, Fisher MB, Hines M, Kent C, Kudlacz EM, Lillie BM, Magnuson KS, McCurdy SP, Munchhof MJ, Perry BD, Sawyer PS, Strelevitz TJ, Subramanyam C, Sun J, Whipple DA, Changelian PS

Discovery of CP-690,550: a potent and selective Janus kinase (JAK) inhibitor for the treatment of autoimmune diseases and organ transplant rejection.

J Med Chem. 2010 Dec 23;53(24):8468-84. doi: 10.1021/jm1004286. Epub 2010 Nov 24.

PubMed ID
21105711 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
TofacitinibCytochrome P450 2C19IC 50 (nM)>52000N/AN/ADetails
TofacitinibCytochrome P450 3A4IC 50 (nM)>52000N/AN/ADetails
TofacitinibNon-receptor tyrosine-protein kinase TYK2IC 50 (nM)34N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK2IC 50 (nM)1.6N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3IC 50 (nM)1N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3IC 50 (nM)3.2N/AN/ADetails
TofacitinibTyrosine-protein kinase JAK3IC 50 (nM)3.3N/AN/ADetails