Discovery of CP-690,550: A Potent and Selective Janus Kinase (JAK) Inhibitor for the Treatment of Autoimmune Diseases and Organ Transplant Rejection
| Autor: | Brett M. Lillie, Matthew Frank Brown, Bret D. Perry, Mark Edward Flanagan, Chakrapani Subramanyam, Kudlacz Elizabeth M, Jianmin Sun, Michael B. Fisher, Todd Andrew Blumenkopf, Chang Shang-Poa, Perry S. Sawyer, Timothy J. Strelevitz, Sandra P. McCurdy, William H. Brissette, Craig R. Kent, Paul S. Changelian, Jonathan L. Doty, Michael John Munchhof, David A Whipple, Jeffrey M. Casavant, Michael Hines, Kelly S. Magnuson, Eileen A. Elliott |
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| Rok vydání: | 2010 |
| Předmět: |
Graft Rejection
Male Models Molecular Cell Membrane Permeability T-Lymphocytes Inflammatory arthritis T cell Cyclohexane Monoterpenes In Vitro Techniques Pharmacology Lymphocyte Activation Autoimmune Diseases Rats Sprague-Dawley Structure-Activity Relationship Dogs Piperidines Cell Line Tumor Drug Discovery medicine Animals Humans Structure–activity relationship Pyrroles Tissue Distribution Cell Proliferation Janus Kinases chemistry.chemical_classification Chemistry Stereoisomerism Blood Proteins Fibroblasts medicine.disease Rats Macaca fascicularis Pyrimidines Enzyme medicine.anatomical_structure Cell culture Rheumatoid arthritis Monoterpenes Molecular Medicine Female Caco-2 Cells Janus kinase Tyrosine kinase Protein Binding |
| Zdroj: | Journal of Medicinal Chemistry. 53:8468-8484 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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