Discovery of 1-Amino-5H-pyrido[4,3-b]indol-4-carboxamide Inhibitors of Janus Kinase 2 (JAK2) for the Treatment of Myeloproliferative Disorders

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• 作者：Jongwon Lim ; Brandon Taoka ; Ryan D. Otte ; Kerrie Spencer ; Christopher J. Dinsmore ; Michael D. Altman ; Grace Chan ; Craig Rosenstein ; Sujata Sharma ; Hua-Poo Su ; Alexander A. Szewczak ; Lin Xu ; Hong Yin ; Joan Zugay-Murphy ; C. Gary Marshall ; Jonathan R. Young
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：October 27, 2011
• 年：2011
• 卷：54
• 期：20
• 页码：7334-7349
• 全文大小：1184K
• 年卷期：v.54,no.20(October 27, 2011)
• ISSN：1520-4804

文摘

The JAK-STAT pathway mediates signaling by cytokines, which control survival, proliferation, and differentiation of a variety of cells. In recent years, a single point mutation (V617F) in the tyrosine kinase JAK2 was found to be present with a high incidence in myeloproliferative disorders (MPDs). This mutation led to hyperactivation of JAK2, cytokine-independent signaling, and subsequent activation of downstream signaling networks. The genetic, biological, and physiological evidence suggests that JAK2 inhibitors could be effective in treating MPDs. De novo design efforts of new scaffolds identified 1-amino-5H-pyrido[4,3-b]indol-4-carboxamides as a new viable lead series. Subsequent optimization of cell potency, metabolic stability, and off-target activities of the leads led to the discovery of 7-(2-aminopyrimidin-5-yl)-1-{[(1R)-1-cyclopropyl-2,2,2-trifluoroethyl]amino}-5H-pyrido[4,3-b]indole-4-carboxamide (65). Compound 65 is a potent, orally active inhibitor of JAK2 with excellent selectivity, PK profile, and in vivo efficacy in animal models.