Discovery of Potent and Selective Pyrazolopyrimidine Janus Kinase 2 Inhibitors

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• 作者：Emily J. Hanan ; Anne van Abbema ; Kathy Barrett ; Wade S. Blair ; Jeff Blaney ; Christine Chang ; Charles Eigenbrot ; Sean Flynn ; Paul Gibbons ; Christopher A. Hurley ; Jane R. Kenny ; Janusz Kulagowski ; Leslie Lee ; Steven R. Magnuson ; Claire Morris ; Jeremy Murray ; Richard M. Pastor ; Tom Rawson ; Michael Siu ; Mark Ultsch ; Aihe Zhou ; Deepak Sampath ; Joseph P. Lyssikatos
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：November 26, 2012
• 年：2012
• 卷：55
• 期：22
• 页码：10090-10107
• 全文大小：613K
• 年卷期：v.55,no.22(November 26, 2012)
• ISSN：1520-4804

文摘

The discovery of somatic Jak2 mutations in patients with chronic myeloproliferative neoplasms has led to significant interest in discovering selective Jak2 inhibitors for use in treating these disorders. A high-throughput screening effort identified the pyrazolo[1,5-a]pyrimidine scaffold as a potent inhibitor of Jak2. Optimization of lead compounds 7a鈥?b>b and 8 in this chemical series for activity against Jak2, selectivity against other Jak family kinases, and good in vivo pharmacokinetic properties led to the discovery of 7j. In a SET2 xenograft model that is dependent on Jak2 for growth, 7j demonstrated a time-dependent knock-down of pSTAT5, a downstream target of Jak2.