Discovery of 5-Chloro-N2-[(1S)-1-(5-fluoropyrimidin-2-yl)ethyl]-N4-(5-methyl-1H-pyrazol-3-yl)pyrimidine-2,4-diamine (AZD1480) as a Novel Inhibitor of

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• 作者：Stephanos Ioannidis ; Michelle L. Lamb ; Tao Wang ; Lynsie Almeida ; Michael H. Block ; Audrey M. Davies ; Bo Peng ; Mei Su ; Hai-Jun Zhang ; Ethan Hoffmann ; Caroline Rivard ; Isabelle Green ; Tina Howard ; Hannah Pollard ; Jon Read ; Marat Alimzhanov ; Geraldine Bebernitz ; Kirsten Bell ; Minwei Ye ; Dennis Huszar ; Michael Zinda
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：January 13, 2011
• 年：2011
• 卷：54
• 期：1
• 页码：262-276
• 全文大小：1239K
• 年卷期：v.54,no.1(January 13, 2011)
• ISSN：1520-4804

文摘

The myeloproliferative neoplasms, polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis are a heterogeneous but related group of hematological malignancies characterized by clonal expansion of one or more myeloid lineages. The discovery of the Jak2 V617F gain of function mutation highlighted Jak2 as a potential therapeutic target in the MPNs. Herein, we disclose the discovery of a series of pyrazol-3-yl pyrimidin-4-amines and the identification of 9e (AZD1480) as a potent Jak2 inhibitor. 9e inhibits signaling and proliferation of Jak2 V617F cell lines in vitro, demonstrates in vivo efficacy in a TEL-Jak2 model, has excellent physical properties and preclinical pharmacokinetics, and is currently being evaluated in Phase I clinical trials.