Discovery of 1-Methyl-1H-imidazole Derivatives as Potent Jak2 Inhibitors

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• 作者：Qibin Su ; Stephanos Ioannidis ; Claudio Chuaqui ; Lynsie Almeida ; Marat Alimzhanov ; Geraldine Bebernitz ; Kirsten Bell ; Michael Block ; Tina Howard ; Shan Huang ; Dennis Huszar ; Jon A. Read ; Caroline Rivard Costa ; Jie Shi ; Mei Su ; Minwei Ye ; Michael Zinda
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：January 9, 2014
• 年：2014
• 卷：57
• 期：1
• 页码：144-158
• 全文大小：698K
• ISSN：1520-4804

文摘

Structure based design, synthesis, and biological evaluation of a novel series of 1-methyl-1H-imidazole, as potent Jak2 inhibitors to modulate the Jak/STAT pathway, are described. Using the C-ring fragment from our first clinical candidate AZD1480 (24), optimization of the series led to the discovery of compound 19a, a potent, orally bioavailable Jak2 inhibitor. Compound 19a displayed a high level of cellular activity in hematopoietic cell lines harboring the V617F mutation and in murine BaF3 TEL-Jak2 cells. Compound 19a demonstrated significant tumor growth inhibition in a UKE-1 xenograft model within a well-tolerated dose range.