Structure-Based Design of Selective Janus Kinase 2 Imidazo[4,5-d]pyrrolo[2,3-b]pyridine Inhibitors

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• 作者：Amy C. Hart ; Gretchen M. Schroeder ; Honghe Wan ; James Grebinski ; Jennifer Inghrim ; James Kempson ; Junqing Guo ; William J. Pitts ; John S. Tokarski ; John S. Sack ; Javed A. Khan ; Jonathan Lippy ; Matthew V. Lorenzi ; Dan You ; Theresa McDevitt ; Ragini Vuppugalla ; Yueping Zhang ; Louis J. Lombardo ; George L. Trainor ; Ashok V. Purandare
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：August 13, 2015
• 年：2015
• 卷：6
• 期：8
• 页码：845-849
• 全文大小：384K
• ISSN：1948-5875

文摘

Early hit to lead work on a pyrrolopyridine chemotype provided access to compounds with biochemical and cellular potency against Janus kinase 2 (JAK2). Structure-based drug design along the extended hinge region of JAK2 led to the identification of an important H-bond interaction with the side chain of Tyr 931, which improved JAK family selectivity. The 4,5-dimethyl thiazole analogue 18 demonstrated high levels of JAK family selectivity and was identified as a promising lead for the program.