Aminopyridine-Based c-Jun N-Terminal Kinase Inhibitors with Cellular Activity and Minimal Cross-Kinase Activity

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• 作者：Bruce G. Szczepankiewicz ; Christi Kosogof ; Lissa T. J. Nelson ; Gang Liu ; Bo Liu ; Hongyu Zhao ; Michael D. Serby ; Zhili Xin ; Mei Liu ; Rebecca J. Gum ; Deanna L. Haasch ; Sanyi Wang ; Jill E. Clampit ; Eric
• 刊名：Journal of Medicinal Chemistry
• 出版年：2006
• 出版时间：June 15, 2006
• 年：2006
• 卷：49
• 期：12
• 页码：3563 - 3580
• 全文大小：424K
• 年卷期：v.49,no.12(June 15, 2006)
• ISSN：1520-4804

文摘

The c-Jun N-terminal kinases (JNK-1, -2, and -3) are members of the mitogen activated protein (MAP)kinase family of enzymes. They are activated in response to certain cytokines, as well as by cellular stressesincluding chemotoxins, peroxides, and irradiation. They have been implicated in the pathology of a varietyof different diseases with an inflammatory component including asthma, stroke, Alzheimer's disease, andtype 2 diabetes mellitus. In this work, high-throughput screening identified a JNK inhibitor with an excellentkinase selectivity profile. Using X-ray crystallography and biochemical screening to guide our leadoptimization, we prepared compounds with inhibitory potencies in the low-double-digit nanomolar range,activity in whole cells, and pharmacokinetics suitable for in vivo use. The new compounds were over 1000-fold selective for JNK-1 and -2 over other MAP kinases including ERK2, p38, and p38 and showed littleinhibitory activity against a panel of 74 kinases.