Discovery of Mer Specific Tyrosine Kinase Inhibitors for the Treatment and Prevention of Thrombosis

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• 作者：Weihe Zhang ; Andrew L. McIver ; Michael A. Stashko ; Deborah DeRyckere ; Brian R. Branchford ; Debra Hunter ; Dmitri Kireev ; Michael J. Miley ; Jacqueline Norris-Drouin ; Wendy M. Stewart ; Minjung Lee ; Susan Sather ; Yingqiu Zhou ; Jorge A. Di Paola ; Mischa Machius ; William P. Janzen ; H. Shelton Earp ; Douglas K. Graham ; Stephen V. Frye ; Xiaodong Wang
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：December 12, 2013
• 年：2013
• 卷：56
• 期：23
• 页码：9693-9700
• 全文大小：503K
• 年卷期：v.56,no.23(December 12, 2013)
• ISSN：1520-4804

文摘

The role of Mer kinase in regulating the second phase of platelet activation generates an opportunity to use Mer inhibitors for preventing thrombosis with diminished likelihood for bleeding as compared to current therapies. Toward this end, we have discovered a novel, Mer kinase specific substituted-pyrimidine scaffold using a structure-based drug design and a pseudo ring replacement strategy. The cocrystal structure of Mer with two compounds (7 and 22) possessing distinct activity have been determined. Subsequent SAR studies identified compound 23 (UNC2881) as a lead compound for in vivo evaluation. When applied to live cells, 23 inhibits steady-state Mer kinase phosphorylation with an IC₅₀ value of 22 nM. Treatment with 23 is also sufficient to block EGF-mediated stimulation of a chimeric receptor containing the intracellular domain of Mer fused to the extracellular domain of EGFR. In addition, 23 potently inhibits collagen-induced platelet aggregation, suggesting that this class of inhibitors may have utility for prevention and/or treatment of pathologic thrombosis.