Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase

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• 作者：Kevin S. Currie ; Jeffrey E. Kropf ; Tony Lee ; Peter Blomgren ; Jianjun Xu ; Zhongdong Zhao ; Steve Gallion ; J. Andrew Whitney ; Deborah Maclin ; Eric B. Lansdon ; Patricia Maciejewski ; Ann Marie Rossi ; Hong Rong ; Jennifer Macaluso ; James Barbosa ; Julie A. Di Paolo ; Scott A. Mitchell
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：May 8, 2014
• 年：2014
• 卷：57
• 期：9
• 页码：3856-3873
• 全文大小：754K
• 年卷期：v.57,no.9(May 8, 2014)
• ISSN：1520-4804

文摘

Spleen tyrosine kinase (Syk) is an attractive drug target in autoimmune, inflammatory, and oncology disease indications. The most advanced Syk inhibitor, R406, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered by dose-limiting adverse effects that have been attributed, at least in part, to the off-target activities of 1. It is expected that a more selective Syk inhibitor would provide a greater therapeutic window. Herein we report the discovery and optimization of a novel series of imidazo[1,2-a]pyrazine Syk inhibitors. This work culminated in the identification of GS-9973, 68, a highly selective and orally efficacious Syk inhibitor which is currently undergoing clinical evaluation for autoimmune and oncology indications.