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

被引：140

作者：

Currie, Kevin S. ^{[1
]}

Kropf, Jeffrey E. ^{[1
]}

Lee, Tony ^{[1
]}

Blomgren, Peter ^{[1
]}

Xu, Jianjun ^{[1
]}

Zhao, Zhongdong ^{[1
]}

Gallion, Steve ^{[5
]}

Whitney, J. Andrew ^{[2
]}

Maclin, Deborah ^{[3
]}

Lansdon, Eric B. ^{[4
]}

Maciejewski, Patricia ^{[2
]}

Rossi, Ann Marie ^{[2
]}

Rong, Hong ^{[2
]}

Macaluso, Jennifer ^{[2
]}

Barbosa, James ^{[2
]}

Di Paolo, Julie A. ^{[2
]}

Mitchell, Scott A. ^{[1
]}

机构：

[1] Gilead Sci Inc, Dept Chem, Branford, CT 06405 USA

[2] Gilead Sci Inc, Dept Biol, Branford, CT 06405 USA

[3] Gilead Sci Inc, Dept Drug Metab, Branford, CT 06405 USA

[4] Gilead Sci Inc, Dept Struct Chem, Foster City, CA 94404 USA

[5] Atheon Pharma Inc, Dept Informat & Modeling, Waltham, MA 02451 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 09期

关键词：

NON-HODGKIN-LYMPHOMA; RHEUMATOID-ARTHRITIS; FOSTAMATINIB DISODIUM; SYK; INFLAMMATION; DISEASE; MODELS; POTENT; ACTIVATION; EXPRESSION;

D O I：

10.1021/jm500228a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

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.

引用

页码：3856 / 3873

页数：18

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