Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase
Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase
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DOI：
10.1021/jm500228a
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发表时间：
2014-05-08
影响因子：
7.3
通讯作者：
Mitchell, Scott A.
中科院分区：
文献类型：
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作者：
Currie, Kevin S.;Kropf, Jeffrey E.;Mitchell, Scott A.
脾酪氨酸激酶(Syk)在自身免疫性、炎症性和肿瘤性疾病中是一个有吸引力的药物靶点。最先进的Syk抑制剂R406，1(或其前体药物福斯塔替尼，2)已在多个治疗适应症中显示出有效性，但其临床进展受到剂量限制副作用的阻碍，这些副作用至少部分归因于1的靶外活性。预计更具选择性的Syk抑制剂将提供更大的治疗窗口。在此，我们报道了一系列新的咪唑并[1，2-a]吡嗪Syk抑制剂的发现和优化。这项工作最终确定了GS-9973，68，一种高度选择性和口服有效的Syk抑制剂，目前正在进行自身免疫和肿瘤学适应症的临床评估。
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.