Discovery of GS-9973, a Selective
and Orally Efficacious
Inhibitor of Spleen Tyrosine Kinase
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Abstract
Spleen
tyrosine kinase (Syk) is an attractive drug target in autoimmune,
inflammatory, and oncology disease indications. The most advanced
Syk inhibitor, R406, <b>1</b> (or its prodrug form fostamatinib, <b>2</b>), 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 <b>1</b>. 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-<i>a</i>]pyrazine Syk inhibitors. This work culminated in the identification
of GS-9973, <b>68</b>, a highly selective and orally efficacious
Syk inhibitor which is currently undergoing clinical evaluation for
autoimmune and oncology indications