2 research outputs found
Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase
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 imidazoÂ[1,2-<i>a</i>]Âpyrazine 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
Discovery of Potent and Selective Tricyclic Inhibitors of Bruton’s Tyrosine Kinase with Improved Druglike Properties
In our continued effort to discover
and develop best-in-class Bruton’s tyrosine kinase (Btk) inhibitors
for the treatment of B-cell lymphomas, rheumatoid arthritis, and systemic
lupus erythematosus, we devised a series of novel tricyclic compounds
that improved upon the druglike properties of our previous chemical
matter. Compounds exemplified by <b>G-744</b> are highly potent,
selective for Btk, metabolically stable, well tolerated, and efficacious
in an animal model of arthritis