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, 1 (or its prodrug form fostamatinib, 2), has shown efficacy in multiple therapeutic indications, but its clinical progress has been hampered...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2014-05, Vol.57 (9), p.3856-3873
Main Authors: Currie, Kevin S, Kropf, Jeffrey E, Lee, Tony, Blomgren, Peter, Xu, Jianjun, Zhao, Zhongdong, Gallion, Steve, Whitney, J. Andrew, Maclin, Deborah, Lansdon, Eric B, Maciejewski, Patricia, Rossi, Ann Marie, Rong, Hong, Macaluso, Jennifer, Barbosa, James, Di Paolo, Julie A, Mitchell, Scott A
Format: Article
Language:English
Subjects:
Administration, Oral
Animals
Cells, Cultured
Drug Discovery
Humans
Indazoles - administration & dosage
Indazoles - chemistry
Indazoles - pharmacology
Magnetic Resonance Spectroscopy
Mice
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - chemistry
Protein Kinase Inhibitors - pharmacology
Protein-Tyrosine Kinases - antagonists & inhibitors
Pyrazines - administration & dosage
Pyrazines - chemistry
Pyrazines - pharmacology
Rats
Spectrometry, Mass, Electrospray Ionization
Spleen - drug effects
Spleen - enzymology
Structure-Activity Relationship
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Summary: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.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm500228a