Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase
Autor: | J. Andrew Whitney, Kevin S. Currie, Deborah Maclin, James Barbosa, Kropf Jeffrey E, Ann Marie Rossi, Eric B. Lansdon, Jennifer Macaluso, Scott A. Mitchell, Hong Rong, Tony Lee, Jianjun Xu, Steve Gallion, Patricia Maciejewski, Julie Di Paolo, Peter A. Blomgren, Zhongdong Zhao |
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Rok vydání: | 2014 |
Předmět: |
Spectrometry
Mass Electrospray Ionization Indazoles Magnetic Resonance Spectroscopy Administration Oral Syk Pharmacology Fostamatinib Mice Structure-Activity Relationship Drug Discovery medicine Animals Humans Structure–activity relationship Adverse effect Protein Kinase Inhibitors Cells Cultured Chemistry Drug discovery hemic and immune systems Protein-Tyrosine Kinases Prodrug Highly selective Rats Pyrazines Molecular Medicine Clinical evaluation Spleen medicine.drug |
Zdroj: | Journal of Medicinal Chemistry. 57:3856-3873 |
ISSN: | 1520-4804 0022-2623 |
DOI: | 10.1021/jm500228a |
Popis: | 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. |
Databáze: | OpenAIRE |
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