Discovery of GS-9973, a Selective and Orally Efficacious Inhibitor of Spleen Tyrosine Kinase

• Published in: Journal of medicinal chemistry Vol. 57; no. 9; pp. 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: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.05.2014; Amer Chemical Soc
• Subjects: Administration, Oral; Animals; Cells, Cultured; Chemistry, Medicinal; Drug Discovery; Humans; Indazoles - administration & dosage; Indazoles - chemistry; Indazoles - pharmacology; Life Sciences & Biomedicine; Magnetic Resonance Spectroscopy; Mice; Pharmacology & Pharmacy; 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; Science & Technology; Spectrometry, Mass, Electrospray Ionization; Spleen - drug effects; Spleen - enzymology; Structure-Activity Relationship; RHEUMATOID-ARTHRITIS; POTENT; ACTIVATION; SYK; MODELS; INFLAMMATION; FOSTAMATINIB DISODIUM; DISEASE; NON-HODGKIN-LYMPHOMA; EXPRESSION

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...