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 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.
Department of Chemistry, ‡Department of Biology, and §Department of Drug Metabolism, Gilead Sciences, Inc. , Branford, Connecticut 06405, United States.
Kevin S
KS
Currie
Jeffrey E
JE
Kropf
Tony
T
Lee
Peter
P
Blomgren
Jianjun
J
Xu
Zhongdong
Z
Zhao
Steve
S
Gallion
J Andrew
JA
Whitney
Deborah
D
Maclin
Eric B
EB
Lansdon
Patricia
P
Maciejewski
Ann Marie
AM
Rossi
Hong
H
Rong
Jennifer
J
Macaluso
James
J
Barbosa
Julie A
JA
Di Paolo
Scott A
SA
Mitchell
D000284:Administration, Oral; D000818:Animals; D002478:Cells, Cultured; D055808:Drug Discovery; D006801:Humans; D007191:Indazoles / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013154:Spleen / Q000187:drug effects* / Q000201:enzymology; D013329:Structure-Activity Relationship; D009025:Morpholines
D007191:Indazoles; D047428:Protein Kinase Inhibitors; D011505:Protein-Tyrosine Kinases; D011719:Pyrazines; C000589391:6-(1H-indazol-6-yl)-N-(4-morpholinophenyl)imidazo(1,2-a)pyrazin-8-amine; D009025:Morpholines