Discovery of 5-(2-amino-[1,2,4]triazolo[1,5-a]pyridin-7-yl)-N-(tert-butyl)pyridine-3-sulfonamide (CZC24758), as a potent, orally bioavailable and selective inhibitor of PI3K for the treatment of inflammatory disease.
Herein, we disclose the discovery of a series of 7-substituted triazolopyridines which culminated in the identification of 14 (CZC24758), a potent, orally bioavailable small-molecule inhibitor of PI3Kγ, an attractive drug target for inflammatory and autoimmune disorders. Compound 14 has excellent selectivity across the kinome, demonstrates good potency in cell based assays and furthermore exhibits in vivo efficacy in a collagen induced arthritis model in mouse after oral dosing.
Cellzome Ltd, Chesterford Research Park, Little Chesterford CB10 1XL, UK. sunosem@hotmail.co.jp
Mihiro
M
Sunose
Kathryn
K
Bell
Katie
K
Ellard
Giovanna
G
Bergamini
Gitte
G
Neubauer
Thilo
T
Werner
Nigel
N
Ramsden
D000818:Animals; D055808:Drug Discovery; D006098:Granulocytes / Q000187:drug effects; D006860:Hydrogen Bonding; D007249:Inflammation / Q000188:drug therapy; D008297:Male; D051379:Mice; D008861:Microsomes / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000627:therapeutic use; D014230:Triazoles / Q000737:chemistry / Q000627:therapeutic use
C576911:5-(2-amino-(1,2,4)triazolo(1,5-a)pyridin-7-yl)-N-(tert-butyl)pyridine-3-sulfonamide; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011725:Pyridines; D013449:Sulfonamides; D014230:Triazoles