Discovery of novel PI3Kγ/δ inhibitors as potential agents for inflammation.
Dual PI3Kγ/δ inhibitors have recently been shown to be suitable targets for inflammatory and respiratory diseases. In a recent study we described the discovery of selective PI3Kγ inhibitors based on a triazolopyridine scaffold. Herein, we describe the elaboration of this structural class into dual PI3Kγ/δ inhibitors with excellent selectivity over the other PI3K isoforms and the general kinome. Structural optimization led to the identification of two derivatives which showed significant efficacy in an acute model of lung inflammation.
Cellzome Ltd, Chesterford Research Park, Little Chesterford CB10 1XL, UK. catherineellard@aol.com
Katie
K
Ellard
Mihiro
M
Sunose
Kathryn
K
Bell
Nigel
N
Ramsden
Giovanna
G
Bergamini
Gitte
G
Neubauer
D055808:Drug Discovery; D007249:Inflammation / Q000188:drug therapy; D008958:Models, Molecular; D015394:Molecular Structure; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors