title: SAR studies around a series of triazolopyridines as potent and selective PI3Kγ inhibitors.
abstract: Herein we describe the SAR of a novel series of 6-aryl-2-amino-triazolopyridines as potent and selective PI3Kγ inhibitors. The 6-aryl-triazolopyridine core was identified by chemoproteomic screening of a kinase focused library. Rapid chemical expansion around a bi-functional core identified the key features required for PI3Kγ activity and selectivity. The series was optimized to afford 43 (CZC19945), a potent PI3Kγ inhibitor with high oral bioavailability and selectivity over PI3Kα and PI3Kδ. Modification to the core afforded 53 (CZC24832) which showed increased selectivity over the entire kinome in particular over PI3Kβ.
authors: Cellzome Ltd, Chesterford Research Park, Cambridge, CB10 1XL, United Kingdom. ksmelt@onetel.com
authors: Kathryn
authors: K
authors: Bell
authors: Mihiro
authors: M
authors: Sunose
authors: Katie
authors: K
authors: Ellard
authors: Andrew
authors: A
authors: Cansfield
authors: Jess
authors: J
authors: Taylor
authors: Warren
authors: W
authors: Miller
authors: Nigel
authors: N
authors: Ramsden
authors: Giovanna
authors: G
authors: Bergamini
authors: Gitte
authors: G
authors: Neubauer
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001168:Arthritis / Q000188:drug therapy; D001665:Binding Sites; D045744:Cell Line, Tumor; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000378:metabolism; D003198:Computer Simulation; D004195:Disease Models, Animal; D006207:Half-Life; D006801:Humans; D051379:Mice; D008861:Microsomes / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms / Q000037:antagonists & inhibitors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D020033:Protein Isoforms; D011725:Pyridines; D058544:Class Ib Phosphatidylinositol 3-Kinase