title: Discovery and in vivo evaluation of dual PI3Kβ/δ inhibitors.
abstract: Structure-based rational design led to the synthesis of a novel series of potent PI3K inhibitors. The optimized pyrrolopyridine analogue 63 was a potent and selective PI3Kβ/δ dual inhibitor that displayed suitable physicochemical properties and pharmacokinetic profile for animal studies. Analogue 63 was found to be efficacious in animal models of inflammation including a keyhole limpet hemocyanin (KLH) study and a collagen-induced arthritis (CIA) disease model of rheumatoid arthritis. These studies highlight the potential therapeutic value of inhibiting both the PI3Kβ and δ isoforms in the treatment of a number of inflammatory diseases.
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc., 1120 Veterans Boulevard, South San Francisco, California 94080, USA. felgonza@amgen.com
authors.forename: Felix
authors.initials: F
authors.lastname: Gonzalez-Lopez de Turiso
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Shin
authors.forename: Matthew
authors.initials: M
authors.lastname: Brown
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: David
authors.initials: D
authors.lastname: Fong
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Hao
authors.forename: Xiao
authors.initials: X
authors.lastname: He
authors.forename: Kirk
authors.initials: K
authors.lastname: Henne
authors.forename: Yi-Ling
authors.initials: YL
authors.lastname: Hu
authors.forename: Michael G
authors.initials: MG
authors.lastname: Johnson
authors.forename: Todd
authors.initials: T
authors.lastname: Kohn
authors.forename: Julia
authors.initials: J
authors.lastname: Lohman
authors.forename: Helen J
authors.initials: HJ
authors.lastname: McBride
authors.forename: Lawrence R
authors.initials: LR
authors.lastname: McGee
authors.forename: Julio C
authors.initials: JC
authors.lastname: Medina
authors.forename: Daniela
authors.initials: D
authors.lastname: Metz
authors.forename: Kent
authors.initials: K
authors.lastname: Miner
authors.forename: Deanna
authors.initials: D
authors.lastname: Mohn
authors.forename: Vatee
authors.initials: V
authors.lastname: Pattaropong
authors.forename: Jennifer
authors.initials: J
authors.lastname: Seganish
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Simard
authors.forename: Sharon
authors.initials: S
authors.lastname: Wannberg
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Cushing
mesh_terms: D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical; D008958:Models, Molecular; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*
chemical_list: D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors