title: Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors.
abstract: Lead optimization efforts resulted in the discovery of two potent, selective, and orally bioavailable PI3Kδ inhibitors, 1 (AM-8508) and 2 (AM-9635), with good pharmacokinetic properties. The compounds inhibit B cell receptor (BCR)-mediated AKT phosphorylation (pAKT) in PI3Kδ-dependent in vitro cell based assays. These compounds which share a benzimidazole bicycle are effective when administered in vivo at unbound concentrations consistent with their in vitro cell potency as a consequence of improved unbound drug concentration with lower unbound clearance. Furthermore, the compounds demonstrated efficacy in a Keyhole Limpet Hemocyanin (KLH) study in rats, where the blockade of PI3Kδ activity by inhibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.
authors.forename: Youngsook
authors.initials: Y
authors.lastname: Shin
authors.forename: Julia
authors.initials: J
authors.lastname: Suchomel
authors.forename: Mario
authors.initials: M
authors.lastname: Cardozo
authors.forename: Jason
authors.initials: J
authors.lastname: Duquette
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: Ron C
authors.initials: RC
authors.lastname: Kelly
authors.forename: John
authors.initials: J
authors.lastname: McCarter
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: Tisha
authors.initials: T
authors.lastname: San Miguel
authors.forename: Deanna
authors.initials: D
authors.lastname: Mohn
authors.forename: Thuy
authors.initials: T
authors.lastname: Tran
authors.forename: Christine
authors.initials: C
authors.lastname: Vissinga
authors.forename: Simon
authors.initials: S
authors.lastname: Wong
authors.forename: Sharon
authors.initials: S
authors.lastname: Wannberg
authors.affiliation: Department of Therapeutic Discovery, Amgen Inc. , 360 Binney Street, Cambridge, Massachusetts 02142, United States.
authors.forename: Douglas A
authors.initials: DA
authors.lastname: Whittington
authors.forename: John
authors.initials: J
authors.lastname: Whoriskey
authors.forename: Gang
authors.initials: G
authors.lastname: Yu
authors.forename: Leeanne
authors.initials: L
authors.lastname: Zalameda
authors.forename: Xuxia
authors.initials: X
authors.lastname: Zhang
authors.forename: Timothy D
authors.initials: TD
authors.lastname: Cushing
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects; D001562:Benzimidazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D006433:Hemocyanins / Q000187:drug effects; D006801:Humans; D007074:Immunoglobulin G / Q000187:drug effects; D007075:Immunoglobulin M / Q000187:drug effects; D051379:Mice; D008958:Models, Molecular; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
chemical_list: C000607647:AM-8508; C000607648:AM-9635; D001562:Benzimidazoles; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin