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ID: ALA4715688
Journal: J Med Chem
Title: Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors.
Authors: Shin Y,Suchomel J,Cardozo M,Duquette J,He X,Henne K,Hu YL,Kelly RC,McCarter J,McGee LR,Medina JC,Metz D,San Miguel T,Mohn D,Tran T,Vissinga C,Wong S,Wannberg S,Whittington DA,Whoriskey J,Yu G,Zalameda L,Zhang X,Cushing TD
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.
CiteXplore: 26652588