1338484-00-6Relevant articles and documents
Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors
Shin, Youngsook,Suchomel, Julia,Cardozo, Mario,Duquette, Jason,He, Xiao,Henne, Kirk,Hu, Yi-Ling,Kelly, Ron C.,McCarter, John,McGee, Lawrence R.,Medina, Julio C.,Metz, Daniela,San Miguel, Tisha,Mohn, Deanna,Tran, Thuy,Vissinga, Christine,Wong, Simon,Wannberg, Sharon,Whittington, Douglas A.,Whoriskey, John,Yu, Gang,Zalameda, Leeanne,Zhang, Xuxia,Cushing, Timothy D.
, p. 431 - 447 (2016/01/28)
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 inbibitors 1 and 2 led to effective inhibition of antigen-specific IgG and IgM formation after immunization with KLH.
