Q1 · MEDICINE
Article
Author: McCarter, John ; Zhang, Xuxia ; Medina, Julio C. ; Cardozo, Mario ; Zalameda, Leeanne ; Shin, Youngsook ; He, Xiao ; San Miguel, Tisha ; Cushing, Timothy D. ; Metz, Daniela ; Mohn, Deanna ; Suchomel, Julia ; Hu, Yi-Ling ; Whittington, Douglas A. ; Kelly, Ron C. ; McGee, Lawrence R. ; Wannberg, Sharon ; Whoriskey, John ; Duquette, Jason ; Wong, Simon ; Tran, Thuy ; Vissinga, Christine ; Yu, Gang ; Henne, Kirk
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.