Discovery, Optimization, and in Vivo Evaluation of Benzimidazole Derivatives AM-8508 and AM-9635 as Potent and Selective PI3Kδ Inhibitors
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- 作者：Youngsook Shin ; Julia Suchomel ; Mario Cardozo ; Jason Duquette ; Xiao He ; Kirk Henne ; Yi-Ling Hu ; Ron C. Kelly ; John McCarter ; Lawrence R. McGee ; Julio C. Medina ; Daniela Metz ; Tisha San Miguel ; Deanna Mohn ; Thuy Tran ; Christine Vissinga ; Simon Wong ; Sharon Wannberg ; Douglas A. Whittington ; John Whoriskey ; Gang Yu ; Leeanne Zalameda ; Xuxia Zhang ; Timothy D. Cushing
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：January 14, 2016
- 年：2016
- 卷：59
- 期：1
- 页码：431-447
- 全文大小：793K
- ISSN：1520-4804
文摘
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.