Discovery and in Vivo Evaluation of (<i>S</i>)-<i>N</i>-(1-(7-Fluoro-2-(pyridin-2-yl)quinolin-3-yl)ethyl)-9<i>H</i>-purin-6-amine (AMG319) and Related PI3Kδ Inhibitors for Inflammation and Autoimmune Disease

Abstract

The development and optimization of a series of quinolinylpurines as potent and selective PI3Kδ kinase inhibitors with excellent physicochemical properties are described. This medicinal chemistry effort led to the identification of 1 (AMG319), a compound with an IC50 of 16 nM in a human whole blood assay (HWB), excellent selectivity over a large panel of protein kinases, and a high level of in vivo efficacy as measured by two rodent disease models of inflammation.