Design of Selective Benzoxazepin PI3Kδ InhibitorsThrough Control of Dihedral Angles

摘要

A novel selective benzoxazepin inhibitor of PI3Kδ has been discovered. Beginning from compound >3, an αPI3K inhibitor, we utilized structure-based drug design and computational analysis of dihedral torsion angles to optimize for PI3Kδ isoform potency and isoform selectivity. Further medicinal chemistry optimization of the series led to the identification of >24, a highly potent and selective inhibitor of PI3Kδ.