Optimization of Orally Bioavailable PI3K delta Inhibitors and Identification of Vps34 as a key off-target activity.

Optimisation of a lead series of PI3Kδ inhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for the class III PI3K, Vps34, as for PI3Kδ and compound 19 was not well-tolerated in a 7 day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kδ over Vps34 and a focus on oral PK properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposures to compound 19.