Structure Overhaul Affords a Potent Purine PI3Kδ Inhibitor with Improved Tolerability

PI3Kδ
catalytic activity is required for immune cell activation,
and has been implicated in inflammatory diseases as well as hematological
malignancies in which the AKT pathway is overactive. A purine PI3Kδ
inhibitor bearing a benzimidazolone–piperidine motif was found
to be poorly tolerated in dog, which was attributed to diffuse vascular
injury. Several strategies were implemented to mitigate this finding,
including reconstruction of the benzimidazolone–piperidine
selectivity motif. Structure-based design led to the identification
of O- and N-linked heterocycloalkyls,
with pyrrolidines being particularly ligand efficient and kinome selective,
and having an improved safety pharmacology profile. A representative
was advanced into a dog tolerability study where it was found to be
well tolerated, with no histopathological evidence of vascular injury.