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Optimization of Orally Bioavailable PI3KdeltaInhibitors and Identification of Vps34 as a Key Selectivity Target
Optimization of a lead series of PI3Kdeltainhibitors based on a dihydroisobenzofuran core led to the identification of potent, orally bioavailable compound 19. Selectivity profiling of compound 19 showed similar potency for class III PI3K, Vps34, and PI3Kdelta, and compound 19 was not well-tolerated in a 7-day rat toxicity study. Structure-based design led to an improvement in selectivity for PI3Kdeltaover Vps34 and, a focus on oral phramacokinetics properties resulted in the discovery of compound 41, which showed improved toxicological outcomes at similar exposure levels to compound 19.
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Reference£º
Isoquinoline – Wikipedia,
Isoquinoline | C9H7N – PubChem