Discovery, Optimization, and Evaluation of Quinazolinone Derivatives with Novel Linkers as Orally Efficacious Phosphoinositide-3-Kinase Delta Inhibitors for Treatment of Inflammatory Diseases

Guided
by molecular docking, a commonly used open-chain linker
was cyclized into a five-membered pyrrolidine to lock the overall
conformation of the propeller-shaped molecule. Different substituents
were introduced into the pyrrolidine moiety to block oxidative metabolism.
Surprisingly, it was found that a small methyl substituent could be
used to alleviate the oxidative metabolism of pyrrolidine while maintaining
or enhancing potency, which could be described as a “magic
methyl”. Further optimization around the “3rd blade”
of the propeller led to identification of a series of potent and selective
PI3Kδ inhibitors. Among them, compound 50 afforded
an optimum balance of PK profiles and potency. Oral administration
of 50 attenuated the arthritis severity in a dose-dependent
manner in a collagen-induced arthritis model without obvious toxicity.
Furthermore, 50 demonstrated excellent pharmacokinetic
properties with high bioavailability, suggesting that 50 might be an acceptable candidate for treatment of inflammatory diseases.