Discovery and Optimization of 4-Methylquinazoline Derivatives as Highly Selective PI3Kδ Inhibitors for the Treatment...

Phosphoinositide 3-kinase δ (PI3Kδ) has emerged as a promising therapeutic target for inflammatory respiratory diseases. Herein, we report the design and synthesis of a novel series of 4-methylquinazoline derivatives as potent and highly selective PI3Kδ inhibitors for the treatment of acute lung injury (ALI). Guided by structure-based drug design optimization of a pan-PI3K inhibitor scaffold, the lead compound 48 was identified, exhibiting single-digit nanomolar potency against PI3Kδ and exceptional selectivity over other class I PI3K isoforms. Mechanistically, compound 48 effectively modulated immune responses by suppressing pro-inflammatory M1 macrophage polarization while promoting the anti-inflammatory M2 phenotype. Possessing favorable pharmacokinetic properties, compound 48 was evaluated in murine models of LPS-induced ALI and septic lung injury, where it significantly attenuated pulmonary edema and inflammatory infiltration. Collectively, compound 48 represents a promising preclinical candidate for the therapeutic intervention of ALI.