Selective pulmonary vasorelaxant effects of an N2,N4-diaminoquinazoline PDE5 inhibitor involving endothelial signaling and ion channel modulation.

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by elevated pulmonary vascular resistance and right ventricular overload. Phosphodiesterase type-5 (PDE5) inhibitors are standard therapy but are limited by systemic vasodilation and side effects. N2,N4-diaminoquinazoline and N2,N6-diaminopurine derivatives have been identified as selective PDE5 inhibitors, however, achieving pulmonary vascular selectivity remains challenging. This study therefore evaluated the vasorelaxant effects of seven potent derivatives developed from the initial lead compound A with novel bioisosteric modifications. Their mechanisms of action were investigated in isolated rat pulmonary arteries and aorta. All compounds induced concentration-dependent vasorelaxation, with N4-benzyl-N2-(4-((4-methylpiperazin-1-yl)sulfonyl)phenyl)quinazoline-2,4-diamine (compound 6) demonstrating greater vasorelaxation in pulmonary arteries versus aorta (SI = 9.9 vs 5.6 for A and 2.1 for Sildenafil). In endothelium-intact vessels, inhibition of eNOS, cyclooxygenase, or EDHF attenuated vasorelaxation-induced by 6, whereas in endothelium-denuded vessels, blocking guanylate cyclase or KV channels reduced vasorelaxation, with KCa channels contributing in a modulatory manner. Importantly, 6 reduced extracellular Ca2+ influx through both voltage- and receptor-operated Ca2+ channels and reduced sarcoplasmic reticulum Ca2+ release, without affecting SNP-induced vasorelaxation. From molecular docking and pharmacophoric analysis, we postulate that the observed effects on Ca2+ influx may be associated with the introduction of a basic center into the original lead molecule A. This modified pharmacophore shares structural similarities with other heteroaromatic ion channel blockers that are capable of binding to VOCC and ROCC related targets. These findings demonstrate that 6 induces preferential pulmonary artery vasorelaxation under ex vivo conditions through multi-target mechanisms, supporting its potential as a therapeutic candidate for PAH.