3-[[4-(Benzylamino)quinazolin-2-yl] Amino] Benzenesulfonamide, a Quinazoline-Based PDE5 Inhibitor, Induces Vasorelaxation in Rat Mesenteric Arteries via Multiple Mechanisms.

We synthesised a series of N2,N4-diaminoquinazoline derivatives, among which 3-[[4-(benzylamino)quinazolin-2-yl]amino]benzenesulfonamide (compound 5) exhibited potent phosphodiesterase type 5 (PDE5) inhibitory activity. Increasing evidence suggests that PDE5 inhibition is a promising therapeutic strategy for peripheral vascular disease. This study aimed to investigate vasorelaxant effects of 5 and its underlying mechanisms in rat mesenteric arteries. Compound 5 was synthesised and purified, and evaluated its vascular activity using organ bath assay. Molecular docking was performed to identify its potential molecular targets. Compound 5 (0.0001-30 μM) induced relaxation of phenylephrine (PE)-precontracted mesenteric arteries (EC50 = 0.76 ± 0.29 μM; Emax = 95.6% ± 1.1%). This effect was attenuated by endothelium removal (EC50 = 5.24 ± 0.98 μM) and by L-NAME (eNOS inhibitor). Compound 5 enhanced sodium nitroprusside-induced relaxation, supporting modulation of the NO-sGC-cGMP axis via PDE5 inhibition. Iberiotoxin (BKCa blocker) reduced relaxation, whereas 4-aminopyridine (KV blocker) and glibenclamide (KATP blocker) had no effect. Compound 5 inhibited vasoconstriction mediated by extracellular Ca2+ influx via receptor-operated Ca2+ channels (ROCCs) and α1-adrenergic receptor activation. Molecular docking provided qualitative support for PDE5A, BKCa channels and α1-adrenergic receptor as potential targets. In conclusion, 5 induces potent vasorelaxation in resistance arteries through eNOS/NO/cGMP signalling, BKCa channel activation and inhibition of ROCCs and α1-adrenergic receptors, supporting its potential as a therapeutic candidate for peripheral vascular disorders.