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

ABSTRACT We synthesised a series of N 2 , N 4 ‐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 (EC 50 = 0.76 ± 0.29 μM; E max = 95.6% ± 1.1%). This effect was attenuated by endothelium removal (EC 50 = 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 (BK Ca blocker) reduced relaxation, whereas 4‐aminopyridine (K V blocker) and glibenclamide (K ATP blocker) had no effect. Compound 5 inhibited vasoconstriction mediated by extracellular Ca 2+ influx via receptor‐operated Ca 2+ channels (ROCCs) and α 1 ‐adrenergic receptor activation. Molecular docking provided qualitative support for PDE5A, BK Ca channels and α 1 ‐adrenergic receptor as potential targets. In conclusion, 5 induces potent vasorelaxation in resistance arteries through eNOS/NO/cGMP signalling, BK Ca channel activation and inhibition of ROCCs and α 1 ‐adrenergic receptors, supporting its potential as a therapeutic candidate for peripheral vascular disorders.