Phosphodiesterase-5 inhibitory and vasodilator actions of quinazoline derivatives

Abstract

Phosphodiesterase-5 (PDE5) inhibitors are the gold standard treatment for pulmonary arterial hypertension (PAH), but a lack of selectivity for this enzyme can induce systemic side effects. A new series of quinazoline derivatives, N2,N4-disubstituted quinazoline 2,4-diamines, was developed, with compounds 4, 5, 8, 9, 10 and 11 showing good selectivity for rat PDE5. The aim of the thesis was to characterize their inhibitory effects on human PDE5, their vasorelaxant effects and related mechanisms on the pulmonary artery (PA) compared with the aorta and mesenteric artery (MA), as well as their vascular smooth muscle cells (VSMC) and hepatic toxicity (viability and induction/inhibition of rat cytochrome P450 (CYP)). Compounds 5 and 11 showed the strongest inhibitory activity of human PDE5, with no cytotoxicity for VSMC. These 2 compounds induced a vasodilatory effect on PA, which was less effective than sildenafil but more selective for PA compared with the aorta. Their vasorelaxant effects in PA were partly endothelium-dependent. They involve potentiation of the nitric oxide (NO)/soluble guanylate cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway and inhibition of calcium fluxes (extracellular and intracellular). Their vasodilatory mechanisms were different in MA, where they are KCa channel activators, calcium channel blockers, and alpha-1 (α1)-adrenergic antagonists. Compounds 5 and 11 did not reduce hepatocyte viability but had a weak CYP3A inhibitory effect at 10 µM similar to sildenafil. Unlike these 2 above compounds, compound 8 showed better aortic selectivity than PA, leading to assess its effect on systemic vasculature using nifedipine as a comparator. In MA, the vasorelaxant effect of compound 8 was comparable to that of nifedipine. Mechanistically, the effect of compound 8 is endothelium-independent, based on the potentiation of the sGC/cGMP pathway, opening of the KCa channel, inhibition of calcium influx, and antagonism of α1-adrenergic receptors. Intravenous administration of compound 8 (0.05 and 0.1 mg/kg) induced arterial hypotension, similar to nifedipine in lowering diastolic and mean arterial pressure, but its effect on lowering systolic arterial pressure was less than nifedipine. Compound 8 did not affect hepatocyte viability and CYP activities, except at high concentrations (>10 µM) at which a weak inhibitory effect on CYP1A and 3A was observed. In contrast, nifedipine showed a strong inductive effect on CYP1A, 2B, 2C and 3A activities. In conclusion, this thesis enabled to identify 2 compounds (5 and 11) that combine a good inhibitory effect on human PDE5, good selectivity for pulmonary vasculature via endothelium-dependent and independent effects, a low hepatic toxicity and a low risk of drug interaction via CYPs. The present study has also identified a new compound (compound 8) with a potent endothelium-independent vasorelaxant effect on resistance vessels, resulting in a hypotensive effect and associated with a low risk of hepatic toxicity/drug interactions. These results demonstrated that N2,N4-disubstituted quinazoline 2,4-diamines can serve as a basis for the development of new drugs for PAH or arterial hypertension. These studies paved the way for future in vivo studies to test (i) the effects of compounds 5 and 11 on animal models of PAH and (ii) the effects of compound 8 on animal models of arterial hypertension.

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