Synthesis and vasodilator activity of 3,4-dihydropyrimidin-2(1H)-ones bearing urea, thiourea, and sulfonylurea moieties

A series of novel 3,4-dihydropyrimidin-2(1H)-ones bearing urea, thiourea, and sulfonylurea moieties were synthesized and pharmacologically evaluated as vasodilator agents. The most interesting vasodilators were the thiourea derivatives 6a and 6b and the urea derivatives 6f-6i and 7f-7h, although the ureas were relatively more active than thioureas. Twenty-fold more active than diazoxide, the urea 6g was the most potent vasodilator ([EC.sub.50] = 0.983 [+ or -] 0.061 [micro]mol/L) and proved to act as a voltage-gated calcium channel blocker. The lack of activity of sulfonylureas, 6k and 7j, could be attributed to their partial ionization at the physiological pH because of their acidic character. It should be interesting to investigate a larger number of compounds, including N-methylated sulfonylureas, to increase the vasodilator activity and to explore other biological models. Key words: 3,4-dihydropyrimidin-2(1H)-ones, voltage-gated calcium channel blockers, vasodilator activity, urea, thiourea, sulfonylurea. Nous avons synthesis une serie de nouvelles 3,4-dihydropyrimidin-2(1H)-ones portant des groupes uree, thiouree et sulfonyluree et avons evalue leur activite pharmacologique en tant qu'agents vasodilatateurs. Les vasodilatateurs les plus interessants etaient les derives de thiouree 6a et 6b et les derives d'uree 6f-6i et 7f-7h, les urees ayant ete relativement plus actives que les thiourees. L'uree 6g, 20 fois plus active que le diazoxyde, a montre l'activite vasodilatatrice la plus elevee ([EC.sub.50] = 0,983 [+ or -] 0,061 [micro]mol/L) et un mode d'action par blocage des canaux calciques sensible a la tension. L'absence d'activite des sulfonylurees 6k et 7j pourrait s'expliquer par leur caractere acide entrainant une ionisation partielle a pH physiologique. Il pourrait etre interessant d'etudier un plus grand nombre de composes, dont des sulfonylurees N-methylees, en vue d'augmenter l'activite vasodilatatrice et d'explorer d'autres modeles biologiques. [Traduit par la Redaction] Mots-cles: 3,4-dihydropyrimidin-2(1H)-ones, bloqueurs de canaux calciques sensibles a la tension, activite vasodilatatrice, uree, thiouree, sulfonyluree.
Introduction Voltage-gated calcium channel blockers belong to a large class of drugs used in the treatment of cardiovascular diseases such as arterial hypertension, angina pectoris, and cardiac arrhythmias. (1) Such [...]