Ferrocenyl, Alkyl, and Aryl‐pyrido[2,3‐d]pyrimidines as Vasorelaxant of Smooth Muscle of Rat Aorta via cAMP Conservation Through Phosphodiesterase Inhibition.

New pyrido[2,3-d]pyrimidines , , , and have been synthesized. The vasorelaxant effect on smooth muscle isolated from rat aorta, via PDEs inhibition, of these compounds along with other pyrido[2,3-d]pyrimidines reported earlier by our group, has also been determined. These pyrido[2,3-d]pyrimidines were synthesized by the reaction of ferrocenyl-ethynyl ketones () or α-alkynyl ketones () with 6-amino-1,3-dimethyluracil using [Ni(CN)4]−4 as an active catalytic species, formed in situ in a Ni(CN)2/NaOH/H2O/CO/KCN aqueous system. Evaluation of the vasorelaxant effect of compounds demonstrated that all compounds relax the tissue in a concentration-dependent manner. The structural changes do not alter the effectiveness; however, there are differences related to potency expressed as EC50. Compounds (7-ferrocenyl-1,3-dimethyl-5-(m-tolyl)-pyrido[2,3-d]pyrimidine) and (7-ferrocenyl-1,3-dipropyl-5-(4-metoxyphenyl)-pyrido[2,3-d]pyrimidine) were the most potent compounds, even more than rolipram, reference drug; the EC50 was 0.41 ± 0.02 μM and 0.81 ± 0.11 μM for and , correspondingly. The EC50 of compounds (7-ferrocenyl-1,3-dimethyl-5-phenyl-pyrido[2,3-d]pyrimidine), (7-ferrocenyl-5-(3,5-dimethoxyphenyl)-1,3-dimethylpyrido[2,3-d]pyrimidine), and (5-n-butyl-7-ethyl-1,3-dimethylpyrido[2,3-d]pyrimidine) was similar to EC50 of rolipram. Compounds significantly induce concentration-dependent vasorelaxation in endothelium-intact aortic rings. In addition, the relaxation responses to each compound in either endothelium-intact or endothelium denuded aortic rings were comparable, suggesting that removal of the functional endothelium has no significant influence on its intrinsic vasorelaxant activity. In vitro capability of conserving cyclic-AMP or cyclic-GMP (adenosine and guanosine 3′, 5′-cyclic monophosphate) via PDE inhibition for compounds and was evaluated. Compounds and show the highest percent inhibition effect (94.83% and 83.98%, respectively) for the decomposition of c-AMP. Docking studies showed that the compound was selective for the inhibition of PDE-4.