Design, Synthesis and ex vivo Study of the Vasorelaxant Activity Induced by Isosteric Derivatives of Dihydropyridines (NH→O)

6-Amino-3-Methyl-4-(2-nitrophenyl)-1,4-Dihydropyrano[2,3-c]Pyrazole-5-Carbonitrile Shows Antihypertensive and Vasorelaxant Action via Calcium Channel Blockade

“…3b, compound 1 (55 and 98 μM) significantly reduced contraction induced by CaCl 2 in a concentration-dependent manner causing that, at the concentration of 98 μM, contraction was totally abolished. This supports the concept that test sample 1 possesses Ca 2 + entry-blocking activity, since it was developed and synthesized as isosteric derivative of dihydropyridines (DHP) such as nifedipine [4,21,23], a potent calcium channel blocker, which is widely used as an antihypertensive agent [24]. Finally, a third experiment was conducted to clearly establish the functional mechanism of action of 1, which consisted in the use of a direct L-type calcium channel agonist, FPL-64176 (FPL).…”

“…Compound 1 was obtained previously [4]. Carbamoylcholine chloride (carbachol), ( ± )-noradrenaline bitartrate hydrate (NA), serotonin chloride (5-HT), nifedipine, 1H- [1,2,4]oxadiazolo [4,3-a]quinoxalin-1-one (ODQ), glibenclamide, tetraethylammonium chloride (TEA), FPL 64176, components of physiological solution, and dimethylsulfoxide (DMSO) were purchased from Sigma-Aldrich Co. (St. Louis, MO, USA). For ex vivo and in vivo experiments, compound 1 was dissolved in distilled water and DMSO (1 % and 10 % v/v, respectively).…”

“…Therefore, several research groups currently focus on discover and develop new antihypertensive agents to counteract those effects following new strategies, such as the rationalized structural modification of drugs with potent therapeutic activity, with specific mechanism of action or by the multitarget actions. In this regard, compounds derived from dihydropyridines as nifedipine, a powerful calcium channel blocker used for the treatment of HBP and angina pectoris [3], are useful for the design and synthesis of novel calcium channel blockers with significant vasorelaxant action used for developing new antihypertensive drugs [4]. In this context, previously we obtained new isosteric 4H-pyrane derivatives of dihydropyridines, which showed potent vasorelaxation [4], being 6-amino-3-methyl-4-(2nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) one of the most active compounds of the series (▶ Fig.…”

“…In this regard, compounds derived from dihydropyridines as nifedipine, a powerful calcium channel blocker used for the treatment of HBP and angina pectoris [3], are useful for the design and synthesis of novel calcium channel blockers with significant vasorelaxant action used for developing new antihypertensive drugs [4]. In this context, previously we obtained new isosteric 4H-pyrane derivatives of dihydropyridines, which showed potent vasorelaxation [4], being 6-amino-3-methyl-4-(2nitrophenyl)-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile (1) one of the most active compounds of the series (▶ Fig. 1).…”

Synthesis of Novel Hybrid 4H-Pyran-lipoic and 4H-Pyran-azetidine Derivatives

“…17 Our research group has conducted previous studies regarding this core, showing that this skeleton has vasorelaxant activity. 18,19 Furthermore, it was demonstrated that if an electron-withdrawing group was incorporated into the structure, the biological activity can be increased. Their physiological mechanism was also determined and found to proceed through inhibitors of calcium channels.…”