Synthesis of Some Novel Organic Nitrates and Comparative in Vitro Study of Their Vasodilator Profile

Abstract

Synthesis and structural characterization of the 4-phenylbutane-1,2-diyl dinitrate and of the erythro and threo diastereoisomers of 4-phenylbutane-1,2,3-triyl trinitrate as well as the HPLC chiral separation of the corresponding racemic mixtures are reported. Vasodilator activity of the single enantiomers of these products, of 4-phenylbutyl nitrate, and of the previously described phenylpropyl analogues were assessed on rat aorta strips precontracted with phenylephrine. The compounds were able to relax the contracted tissue in a concentration dependent manner. In the couples of antipodes, a complete lack of enantioselectivity was observed as far as the vasodilator potency is concerned. The concentration response curves of the products, with the exception of those of all the trinitrooxy substituted models, were rightward shifted in the presence of ALDH-2 inhibitors. Mono and dinitrates, but not trinitrates, displayed in vitro cross-tolerance with GTN. This new series of nitric acid esters is an interesting tool that can help to shed light on the unresolved puzzle of nitrate pharmacology. Selected members are worthy of additional study as potential drugs.

New Takes on Nitrate Ester Chemistry: Salts with Oxygen‐Rich Ammonium Cations

“…Also, recent reports indicate that similar materials are potentially biological active. [28][29][30][31][32][33][34]…”

“…Their neutral parent bases, such as tris(2-nitroxyethyl)amine, are reactive as well, forming energy poor cyclic materials and intractable polymers. They have, however, been recently reinvestigated for pharmaceutical applications [28][29][30][31][32][33][34].…”

In vitro preventive effects of nitrate tolerance by a polyphenol-enriched extract of Hibiscus sabdariffa

“…Regarding the methodological approach, we used an in vitro nitrates tolerance induction model, which was already validated in numerous studies (Wang et al, 2002a;Van de Voorde et al, 1987Stewart et al, 1989;Ratz et al, 2000;Otto et al, 2005;Chegaev et al, 2009;Bennett et al, 1988;Sarr et al, 2005). To do this, we used aortic denuded-rings in order to avoid possible interference between the exogenous nitrogen oxide (NO) from nitroglycerin and endothelium-derived one.…”

Multitarget Antioxidant NO-Donor Organic Nitrates: A Novel Approach to Overcome Nitrates Tolerance, an Ex Vivo Study

“…In a previous work [ 22 ] we described the synthesis and the in vitro vasodilator profile of a new series of compounds, in which the phenyl group was introduced into the molecule of GTN; analogues obtained formally by elimination of one or two nitrooxy groups were also synthesized and characterized. On the basis of the results obtained, in this paper we report the ex vivo characterization of the tolerance profile of the nitrooxyphenylalkyl derivatives 1 - 3 ( Figure 1 ).…”