New organic nitrate-containing benzyloxy isonipecotanilide derivatives with vasodilatory and anti-platelet activity

European Journal of Pharmaceutical Sciences : Official Journal of the European Federation for Pharmaceutical Sciences
Modesto de CandiaCosimo D Altomare

Abstract

A number of new nitric oxide (NO)-precursors were synthesized by grafting nitrate-containing moieties on the structures of the benzyloxy isonipecotanilide derivatives 1 and 2 already reported as moderately potent antiplatelet agents. Various nitrooxy (ONO2)-alkyl side chains were covalently linked to the piperidine nitrogen of the parent compounds through carbamate and amide linkage, and the synthesis of a benzyl nitrate analog (15) of compound 1 was also achieved. The in vitro vasodilatory activities, as well as platelet anti-aggregatory effects, of the newly synthesized organic nitrates were assessed. The (ONO2)methyl carbamate-based derivative 5a and the benzyl nitrate analog 15, which on the other hand retain activity as inhibitors of ADP-induced platelet aggregation, exhibited strong NO-mediated vasodilatory effects on pre-contracted rat aorta strips, with EC50 values in the low nanomolar range (13 and 29 nM, respectively). Experiments carried out with the selectively inhibited soluble guanylate cyclase (sGC), which is the key enzyme of the NO-mediated pathway leading to vascular smooth muscle relaxation, confirmed the involvement of NO in the observed vasodilation. The nitrate derivatives proved to be stable in acidic aqu...Continue Reading

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Citations

Jun 15, 2015·Bioorganic & Medicinal Chemistry·Gerda Brunhofer-BolzerThomas Erker
Apr 20, 2016·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Yean Chun LohMun Fei Yam
Aug 7, 2017·Molecular Pharmaceutics·Tommaso CassanoCosimo D Altomare

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