A NEW, VASOACTIVE HYBRID ASPIRIN CONTAINING NITROGEN MONOXIDE-RELEASING MOLSIDOMINE MOIETY

Szőke, Kitti and Czompa, Attila and Lekli, István and Szabados-Fürjesi, Péter and Csávás, Magdolna and Herczeg, Mihály and Borbás, Anikó and Herczegh, Pál (2019) A NEW, VASOACTIVE HYBRID ASPIRIN CONTAINING NITROGEN MONOXIDE-RELEASING MOLSIDOMINE MOIETY. EUROPEAN JOURNAL OF PHARMACEUTICAL SCIENCES, 131. pp. 159-166. ISSN 0928-0987

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Abstract

Ischemic heart conditions are among the main causes of sudden cardiac death worldwide. One of the strategies for avoiding myocardial infarction is the low-dose, prophylactic use of acetylsalicylic acid (ASA), an inhibitor of platelet aggregation. To avoid the gastrointestinal damage, ASA prodrugs bearing nitric oxide (NO)-donating moiety covalently conjugated to ASA have been synthesized and evaluated extensively worldwide. Herein the synthesis of a new hybrid ASA ester covalently attached to the NO donor linsidomine, an active metabolite of molsidomine (MOL) is reported. Cell viability assay and hemolysis tests were performed in H9c2 cells and rat erythrocytes, respectively. Our new compound, the ERJ-500 not affected negatively the viability of living cells in the concentration range of 100 nM to 100 µM. Using the ex vivo Langendorff method on hearts originated from female rats, compound ERJ-500 displayed a dose-dependent, outwashable vasodilative effect in coronary arteries. Vasodilation was observed on isolated working heart model as well, with elevated stroke volume in hearts treated with ERJ-500. Furthermore, a decreased infarct size was also noticed in ERJ-500 treated hearts after ischemia/reperfusion. Based on these observations it can be expected that our new hybrid ASA may contribute to new pharmacological tool in the therapy of ischemic heart conditions and associated syndromes.

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