New NO-donors with antithrombotic and vasodilating activities, I: 3-Arylalkyl-N-nitroso-5-sydnone imines.
Nine nitrosimino title compounds were prepared. They inhibit the aggregation of human platelets induced by collagen with an IC50 = 0.7--33 mumol/L. The most active substance is the 3-phenylethyl derivative 6b. The in vitro effect is mediated by an active metabolite which is formed by a photochemical reaction in the aggregometer. As the corresponding and so far unknown sydnone-5-cyanimines have no effect on platelets the metabolite is most certainly a NO-species. The activity of the sydnone-5-nitrimine 5b is in the same order of magnitude (IC50 = 7.5 mumol/L) as in the nitrosimines of type 6. The most active compound 6b was investigated for antithrombotic properties in a thrombosis model, where the thrombus formation was induced by a laser-beam. 2 h after oral administration of 60 mg/kg of 6b to rats in venoles a 28% inhibition of thrombin formation was found. In arterioles this effect is more evident and a 48% inhibition is seen (the thrombus formation index is 2.6 and 3.9, respectively). These results suggest that the active metabolite is formed as well in vivo.
Rehse
K
K
Institut für Pharmazie der Freien Universität Berlin.
Kämpfe
M
M
Schleifer
K J
KJ
D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D013558:Sydnones / Q000138:chemical synthesis* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
D005343:Fibrinolytic Agents; D013558:Sydnones; D014665:Vasodilator Agents