New NO-donors with antithrombotic and vasodilating activities, VI: thiazole-2-nitrosimines.
24 new thiazole-2-nitrosimines were prepared and described by means of spectroscopical methods (NMR, IR, MS, UV). At pH 7 in cell free systems as well as in platelet rich plasma the compounds are stable against hydrolysis and do not react with the platelet glutathione. The chemical stability is underlined by the mass spectra: M+. is of high intensity and sometimes even forms the base peak (e.g. 8a). Thermal elimination of N2 is of minor importance. The =N-NO bond in solution is susceptible to cleavage by visible light. The metabolite so formed is able to inhibit the platelet aggregation induced by collagen (Born-test). Five compounds exhibit this activity in concentrations below 10 mumol/L (IC50). This is due to the release of a NO species, as could be demonstrated by the stimulation of soluble guanylate cyclase in a cell free system (e.g. 8a, KM = 72 mumol/L). In vivo the nitrosimines show antithrombotic properties. Two h after a single oral dose of 8g (60 mg/kg) a 57% inhibition of the laser induced thrombus formation in the mesenteric arterioles of rats is observed. After 8 h a 43% inhibition still is seen.
Rehse
K
K
Institut für Pharmazie der Freien Universität Berlin.
Lüdtke
E
E
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D009602:Nitrosamines / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D014665:Vasodilator Agents / Q000138:chemical synthesis* / Q000494:pharmacology
D005343:Fibrinolytic Agents; D009602:Nitrosamines; D013844:Thiazoles; D014665:Vasodilator Agents