Inhibition of blood platelet aggregation by dioxo-ene compounds.
Compounds with a conjugated oxo-ene-oxo system were tested for inhibition of blood platelet aggregation. All compounds with this structure in trans configuration were effective inhibitors of aggregation induced by thrombin and by arachidonic acid. While the oxo-trans-ene-oxo system is prerequisite for such activity, other structural features of the compounds may be varied without loss of activity. Inhibition is exemplified by 9,12-dioxo-trans-10- and 10,13-dioxo-trans-11-octadecenoic acids and their methyl esters, by 11,14-dioxo-trans-12- eicosenoic acid, by 4,7-dioxo-trans-5- decene and by trans- dibenzoylethylene . The half-inhibition concentrations are in the order of 2-6 microM, with complete inhibition at 8-20 microM. According to experiments with the inhibiting 9,12-dioxo-trans-10-octadecenoic acid, the normal oxygenation of exogenous arachidonic acid by platelets is not affected but the thrombin-induced internal release of this acid seems to be abolished by the inhibitor. The inhibition of aggregation in the presence of exogenous arachidonic acid and its products suggests that the inhibitor also interferes with other events leading to aggregation. By implication from other properties of the oxo-trans-ene-oxo system, reaction with SH groups may be a mechanism for inhibition.
D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D007651:Keto Acids / Q000494:pharmacology*; D010101:Oxygen Consumption / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000494:pharmacology
D001095:Arachidonic Acids; D005231:Fatty Acids, Unsaturated; D007651:Keto Acids; D016718:Arachidonic Acid; D013917:Thrombin