Structure-activity studies of aspirin and related compounds on platelet aggregation, arachidonic acid metabolism in platelets and artery, and arterial prostacyclin activity.

A series of benzoic acid derivatives was tested for specificity of action on human platelet function and platelet prostaglandin (PG) synthesis versus prostacyclin (PGI2) production by rat and rabbit aorta rings. None of the agents tested was more specific for one system than the other. ASA was more potent than 2-propionyloxybenzoic acid (2-PBA) in inhibiting platelet function and platelet PG synthesis although the potencies of these agents were comparable in inhibiting PGI2 synthesis. 3-Propionyloxybenzoic acid (3-PBA) caused increased activity in both systems while 2-acetylbenzoic acid (ABA) had only minor effects. A cyclical derivative, 3-methylphthalide (3-MP), inhibited both platelet function and PGI2 synthesis although it did not inhibit cyclo-oxygenase activity, suggesting a novel mechanism of action. Thus only minor changes in the ASA molecule could be effected without significant changes in pharmacological activity. The investigation of novel agents such as 3-MP may lead to a better understanding of arachidonate metabolism in different tissues and possibly to the development of more tissue-specific drugs.