Vasodilation and inhibition of platelet aggregation by prostacyclins with modified ω-side chain

Abstract

Prostacyclin analogs with modified ω-side chain were synthetized in search of therapeutically useful agents. To characterize the vasodilator and platelet-antiaggregating properties, prostacyclin analogs were tested on systemic blood pressure in anesthetized rats, relaxation of bovine coronary artery and inhibition of arachidonic acid induced human platelet aggregation. The sodium salt of prostacyclin induced a dose dependent decrease of blood pressure with an ED 25 of 0.23 μg/kg i.v., a marked relaxation of bovine coronary artery with an IC 5p of 5.9 ng/ml and a strong inhibition of platelet aggregation with an ED 50 of 3x10 −9 M. Similar results were obtained with prostacyclin-methylester. Replacement of the n-pentyl moiety attached to C-15 of prostacyclin by cyclohexyl, 2-(2-furyl)ethyl, 2-(3-thienyl)ethyl and especially by 3-thienyloxymethyl yielded analogs with comparable prostacyclin properties, while substitution by 1,1-dimethyloxaalkyl residues was followed by a marked loss of activity. The order of potency among the analogs of the sodium salt and methylester of prostacyclin with strong vasodepressor and antiaggregatory properties was identical in all three models used. The three test systems used for evaluation have demonstrated that suitable modifications of the ω-side chain of prostacyclin result in potent vasodilator and plateletantiaggregating agents.