Platelet actions of stable carbocyclic analogues of prostacyclin.

SINCE THE TIME of the discovery of prostacyclin' and the elucidation of its chemical structure as prostaglandin (PG) (5Z)-9 deoxy-6, 9 a-epoxy-&APGF,,2 many synthetic prostacyclin analogues have been prepared and reported in the literature. Although prostacyclin (epoprostenol) is now available for clinical use as the freeze-dried sodium salt that, when mixed with the diluent buffer (sodium chloride 0.15% weight per volume [wtlvol] and glycine buffer solution 0.19% wt/vol; pH 10.5), results in a preparation that will remain stable over 24 hr when stored at 20 to 80 C, there is much interest in synthesizing a chemically stable analogue with a biological profile comparable to that of the parent prostacyclin. Furthermore, the definitive separation of the platelet and vascular activities in an orally active synthetic prostacyclin analogue, both for use as a research tool and as a clinically useful agent, is an ultimate objective in the development of prostacyclin mimetics. Many structural variants of prostacyclin have been synthesized, including 5,6-dihydro analogues, exemplified by 6f3-PGI,,3-5 thia prostacyclins such as (5Z)6,9-thia prostacyclin,6 nitrogen-containing analogues such as 9-deoxy-9a-6-nitrilo-PGF ,7 ring-expanded 5,9-epoxy derivatives such as 9-deoxy-5, 9a-epoxyPGFI,7 and interphenylene analogues.' However, the synthesis and biological actions of stable carbocyclic analogues of prostacyclin, in which the enol-ether oxygen atom is replaced by a methylene group, has attracted much attention and has been described by several groups.9'6 Carbacyclin analogues. Carbacyclin, or (5E)-6a carbaprostaglandin '2 (figure 1, A), inhibits human platelet aggregation induced by a variety of agents including ADP, collagen, and arachidonic acid, while also inhibiting aggregation in platelet-rich plasma (PRP) obtained from several species, including the rabbit, rat, and dog.12 16 In our studies with carbacyclin,'3 this stable analogue was 0.03 times as potent as prostacyclin as an inhibitor of aggregation induced by ADP (table 1), collagen, and arachidonic acid. As with prostacyclin, the antiaggregating activity of carbacyclin was enhanced by preincubation of platelets with theophylline, the phosphodiesterase inhibitor,'3' 1' indicating stimulation of cyclic AMP as its mechanism of inhibitory action. Indeed, other studies have shown an elevation of platelet cyclic AMP after incubation with the analogue. 14 Carbacyclin has been shown to be a potent inhibitor of platelet aggregation ex vivo when infused intravenously in the dog and rabbit, being 0.1 times as active