Pharmacological properties of the new stable prostacyclin analogue 3-Oxa-methano-prostaglandin I.

The pharmacological characteristics of the 3-oxamethano-prostaglandin I1 compound (+)-methyl [2-[(2R,3aS,4R,5R,6aS)-octahydro-5-hydroxy-4- [(E)-(3S,5S)-3-hydroxy-5-methyl-1-nonenyl]-2-pentalenyl]etho xy] acetate (SM-10902, CAS 139403-31-9), a novel stable analogue of prostacyclin and its free acid, SM-10906, were studied. SM-10902 was rapidly deesterified to its free acid in rabbit and human serum. SM-10902 and SM-10906 exhibited antiplatelet potency against ADP-induced aggregation in rabbit and human platelets. In the presence of diisopropyl fluorophosphate, an esterase inhibitor, the antiplatelet activity of SM-10902 was markedly reduced, to much less than that of SM-10906. SM-10906 inhibited platelet aggregation induced by various inducers in several species and enhanced the cyclic AMP (cAMP) level in human platelets. These activities were nearly equal to those of prostaglandin (PG) E1 and less than those of PGI2. SM-10906 relaxed isolated rabbit mesenteric and bovine coronary arteries, and elevated the cAMP level in bovine coronary arteries. SM-10906 given intravenously exhibited a sustained reduction in blood pressure based on vasodilation in ganglion-blocked, angiotensin II-supported rats. SM-10902 applied to the guinea-pig auricles increased the skin temperature, but SM-10906 and PGI2 showed no such effect. In conclusion, SM-10902, which is considered to be a prodrug of SM-10906, was suggested to exert its anti-platelet and vasodilator activities through the increase of cAMP. Since SM-10902 penetrates well into the skin, it may be useful as an external preparation to improve peripheral circulatory insufficiency.