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Antithrombotic effects of KP-10614, a novel and stable prostacyclin (PGI2) analog.

A chemically stable prostacyclin analog, KP-10614 [(4z,16s)-4,5,18,18,19,19-hexadehydro-16,20-dimethyl-delta 6(9;alpha)-9(o)- methano-PGI1], has been compared with two other prostacyclin derivatives (Iloprost and TEI-7165) and one prostaglandin E1 derivative (OP-1206) with respect to ADP-induced in vitro aggregation of human platelets and ex vivo platelet aggregation in rats and dogs, given by bolus injection and i.v. infusion. These compounds were also tested on the systemic arterial blood pressure of rats and dogs. KP-10614 was the most potent inhibitor of in vitro platelet aggregation induced by ADP with IC50 of 1 nM among the compounds studied in this report, and it also showed ex vivo effectiveness at doses much lower than the other three compounds. KP-10614 was also orally active. At oral doses of 25, 50 and 100 micrograms/kg, this new compound caused a dose-dependent inhibition of ex vivo platelet aggregation in rats, whereas the other three compounds were effective only at 500 micrograms/kg or more. In addition, KP-10614 showed definite antithrombotic effects at a dose range of 0.1 to 1 microgram/kg i.v. in various thrombosis models in which platelet aggregation was mainly involved. These results indicate that KP-10614 possesses therapeutic potential in thrombotic diseases.