The antiplatelet and antithrombotic effects of
FR171113, 3-(4-chlorophenyl)-2-(2,4-dichlorobenzoylimino)-5-(methoxycarbonyl methylene)-1,3-thiazolidin-4-one, a non-
peptide protease-activated receptor 1 (PAR1) antagonist, were evaluated in guinea pigs.
FR171113 inhibited Ser-Phe-Leu-Leu-Arg-Asn-NH2 (a synthetic PAR1 agonist
peptide)-induced and
thrombin-induced aggregation of guinea pig platelets in a concentration-dependent manner in vitro (IC50=1.5 and 0.35 microM, respectively). Subcutaneous administration of
FR171113 (0.1-3.2 mg/kg) produced a dose-dependent inhibition of platelet aggregation ex vivo. The ED50 value of
FR171113 for platelet aggregation was 0.49 mg/kg s.c. However,
FR171113 did not have an inhibitory effect on
ADP- or
collagen-induced platelet aggregation in vitro and ex vivo. One hour after
FR171113 treatment at 1.0 mg/kg s.c., significant inhibition of arterial
thrombosis without a prolongation of thrombin time or coagulation time was seen in the FeCl3-induced
carotid artery thrombosis model in guinea pigs. Furthermore,
FR171113 did not prolong bleeding time even at 32 mg/kg s.c., which is a much higher dose than that required in the
thrombosis model. These observations indicate that
FR171113 has desirable antiplatelet effects both in vitro and in vivo and that its in vivo antithrombotic activity is efficacious without causing a prolongation of bleeding time.