Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig.
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.
Kato
Yasuko
Y
Medicinal Biology Research Laboratories, Fujisawa Pharmaceutical Company, Limited, 1-6, 2-chome, Kashima, Yodogawa, Osaka 532-8514, Japan. yasuko_kato@po.fujisawa.co.jp
Kita
Yasuhiro
Y
Hirasawa-Taniyama
Yoshimi
Y
Nishio
Mie
M
Mihara
Kayoko
K
Ito
Kiyotaka
K
Yamanaka
Toshio
T
Seki
Jiro
J
Miyata
Susumu
S
Mutoh
Seitaro
S
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001549:Benzamides / Q000008:administration & dosage / Q000494:pharmacology*; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D002341:Carotid Artery Thrombosis / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy*; D002712:Chlorides; D004305:Dose-Response Relationship, Drug; D005290:Ferric Compounds; D006168:Guinea Pigs; D006493:Heparin / Q000494:pharmacology; D007279:Injections, Subcutaneous; D008297:Male; D010875:Pipecolic Acids / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors; D013449:Sulfonamides; D013844:Thiazoles / Q000008:administration & dosage / Q000494:pharmacology*; D053778:Thiazolidines
D001549:Benzamides; D002712:Chlorides; C403255:FR 171113; D005290:Ferric Compounds; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D018179:Receptors, Thrombin; D013449:Sulfonamides; D013844:Thiazoles; D053778:Thiazolidines; D006493:Heparin; D001120:Arginine; C031942:argatroban; C024555:ferric chloride