Antithrombotic effects of the novel inhibitor of thrombin-induced offtelet aggregation and thrombus formation, 3-[2-[1,1':2',1"]-terphenyl-4'-yl)ethyl]phenoxyacetic acid.
The new compound 3-[2-([1,1':2,1"]-terphenyl-4'yl)ethyl]phenoxyacetic acid (F1070) was synthesized and its effects on platelet aggregation induced by thrombin, thrombin receptor agonist peptide (TRAP), ADP and collagen were evaluated in humans, guinea pigs and rats, and were compared with the effects of he thrombin antagonists argipidine and (D)Phe-Pro-Arg-CH2Cl (FPR). F1070 inhibited the platelet aggregation induced by these agonists and was highly selective in its inhibition of thrombin. F1070 inhibited fibrin formation induced by thrombin, but far less effectively than argipidine. In a guinea pig model of extracorporeal circulation thrombosis, F1070 (10 mg/kg p.o.) significantly inhibited the development of a thrombus. F1070 is thus a key compound that should facilitate the development of new orally active antithrombotic drugs that are specific for thrombin.
Miyamae
T
T
Research Institute, Fuji Chemical Industries Co., Ltd., Toyama, Japan.
Hashizume
H
H
Ogawa
T
T
Okayama
T
T
Nukui
E
E
Oshima
K
K
Morikawa
T
T
Hagiwara
M
M
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D005337:Fibrin / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D010973:Platelet Adhesiveness / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013730:Terphenyl Compounds / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D013927:Thrombosis / Q000097:blood / Q000517:prevention & control*
C104856:F 1070; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D013730:Terphenyl Compounds; D005337:Fibrin