title: The novel and orally active thrombin receptor antagonist E5555 (Atopaxar) inhibits arterial thrombosis without affecting bleeding time in guinea pigs.
abstract: Thrombin is a powerful agonist for platelets, the action of which is mediated by the thrombin receptor protease-activated receptor-1 (PAR-1). Recently, we discovered that E5555 (1-(3-tert-butyl-4-methoxy-5-morpholinophenyl)-2-(5,6-diethoxy-7-fluoro-1-imino-1,3-dihydro-2H-isoindol-2-yl) ethanone hydrobromide) is a potent thrombin receptor antagonist. We evaluated the anti-platelet and anti-thrombotic effects of E5555. E5555 inhibited the binding of a high-affinity thrombin receptor-activating peptide ([(3)H]haTRAP) to PAR-1 with a half maximal inhibitory concentration (IC(50)) value of 0.019μM. E5555 showed potent inhibitory effects on human platelet aggregation induced by thrombin and TRAP with IC(50) values of 0.064 and 0.031μM, respectively, but had no effect on platelet aggregation induced by either ADP or collagen. Similarly, E5555 showed potent and selective inhibitory effects on guinea pig platelet aggregation induced by thrombin and TRAP with IC(50) values of 0.13 and 0.097μM, respectively. The antithrombotic activity of E5555 in vivo was evaluated in a photochemically-induced thrombosis (PIT) model using guinea pigs. Oral administration of E5555 at 30 and 100mg/kg prolonged the time to occlusion by 1.8-fold and 2.4-fold, respectively, compared with controls. Furthermore, E5555 did not prolong bleeding time in guinea pigs at the highest tested dosage of 1000mg/kg. The drug interactions between E5555 and tissue plasminogen activator (tPA) were evaluated. Intravenous administration of 1mg/kg tPA significantly prolonged bleeding time, and its effects were not altered by the oral co-administration of 300mg/kg E5555. These results suggest that E5555 could be a therapeutic option for atherothrombotic disease.
authors.affiliation: Eisai Tsukuba Research Laboratories, Eisai Co., Ltd., 5-1-3 Tokodai, Tsukuba, Ibaraki 300–2635, Japan. m-kogushi@hhc.eisai.co.jp
authors.forename: Motoji
authors.initials: M
authors.lastname: Kogushi
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Matsuoka
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawata
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kuramochi
authors.forename: Shinki
authors.initials: S
authors.lastname: Kawaguchi
authors.forename: Kimiyo
authors.initials: K
authors.lastname: Murakami
authors.forename: Hironobu
authors.initials: H
authors.lastname: Hiyoshi
authors.forename: Shuichi
authors.initials: S
authors.lastname: Suzuki
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Kawahara
authors.forename: Akiharu
authors.initials: A
authors.lastname: Kajiwara
authors.forename: Ieharu
authors.initials: I
authors.lastname: Hishinuma
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000503:physiopathology; D001779:Blood Coagulation Factors / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D006168:Guinea Pigs; D006470:Hemorrhage / Q000503:physiopathology; D006801:Humans; D007097:Imines / Q000008:administration & dosage* / Q000494:pharmacology*; D008297:Male; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology*; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D013927:Thrombosis / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D001779:Blood Coagulation Factors; C540445:E 5555; D005343:Fibrinolytic Agents; D007097:Imines; D011725:Pyridines; D018179:Receptors, Thrombin; D013917:Thrombin