title: Oral administration of the thrombin receptor antagonist E5555 (atopaxar) attenuates intimal thickening following balloon injury in rats.
abstract: Thrombin is a powerful agonist for a variety of cellular responses including platelet aggregation and vascular smooth muscle cell (SMC) proliferation. These actions are mediated by a thrombin receptor known as protease-activated receptor-1 (PAR-1). Recently we discovered that 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 (E5555, atopaxar) is a potent and selective thrombin receptor antagonist. This study characterized the pharmacological effects of E5555 on SMC proliferation in vitro and in a rat model of intimal thickening after balloon injury in vivo. E5555 selectively inhibited rat aortic SMC proliferation induced by thrombin and thrombin receptor-activating peptide (TRAP) with half maximal inhibitory concentration (IC(50)) values of 0.16 and 0.038 μM, respectively. E5555 did not inhibit rat SMC proliferation induced by basic fibroblast growth factor (bFGF) and platelet-derived growth factor (PDGF) at concentrations up to 1μM. In addition, E5555 inhibited human aortic SMC proliferation induced by thrombin at concentrations of 0.3 and 3units/ml with IC(50) values of 0.028 and 0.079 μM, respectively, whereas it did not affect bFGF-induced proliferation at concentrations up to 1μM. Repeated oral administration of 30 mg/kg E5555 (once daily for 16 days) significantly reduced neointimal formation in the balloon-injured rat arterial model. These results suggested that a PAR-1 antagonist could be effective for treating restenosis following vascular intervention in addition to preventing thrombus formation. E5555 could thus have therapeutic potential for restenosis and chronic 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: Hiroko
authors.initials: H
authors.lastname: Kuramochi
authors.forename: Kimiyo
authors.initials: K
authors.lastname: Murakami
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Kawata
authors.forename: Akifumi
authors.initials: A
authors.lastname: Kimura
authors.forename: Kenichi
authors.initials: K
authors.lastname: Chiba
authors.forename: Takashi
authors.initials: T
authors.lastname: Musha
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; D000800:Angioplasty, Balloon / Q000009:adverse effects*; D000818:Animals; D001760:Bleeding Time; D001777:Blood Coagulation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D007097:Imines / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D032389:Myocytes, Smooth Muscle / Q000166:cytology / Q000187:drug effects / Q000473:pathology; D058426:Neointima / Q000188:drug therapy; D010974:Platelet Aggregation / Q000187:drug effects; D011725:Pyridines / Q000008:administration & dosage* / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D018179:Receptors, Thrombin / Q000037:antagonists & inhibitors*; D013917:Thrombin / Q000494:pharmacology; D013997:Time Factors; D017539:Tunica Intima / Q000187:drug effects* / Q000293:injuries / Q000473:pathology*
chemical_list: C540445:E 5555; D007097:Imines; D011725:Pyridines; D018179:Receptors, Thrombin; D013917:Thrombin