title: Inhibitory effect of JTV-803, a new cyclic guanidine derivative, on factor Xa in vitro and in vivo.
abstract: JTV-803, 4-[(2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl]-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate showed a competitive inhibitory effect on human factor Xa, with a K(i) value of 0.019 microM. This compound was 100 times more selective in inhibiting human factor Xa as compared to its inhibitory activity against thrombin, plasmin, and trypsin. JTV-803 was also examined for its inhibitory effect on activated factor Xa obtained from plasma of various animal species. JTV-803 exerted a potent inhibitory effect on human factor Xa (IC(50): 0.081 microM). JTV-803 prolonged activated partial thromboplastin time and prothrombin time in a dose-dependent manner. Oral anticoagulant efficacy of JTV-803 was examined ex vivo for its inhibition of human factor Xa in cynomolgus monkeys. JTV-803 produced more than 20% inhibition of human factor Xa for 8 h. Taken together, the results indicate JTV-803 is a long-acting oral anticoagulant which exerts its effect via specific inhibition of human factor Xa.
authors.affiliation: Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka, 569-1125, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hayashi
authors.forename: A
authors.initials: A
authors.lastname: Hamada
authors.forename: Y
authors.initials: Y
authors.lastname: Okaya
authors.forename: K
authors.initials: K
authors.lastname: Wakitani
authors.forename: K
authors.initials: K
authors.lastname: Aisaka
mesh_terms: D000284:Administration, Oral; D000818:Animals; D006224:Cricetinae; D004151:Dipeptides / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D065427:Factor Xa Inhibitors; D005341:Fibrinolysin / Q000037:antagonists & inhibitors / Q000378:metabolism; D006801:Humans; D007275:Injections, Intravenous; D007546:Isoquinolines / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D009842:Oligopeptides / Q000378:metabolism; D010314:Partial Thromboplastin Time; D010880:Piperidines / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D013045:Species Specificity; D013379:Substrate Specificity; D044005:Tetrahydroisoquinolines; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013918:Thrombin Time; D013997:Time Factors; D014357:Trypsin / Q000187:drug effects / Q000378:metabolism
chemical_list: C442639:4-((2-amidino-1,2,3,4-tetrahydroisoquinolin-7-yloxy)methyl)-1-(4-pyridinyl)piperidine-4-carboxylic acid monomethanesulfonate trihydrate; D004151:Dipeptides; D065427:Factor Xa Inhibitors; D007546:Isoquinolines; D009842:Oligopeptides; D010880:Piperidines; D011725:Pyridines; C110926:S 2403; D044005:Tetrahydroisoquinolines; C015608:benzoyl-Ile-Glu-Gly-Arg-p-nitroanilide; C021129:S 2238; D014357:Trypsin; D013917:Thrombin; D005341:Fibrinolysin