title: Characteristics of the hemostatic action of KFA-1411, an inhibitor of coagulation factor Xa (FXa), in humans and various animals.
abstract: This study examined a low-molecular-weight factor-Xa inhibitor, KFA-1411 (3-[N-(3-amidinophenyl)-N-[N-[4-[1-(1-iminoethyl)piperidin-4- yl]phenyl]carbamoylmethyl]aminomethyl]phenoxyacetic acid monosulfonate-dihydrate). KFA-1411 selectively inhibited FXa among the serine proteases in the human blood-coagulation cascade with a Ki value of 1.73 nM, (selectivity ratio, 15000 versus its action on thrombin). The anticoagulant action of KFA-1411 in human plasma almost equaled that of the selective thrombin inhibitor, argatroban. KFA-1411 did not inhibit platelet aggregation at the concentration at which it showed an anticoagulant action. In contrast, argatroban, heparin, and low-molecular-weight heparin (LMWH; dalteparin) inhibited thrombin-induced platelet aggregation at concentrations lower than those needed for their anticoagulant actions. The FXa-inhibiting action of KFA-1411 differed among animal species, the maximum effect being seen in humans, followed by monkeys and rabbits, with rats and mice showing about one-tenth the potency seen in humans. A species variation was also observed among the values obtained for KFA-1411 in respect of anticoagulant activity in plasma (monkeys again being closest to humans). These results indicate that KFA-1411 may exhibit antithrombotic efficacy without an unwanted platelet-related action in the future treatment of various thrombotic diseases. The experimental model of monkeys is recommended for estimation of the clinical effects and safety of KFA-1411 in humans.
authors.affiliation: Pharmacology Research Laboratory, Research & Development, Kissei Pharmaceutical Co., Ltd., 4365 Kashiwabara, Hotaka, Minamiazumi, Nagano 399-8304, Japan.
authors.forename: Kiyoto
authors.initials: K
authors.lastname: Hara
authors.forename: Toshiki
authors.initials: T
authors.lastname: Honma
authors.forename: Akane
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Atsushi
authors.initials: A
authors.lastname: Matsuzawa
authors.forename: Masahiko
authors.initials: M
authors.lastname: Uchida
authors.forename: Takashi
authors.initials: T
authors.lastname: Koizumi
authors.forename: Satoshi
authors.initials: S
authors.lastname: Akahane
authors.forename: Masami
authors.initials: M
authors.lastname: Kojima
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives; D001777:Blood Coagulation / Q000187:drug effects*; D004285:Dogs; D065427:Factor Xa Inhibitors; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D023421:Models, Animal; D010875:Pipecolic Acids / Q000494:pharmacology; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D012697:Serine Endopeptidases / Q000378:metabolism*; D013449:Sulfonamides
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; C487858:KFA1411; D010875:Pipecolic Acids; D010880:Piperidines; D013449:Sulfonamides; D001120:Arginine; D012697:Serine Endopeptidases; C031942:argatroban