Species differences in anticoagulant and anti-Xa activity of DX-9065a, a highly selective factor Xa inhibitor.
Activation of the blood coagulation cascade results in the formation of factor Xa (FXa) in either its intrinsic or extrinsic pathways, which in turn converts prothrombin to thrombin. We recently described the synthesis and characterization of DX-9065a, a highly selective FXa inhibitor, as an orally active anticoagulant agent (1). Although DX-9065a potently inhibited human FXa (2), a much larger dosage was required to inhibit thrombus formation in a rat thrombosis model (3): The plasma concentration of DX-9065a after administration of a dose which reduced thrombus formation by 50% in rats was in the microM range, or 40 times higher than the Ki value for FXa. From this, several assumptions arise, namely that an unknown mechanism other than FXa inhibition contributes to the antithrombotic effect of DX-9065a, or that the efficacy of DX-9065a differs among species. However, as the anticoagulant effect of DX-9065a was closely consistent with anti-Xa activity in plasma and as DX-9065a inhibited only FXa activity (2), the former assumption could be disregarded. To clarify the latter, we examined the inhibitory effect of DX-9065a on FXa from several animal species and its anticoagulant effect ex vivo in these species. Further, we also compared the anticoagulant effect of DX-9065a in plasma from each species with that of NAPAP, a benzamidine-derived direct thrombin inhibitor (4).
Hara
T
T
Exploratory Research Laboratories II, Daiichi Pharmaceutical Co., Ltd. Tokyo, Japan.
Yokoyama
A
A
Morishima
Y
Y
Kunitada
S
S
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D004285:Dogs; D004333:Drug Administration Routes; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D005260:Female; D000882:Haplorhini; D006801:Humans; D008297:Male; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology*; D011422:Propionates / Q000494:pharmacology*; D011517:Prothrombin Time; D011817:Rabbits; D051381:Rats; D013045:Species Specificity
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D009281:Naphthalenes; D011422:Propionates; D015951:Factor Xa