Fukushi Hirayama

Publications (19)45.56 Total impact

• Article: Discovery of N-[2-hydroxy-6-(4-methoxybenzamido)phenyl]-4- (4-methyl-1,4-diazepan-1-yl)benzamide (darexaban, YM150) as a potent and orally available factor Xa inhibitor.

  Fukushi Hirayama, Hiroyuki Koshio, Tsukasa Ishihara, Shunichiro Hachiya, Keizo Sugasawa, Yuji Koga, Norio Seki, Ryouta Shiraki, Takeshi Shigenaga, Yoshiyuki Iwatsuki, Yumiko Moritani, Kenichi Mori, Takeshi Kadokura, Tomihisa Kawasaki, Yuzo Matsumoto, Shuichi Sakamoto, Shin-ichi Tsukamoto
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  ABSTRACT: Inhibitors of factor Xa (FXa), a crucial serine protease in the coagulation cascade, have attracted a great deal of attention as a target for developing antithrombotic agents. We previously reported findings from our optimization study of a high-throughput screening (HTS) derived lead compound 1a that resulted in the discovery of potent amidine-containing FXa inhibitors represented by compound 2. We also conducted an alternative optimization study of 1a without incorporating a strong basic amidine group, which generally has an adverse effect on the pharmacokinetic profile after oral administration. Replacement of 4-methoxybenzene with a 1,4-benzodiazepine structure and introduction of a hydroxy group at the central benzene led to the discovery of the potent and orally effective factor Xa inhibitor 14i (darexaban, YM150). Subsequent extensive study revealed a unique aspect to the pharmacokinetic profile of this compound, wherein the hydroxy moiety of 14i is rapidly transformed into its glucuronide conjugate 16 (YM-222714) as an active metabolite after oral administration and it plays a major role in expression of potent anticoagulant activity in plasma. The distinctive, potent activity of inhibitor 14i after oral dosing was explained by this unique pharmacokinetic profile and its favorable membrane permeability. Compound 14i is currently undergoing clinical development for prevention and treatment of thromboembolic diseases.
  Journal of Medicinal Chemistry 12/2011; 54(23):8051-65. · 4.80 Impact Factor
• Article: Pharmacological profile of AS1670542, a novel orally-active human thrombopoietin receptor agonist.

  Masaki Abe, Ken-Ichi Suzuki, Chinatsu Sakata, Keizo Sugasawa, Fukushi Hirayama, Yuji Koga, Tomihisa Kawasaki, Shin Naganuma, Hiroyuki Itoh
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  ABSTRACT: Eltrombopag, an orally-active small molecule thrombopoietin (TPO) receptor agonist, was used for the first time in 2008 to treat patients with chronic idiopathic thrombocytopenic purpura. Here, we investigated the pharmacological effect of a new orally-active small molecule TPO receptor agonist which may be effective in treating these patients. 50% effective concentration values for cell proliferation with AS1670542 or eltrombopag were 1.9 and 13nM, respectively, while those for megakaryocyte colony formation from human cord blood CD34(+) cells with AS1670542 or eltrombopag were 260 and 950nM, respectively. On Day 14 after the start of administration, AS1670542 significantly increased the number of human platelets in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice with transplanted human hematopoietic stem cells at 0.3 (P<0.05); in contrast, while administration of eltrombopag also increased the numbers of these platelets at 30mg/kg/day (P=0.058), no statistical significance was noted in the increase. Here, we identified AS1670542, a novel orally-active TPO receptor agonist which mimics the biological activity of TPO and may demonstrate greater in vitro and in vivo pharmacologically efficacy than eltrombopag.
  European journal of pharmacology 10/2010; 650(1):58-63. · 2.59 Impact Factor
• Article: AKR-501 (YM477) a novel orally-active thrombopoietin receptor agonist.

  Mari Fukushima-Shintani, Ken-ichi Suzuki, Yoshiyuki Iwatsuki, Masaki Abe, Keizo Sugasawa, Fukushi Hirayama, Tomihisa Kawasaki, Tatsutoshi Nakahata
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  ABSTRACT: Thrombopoietin (TPO) is the principal physiologic regulator of platelet production. We have searched for small molecule compounds that mimic the action of TPO by using human TPO receptor-expressed in Ba/F3 cells, resulting in the discovery of AKR-501 (YM477). AKR-501 specifically targeted the TPO receptor and stimulated megakaryocytopoiesis throughout the development and maturation of megakaryocytes just as rhTPO did. AKR-501, however, was shown to be effective only in humans and chimpanzees with high species specificity. Therefore, we examined the in vivo platelet-increasing effect of AKR-501 in human platelet producing non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice transplanted with human fetal liver CD34(+) cells. Daily oral administration of AKR-501 dose-dependently increased the number of human platelets in these mice, with significance achieved at doses of 1 mg/kg and above. The peak unbound plasma concentrations of AKR-501 after administration at 1 mg/kg in NOD/SCID mice were similar to those observed following administration of an active oral dose in human subjects. These results suggest that AKR-501 is an orally-active TPO receptor agonist that may be useful in the treatment of patients with thrombocytopenia.
  European Journal Of Haematology 02/2009; 82(4):247-54. · 2.61 Impact Factor
• Article: AKR-501 (YM477) in combination with thrombopoietin enhances human megakaryocytopoiesis.

  Mari Fukushima-Shintani, Ken-ichi Suzuki, Yoshiyuki Iwatsuki, Masaki Abe, Keizo Sugasawa, Fukushi Hirayama, Tomihisa Kawasaki
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  ABSTRACT: AKR-501 (YM477) is an orally active thrombopoietin (TPO) receptor agonist that mimics the biological effect of TPO in vitro and in vivo. Here, we report that AKR-501 in combination with TPO has additive effect on megakaryocytopoiesis. Granulocyte colony-stimulating factor-mobilized human peripheral blood CD34+ cells were cultured with AKR-501, TPO, or a combination of the two in serum-free liquid culture system. The numbers of hematopoietic progenitor cells, megakaryocytic progenitor cells, and megakaryocytes were measured using flow cytometry. Further, the effect of AKR-501 on TPO binding to TPO receptor was examined. Both AKR-501 and TPO alone increased the number of megakaryocytes, and the maximum activities of AKR-501 and TPO were similar. Interestingly, in the presence of TPO concentrations producing maximal stimulation, the addition of AKR-501 increased the number of megakaryocytes to about 200% of that generated with TPO only. In the time course experiment, the combination of AKR-501 and TPO augmented the numbers of hematopoietic progenitor cells and colony-forming unit in culture in the early stages. Thus, the combination of AKR-501 and TPO enhanced not only the differentiation into megakaryocytes, but also the expansion of human hematopoietic progenitor cells. Further, AKR-501 did not inhibit TPO binding to the TPO receptor. This result indicated the possibility that AKR-501 and TPO may act simultaneously on the TPO receptor, and this could be responsible for their additive effect of on megakaryocytopoiesis. This study suggests that AKR-501 would be useful for the treatment of thrombocytopenia even at high plasma levels of endogenous TPO following chemotherapy.
  Experimental Hematology 08/2008; 36(10):1337-42. · 2.90 Impact Factor
• Article: Prodrug-based design, synthesis, and biological evaluation of N-benzenesulfonylpiperidine derivatives as novel, orally active factor Xa inhibitors.

  Tsukasa Ishihara, Norio Seki, Fukushi Hirayama, Masaya Orita, Hiroyuki Koshio, Yuta Taniuchi, Yumiko Sakai-Moritani, Yoshiyuki Iwatsuki, Seiji Kaku, Tomihisa Kawasaki, Yuzo Matsumoto, Shin-ichi Tsukamoto
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  ABSTRACT: We describe here our investigation of a new series of orally active fXa inhibitors based on a prodrug strategy. Solid-phase parallel synthesis identified a unique series of fXa inhibitors with a substituted benzenesulfonyl group as a novel S4 binding element. This series resulted in compound 39, which exhibited potent inhibitory activity against fXa (IC50 = 13 nM) and excellent selectivity over thrombin (>7000-fold). The masking of its highly hydrophilic groups led to the creation of related prodrug 28, which demonstrated an anticoagulant effect after oral dosing.
  Bioorganic & Medicinal Chemistry 06/2007; 15(12):4175-92. · 2.92 Impact Factor
• Article: Design, synthesis and biological activity of selective and orally available TF/FVIIa complex inhibitors containing non-amidine P1 ligands.

  Masanori Miura, Norio Seki, Takanori Koike, Tsukasa Ishihara, Tatsuya Niimi, Fukushi Hirayama, Takeshi Shigenaga, Yumiko Sakai-Moritani, Ayako Tagawa, Tomihisa Kawasaki, Shuichi Sakamoto, Minoru Okada, Mitsuaki Ohta, Shin-Ichi Tsukamoto
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  ABSTRACT: We found the novel selective and orally available non-amidine TF/FVIIa complex inhibitor 21e, 4-({[(1S)-(aminocarbonyl)-3-methylbutyl]amino}carbonyl)-2'-({[4- (aminomethyl)phenyl]amino}carbonyl)-4'-(methylamino)biphenyl-2- carboxylic acid. The derivatives were synthesized by conversions of the isobutyl moiety and the introduction of alkylamino groups to 4'-position of the central phenyl ring of compounds 2a and 2b reported previously. Some compounds show increased in vitro anti-TF/FVIIa and PT prolongation activities. Among them, compound 21e reached and sustained micromolar plasma concentration levels of up to 2h after oral administration in mice. Moreover, compound 21e did not prolong the bleeding time even at the highest dose level in cynomolgus monkeys, while PT was prolonged 3.7-fold increases at this dose.
  Bioorganic & Medicinal Chemistry 02/2007; 15(1):160-73. · 2.92 Impact Factor
• Article: Potent and selective TF/FVIIa inhibitors containing a neutral P1 ligand.

  Masanori Miura, Norio Seki, Takanori Koike, Tsukasa Ishihara, Tatsuya Niimi, Fukushi Hirayama, Takeshi Shigenaga, Yumiko Sakai-Moritani, Tomihisa Kawasaki, Shuichi Sakamoto, Minoru Okada, Mitsuaki Ohta, Shin-ichi Tsukamoto
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  ABSTRACT: Inhibition of tissue factor/factor VIIa complex (TF/FVIIa) is an attractive strategy for antithrombotic therapies. We began with an investigation of a non-amidine TF/FVIIa inhibitor based on a modification of amidine compound 1. Optimization of the substituents on the P1 phenyl portion of the compound 1 led to a neutral or less basic alternative for the 4-amidinophenyl moiety. By further optimization of the substituents on the central phenyl ring, a highly potent and selective TF/FVIIa inhibitor 17d was discovered.
  Bioorganic & Medicinal Chemistry 01/2007; 14(23):7688-705. · 2.92 Impact Factor
• Article: One‐Pot Synthetic Procedure for2,2′‐Disubstituted Biaryls via the Suzuki Coupling Reaction of Aryl Triflates in a Biphasic Solvent System

  Masanori Miura, Takanori Koike, Tsukasa Ishihara, Fukushi Hirayama, Shuichi Sakamoto, Minoru Okada, Mitsuaki Ohta, Shin‐ichi Tsukamoto
  Synthetic Communications 01/2006; 36(24):3809-3820. · 1.06 Impact Factor
• Article: An easy access to 7-methyl-2-naphthalenecarbonitrile.

  Hiroyuki Koshio, Tsukasa Ishihara, Hiroyoshi Yamada, Fukushi Hirayama, Yuzo Matsumoto, Isao Yanagisawa
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  ABSTRACT: A practical and cost-effective procedure has been developed for the synthesis of 7-methyl-2-naphthalenecarbonitrile, the precursor of the anticoagulant agents YM-60828 or YM-96765. This new route generates the key intermediate in only two steps from readily available 3-cyanopropionaldehyde dimethyl acetal and m-tolualdehyde, without requiring chromatographic purification. The synthesis involves condensation of the cyano derivative with the aldehyde and subsequent cyclodehydration.
  CHEMICAL & PHARMACEUTICAL BULLETIN 05/2005; 53(4):448-50. · 1.59 Impact Factor
• Article: Synthesis and biological activity of novel 1,2-disubstituted benzene derivatives as factor Xa inhibitors.

  Hiroyuki Koshio, Fukushi Hirayama, Tsukasa Ishihara, Ryouta Shiraki, Takeshi Shigenaga, Yuta Taniuchi, Kazuo Sato, Yumiko Moritani, Yoshiyuki Iwatsuki, Seiji Kaku, Naoko Katayama, Tomihisa Kawasaki, Yuzo Matsumoto, Shuichi Sakamoto, Shin-ichi Tsukamoto
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  ABSTRACT: Factor Xa (fXa) is a serine protease that plays a pivotal role in the coagulation cascade. High-throughput screening of the Yamanouchi compound library yielded lead compound 1 with the ability to inhibit fXa at micromolar concentrations. To improve its fXa inhibitory activity and its oral anticoagulant activity, the linker between benzamidine and the central benzene ring was modified and a carboxyl group was introduced at the central benzene ring. The resulting compounds 40b (YM-203552), 41a (YM-202054), and 41c (YM-203558) exhibited potent fXa inhibitory activity and oral anticoagulant activity. In particular, YM-203558 exhibited the most potent oral anticoagulant activity, prolonging PT more than 3-fold at 0.5 and 2.0 h. Additionally, these compounds showed a high degree of selectivity for other serine proteases.
  Bioorganic & Medicinal Chemistry 03/2005; 13(4):1305-23. · 2.92 Impact Factor
• Article: Orally active factor Xa inhibitor: synthesis and biological activity of masked amidines as prodrugs of novel 1,4-diazepane derivatives.

  Hiroyuki Koshio, Fukushi Hirayama, Tsukasa Ishihara, Hiroyuki Kaizawa, Takeshi Shigenaga, Yuta Taniuchi, Kazuo Sato, Yumiko Moritani, Yoshiyuki Iwatsuki, Toshio Uemura, Seiji Kaku, Tomihisa Kawasaki, Yuzo Matsumoto, Shuichi Sakamoto, Shin-ichi Tsukamoto
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  ABSTRACT: Factor Xa (fXa) is a serine protease, which plays a pivotal role in the coagulation cascade. To improve the oral anticoagulant activity of fXa inhibitors containing a 1,4-diazepane moiety as the P4 part, a prodrug strategy was examined. Among the compounds evaluated in this study, amidoxime prodrugs bearing an ester moiety, such as compounds 21 and 30, showed effective oral anticoagulant activity in mice.
  Bioorganic & Medicinal Chemistry 11/2004; 12(20):5415-26. · 2.92 Impact Factor
• Article: Synthesis and biological activity of novel 1,4-diazepane derivatives as factor Xa inhibitor with potent anticoagulant and antithrombotic activity.

  Hiroyuki Koshio, Fukushi Hirayama, Tsukasa Ishihara, Yuta Taniuchi, Kazuo Sato, Yumiko Sakai-Moritani, Seiji Kaku, Tomihisa Kawasaki, Yuzo Matsumoto, Shuichi Sakamoto, Shin-ichi Tsukamoto
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  ABSTRACT: Factor Xa (fXa) is a serine protease involved in the coagulation cascade, which has received great interest as a potential target for the development of new antithrombotic drugs. Herein we report a novel series of fXa inhibitors in which the 1,4-diazepane moiety was designed to interact with the S4 aryl-binding domain of the fXa active site. Compound 13 (YM-96765) showed potent fXa inhibitory activity (IC(50) = 6.8 nM) and effective antithrombotic activity without prolonging bleeding time.
  Bioorganic & Medicinal Chemistry 06/2004; 12(9):2179-91. · 2.92 Impact Factor
• Article: Design, synthesis and biological activity of YM-60828 derivatives. Part 2: potent and orally-bioavailable factor Xa inhibitors based on benzothiadiazine-4-one template.

  Fukushi Hirayama, Hiroyuki Koshio, Naoko Katayama, Tsukasa Ishihara, Hiroyuki Kaizawa, Yuta Taniuchi, Kazuo Sato, Yumiko Sakai-Moritani, Seiji Kaku, Hiroyuki Kurihara, Tomihisa Kawasaki, Yuzo Matsumoto, Shuichi Sakamoto, Shin-ichi Tsukamoto
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  ABSTRACT: Compound YM-60828 was previously characterized in our laboratory as a potent, selective and orally-bioavailable Factor Xa (FXa) inhibitor. The L-shape conformation of this compound in the active site of FXa was recognized as an important factor in displaying its FXa inhibitory activity. This led to the exploration of conformationally restricted cyclic scaffolds bearing a similar active conformation. The current study investigated a novel series of benzothiadiazine-4-one based compounds as FXa inhibitors. Structure-activity relationship (SAR) investigations revealed some potent FXa inhibitors that were selected for further in vitro and ex vivo anticoagulant studies. Among them, compound 6j (YM-169920) was proved to be most effective anticoagulant in this series. The synthesis and SAR in addition to docking studies of this class of inhibitors are described.
  Bioorganic & Medicinal Chemistry 03/2003; 11(3):367-81. · 2.92 Impact Factor
• Article: Antithrombotic effects of YM466, a synthesized direct inhibitor of factor Xa, in an arterio‐venous shunt thrombosis model in squirrel monkeys

  Yoshiyuki Iwatsuki, Seiji Kaku, Yumiko Moritani, Yuta Taniuchi, Fukushi Hirayama, Hiroyuki Koshio, Yuzo Matsumoto, Yuji Mano, Tomihisa Kawasaki
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  ABSTRACT: The antithrombotic effects of YM466, a synthetic direct inhibitor of human factor Xa (FXa), were evaluated in an arterio-venous shunt thrombosis model in squirrel monkeys. YM466 significantly inhibited thrombus formation after continuous IV zx infusion at doses of 3–30 µg/kg/h. Although prothrombin time (PT) was significantly prolonged at doses of 10 and 30 µg/kg/h, this effect was small (1.2- and 1.4-fold of the control, respectively). Furthermore, YM466 had no effect on template bleeding time and activated partial thromboplastin time at any dose. Plasma anti-FXa activity increased in a dose-dependent manner correlating with the antithrombotic effect of YM466. Thrombin-antithrombin III complex levels decreased to less than normal levels at 30 µg/kg/h of YM466. Mean plasma concentrations of YM466 measured by LC/MS/MS were 2.5, 10.5, 27.4, and 75.5 ng/ml at doses of 1, 3, 10, and 30 µg/kg/h, respectively. These results suggest that YM466 is a safe antithrombotic agent with low bleeding risk, and that plasma anti-FXa activity may be a suitable parameter for monitoring its antithrombotic effect. Drug Dev. Res. 58:190–195, 2003. © 2003 Wiley-Liss, Inc.
  Drug Development Research 01/2003; 58(2):190 - 195. · 1.19 Impact Factor
• Article: Design, synthesis and biological activity of YM-60828 derivatives: potent and orally-bioavailable factor Xa inhibitors based on naphthoanilide and naphthalensulfonanilide templates.

  Fukushi Hirayama, Hiroyuki Koshio, Tsukasa Ishihara, Susumu Watanuki, Shunichiro Hachiya, Hiroyuki Kaizawa, Takahiro Kuramochi, Naoko Katayama, Hiroyuki Kurihara, Yuta Taniuchi, Kazuo Sato, Yumiko Sakai-Moritani, Seiji Kaku, Tomihisa Kawasaki, Yuzo Matsumoto, Shuichi Sakamoto, Shin-ichi Tsukamoto
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  ABSTRACT: Factor Xa (FXa) is a serine protease which plays a pivotal role in the coagulation cascade. The inhibition of FXa has received great interest as a potential target for the development of new antithrombotic drug. Herein we describe a series of novel 7-amidino-2-naphthoanilide and 7-amidino-2-naphthalensulfonanilide derivatives which are potent FXa inhibitors. These scaffolds are rigid and are allowed to adopt an L-shape conformation which was estimated as the active conformation based on a docking study of YM-60828 with FXa. Optimization of the side chain at the central aniline nitrogen of 7-amidino-2-naphthoanilide has led to several potent and orally active FXa inhibitors. 5h (YM-169964), the best compound of these series, showed potent FXa inhibitory activity (IC(50)=3.9nM) and effectively prolonged prothrombin time by 9.6-fold ex vivo at an oral dose of 3mg/kg in squirrel monkeys.
  Bioorganic & Medicinal Chemistry 09/2002; 10(8):2597-610. · 2.92 Impact Factor
• Article: The discovery of YM-60828: a potent, selective and orally-bioavailable factor Xa inhibitor.

  Fukushi Hirayama, Hiroyuki Koshio, Naoko Katayama, Hiroyuki Kurihara, Yuta Taniuchi, Kazuo Sato, Nami Hisamichi, Yumiko Sakai-Moritani, Tomihisa Kawasaki, Yuzo Matsumoto, Isao Yanagisawa
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  ABSTRACT: Since Factor Xa (FXa) is well known to play a central role in thrombosis and hemostasis, inhibition of FXa is an attractive target for antithrombotic strategies. As a part of our investigation of a non-peptide, orally available FXa inhibitor, we found that a series of N-[(7-amidino-2-naphthyl)methyl]aniline derivatives possessed potent and selective inhibitory activities. Structure--activity relationship (SAR) of the substituent (R(1)) on the central aniline moiety suggested that increasing lipophilicity caused a detrimental effect on anticoagulant activity (prothrombin time assay) in plasma. Several compounds bearing a hydrophilic substituent in R(1) showed not only potent FXa inhibitory activities but also high anticoagulant activities. The best compound in this series was sulfamoylacetic acid derivative (YM-60828) which was a potent, selective and orally bioavailable FXa inhibitor and was chosen for clinical development.
  Bioorganic & Medicinal Chemistry 06/2002; 10(5):1509-23. · 2.92 Impact Factor
• Article: Antithrombotic effects of YM-60828 in three thrombosis models in guinea pigs

  Kazuo Sato, Tomihisa Kawasaki, Nami Hisamichi, Yuta Taniuchi, Fukushi Hirayama, Hiroyuki Koshio, Masato Ichihara, Yuzo Matsumoto
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  ABSTRACT: The antithrombotic effects of a novel factor Xa inhibitor, YM-60828 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]acetic acid dihydrochloride), in three thrombosis models in guinea pigs were studied in comparison with its effect on bleeding time. The antithrombotic effects of YM-60828 were most pronounced in the venous thrombosis and the arterio-venous shunt models but YM-60828 showed 10-fold weaker effects in the carotid thrombosis model. However, YM-60828 prolonged bleeding time at a much higher dose than that required in all thrombosis models. In conclusion, YM-60828 exerted its antithrombotic effects without prolonging bleeding time in all thrombosis models and may be of clinical value not only in venous thrombosis but also in arterial thrombosis.
  European Journal of Pharmacology 06/1998; · 2.52 Impact Factor
• Article: Antithrombotic effect of YM-75466 is separated from its effect on bleeding time and coagulation time

  Kazuo Sato, Seiji Kaku, Fukushi Hirayama, Hiroyuki Koshio, Yuzo Matsumoto, Tomihisa Kawasaki, Yuichi Iizumi
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  ABSTRACT: The antithrombotic effects of YM-75466 ([N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl]sulfamoyl]acetic acid monomethane sulfonate), a novel orally-active factor Xa inhibitor, and its effects on bleeding time and coagulation time were studied in rats and compared with those of warfarin. Both agents were orally administered. In the venous thrombosis model, YM-75466 and warfarin inhibited thrombus formation dose-dependently, with ID50 values of 3.3 and 0.56 mg/kg, respectively. Ex vivo study showed that both YM-75466 and warfarin prolonged prothrombin time dose-dependently, with doses, causing a two-fold prolongation of prothrombin time in the control group, of 89 and 0.38 mg/kg, respectively. In bleeding time studies, YM-75466 and warfarin prolonged bleeding time dose-dependently, with doses, causing a two-fold prolongation of bleeding time in the control group, of >100 and 0.43 mg/kg, respectively. These results show that the antithrombotic effects of YM-75466 are markedly separate from its effects on bleeding time and coagulation time compared with warfarin.
  European Journal of Pharmacology.
• Article: Relationship between the antithrombotic effect of YM-75466, a novel factor Xa inhibitor, and coagulation parameters in rats

  Kazuo Sato, Yuta Taniuchi, Tomihisa Kawasaki, Fukushi Hirayama, Hiroyuki Koshio, Yuzo Matsumoto
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  ABSTRACT: The relationship between the antithrombotic effects of intravenous infusions of YM-75466 [N-[4-[(1-acetimidoyl-4-piperidyl)oxy]phenyl]-N-[(7-amidino-2-naphthyl)methyl] sulfamoyl]acetic acid monomethanesulfonate), a novel factor Xa (FXa) inhibitor, and various coagulation parameters (prothrombin time, activated partial thromboplastin time, thrombin–antithrombin III complex (TAT), anti-FXa activity and anti-thrombin activity) in rats was studied and compared with results for heparin. In the arterio–venous shunt model, both agents exerted antithrombotic effects in a dose-dependent manner. Coagulation parameters were studied simultaneously with antithrombotic effects. YM-75466 did not prolong coagulation time even at the dose which exerted significant antithrombotic effects, while it decreased TAT level in plasma in a dose-dependent manner. YM-75466 exerted anti-FXa activity but not anti-thrombin activity. In contrast, heparin prolonged activated partial thromboplastin time in a dose-dependent manner and decreased TAT level in plasma with increasing inhibition of thrombus formation. Heparin exerted both anti-FXa and anti-thrombin activity in a dose-dependent manner. These results suggest that TAT is a suitable parameter for monitoring the antithrombotic effect of YM-75466 in the arterio–venous shunt model in rats and that YM-75466, unlike heparin, exerts its antithrombotic effect through specific inhibition of FXa without any effect on thrombin.
  European Journal of Pharmacology.