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Chemical Compound Review

SureCN6188057     (2S)-3-(7- carbamimidoylnaphthalen-2- yl)-2...

Synonyms: KB-69403, LS-94815, dx-9065a, AC1L3U17, DX 9065a, ...
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Disease relevance of (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid

  • In the AV shunt model, DX-9065a inhibited thrombus formation to 51% on intravenous administration of 0.23 mg/kg and to 60% when given orally at 23.3 mg/kg [1].
  • Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats [2].
  • However, neither DX-9065a, a selective inhibitor of factor Xa, nor an inactive derivative of factor VIIa (DEGR-F.Vlla) that selectively inhibits factor VIIa activity, had any effect on LPS-induced hypotension despite their potent anticoagulant effects [3].
  • DX-9065a, an orally active factor Xa inhibitor, does not facilitate haemorrhage induced by tail transection or gastric ulcer at the effective doses in rat thrombosis model [4].
  • DS significantly increased CGRP release from isolated rat dorsal root ganglion neurons (DRG) in vitro, while DX-9065a, a selective inhibitor of activated factor X, did not [5].

High impact information on (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid


Chemical compound and disease context of (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid

  • We compared the antithrombotic properties of a factor Xa inhibitor (DX-9065a) with those of a thrombin inhibitor (melagatran) in a rat disseminated intravascular coagulation model and a rat venous thrombosis model [9].
  • Patients whose plasma was tested for suspected lupus anticoagulant and who have been given DX-9065a or Argatroban may have false-positive results with the TTIT tests and DRWT [10].
  • This study compared the antithrombotic activity of a novel FXa inhibitor, ZK-807834 [MW, 527 D; Ki (human FXa), 0.11 nM], with recombinant tick anticoagulant peptide [rTAP; MW, 6,685 D; Ki, (human FXa) = 0.28 nM], and DX-9065a [MW 445 D, Ki (human FXa), 40 nM] in rabbits with arterial thrombosis induced by electrical vascular injury [11].
  • The composite of death, myocardial infarction, or urgent revascularization occurred in 19.5%, 19.3%, and 11.9% (P = 0.125 for heparin vs. high-dose DX-9065a) of patients; major or minor bleeding occurred in 7.7%, 4.2%, and 7.0% of patients; and major bleeding in 3.3%, 0.8%, and 0.9% of patients [12].

Biological context of (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid

  • Intravenous administration of 2.33 mg/kg of DX-9065a did not affect the bleeding time [1].
  • In both DIC models, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin/fibrinogen degradation products (FDP), fibrinogen level, prothrombin time, activated partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi [2].
  • Here, the anti-fXa and anti-prothrombinase activities of DX-9065a which is an active-site directed inhibitor of fXa, and therapeutic heparins which are dependent on antithrombin (AT) for their anticoagulant function, were studied in amidolytic and proteolytic activity assays [13].
  • These results suggest that direct and selective inhibition of factor Xa by DX-9065a is preferable for the treatment of thrombosis in the aspect of lack of compromising primary hemostasis [14].
  • DX-9065a up to 100 microM had no effects on human platelet aggregation [15].

Anatomical context of (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid


Associations of (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid with other chemical compounds

  • In contrast to DX-9065a (10 or 30 mg/kg), warfarin (0.75 mg/kg) significantly prolonged the bleeding time [4].
  • METHODS: To examine the effect of DX-9065a on the factor Xa-induced proliferation of cultured human mesangial cells, we measured thymidine incorporation and cell numbers [8].
  • In particular, (R)-18a having an (R)-configuration at the 2-position of the indoline ring exhibited the most potent FXa inhibitory activity in vitro, more potent than DX-9065a [19].
  • To study the influence of these agents on INR, we used several anti-IIa agents (argatroban, recombinant hirudin, efegatran, and PEG-hirudin) and anti-Xa drugs (pentasaccharides such as fondaparinux and idraparinux, DX-9065a and JTV-803) [20].
  • These include the low molecular weight heparins (LMWHs), antithrombin agents such as the Hirudin, Hirulog and Argatroban and indirect and direct anti-Xa drugs, represented by Pentasaccharide (Arixtra) and DX 9065a, respectively [21].

Gene context of (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid

  • Low concentration DX-9065a did not increase TFPI levels above control (0.8% higher, p = 0.91) [18].
  • DX-9065a inhibited FXa-induced IL-6 mRNA expression and NF-kappaB activation [22].
  • The conversion of pro-MMP-2 to MMP-2 was inhibited by a selective FXa inhibitor (DX-9065a) at 3 to 10 micromol/L [23].
  • Moreover, neither the plasma levels of NO2-/NO3- nor lung iNOS activity were affected by administration of DX-9065a and DEGR-F.VIIa [3].
  • In the experimental model of rat endotoxemia, TF and TF mRNA expression levels in the liver were reduced by DX-9065a [24].

Analytical, diagnostic and therapeutic context of (2S)-3-(7-carbamimidoylnaphthalen-2-yl)-2-[4-[(3S)-1-ethanimidoylpyrrolidin-3-yl]oxyphenyl]propanoic acid

  • After intravenous or oral administration, DX-9065a significantly prolonged APTT and PT with a dose dependent manner [15].
  • A selective inhibitor of factor Xa, DX-9065a, attenuates neutrophil chemoattractant production after ischemia/reperfusion injury of the rat liver [25].
  • Radioimmunoassay method for DX-9065a, an anticoagulant agent. Development, evaluation and application to human plasma [26].
  • DX-9065a prolonged the r-time on thrombelastography [27].
  • However, first clinical trials in healthy volunteers and in patients with cardiovascular diseases demonstrated a predictable pharmacokinetic and pharmacodynamic behavior of DX-9065a after either intravenous bolus injection or constant infusion, as well as its high safety, especially a lower bleeding risk compared with other commonly used drugs [28].


  1. DX-9065a, an orally active, specific inhibitor of factor Xa, inhibits thrombosis without affecting bleeding time in rats. Hara, T., Yokoyama, A., Tanabe, K., Ishihara, H., Iwamoto, M. Thromb. Haemost. (1995) [Pubmed]
  2. Effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against experimental disseminated intravascular coagulation in rats. Yamazaki, M., Asakura, H., Aoshima, K., Saito, M., Jokaji, H., Uotani, C., Kumabashiri, I., Morishita, E., Ikeda, T., Matsuda, T. Thromb. Haemost. (1994) [Pubmed]
  3. Recombinant tissue factor pathway inhibitor prevents lipopolysaccharide-induced systemic hypotension in rats by inhibiting excessive production of nitric oxide. Enkhbaatar, P., Okajima, K., Uchiba, M., Isobe, H., Okabe, H. Thromb. Haemost. (2001) [Pubmed]
  4. DX-9065a, an orally active factor Xa inhibitor, does not facilitate haemorrhage induced by tail transection or gastric ulcer at the effective doses in rat thrombosis model. Tanabe, K., Morishima, Y., Shibutani, T., Terada, Y., Hara, T., Shinohara, Y., Aoyagi, K., Kunitada, S., Kondo, T. Thromb. Haemost. (1999) [Pubmed]
  5. Danaparoid sodium reduces ischemia/reperfusion-induced liver injury in rats by attenuating inflammatory responses. Harada, N., Okajima, K., Kohmura, H., Uchiba, M., Tomita, T. Thromb. Haemost. (2007) [Pubmed]
  6. Studies on the different modes of action of the anticoagulant protease inhibitors DX-9065a and Argatroban. II. Effects on fibrinolysis. Nagashima, H. J. Biol. Chem. (2002) [Pubmed]
  7. Tolerability, pharmacokinetics, and pharmacodynamics of DX-9065a, a new synthetic potent anticoagulant and specific factor Xa inhibitor, in healthy male volunteers. Murayama, N., Tanaka, M., Kunitada, S., Yamada, H., Inoue, T., Terada, Y., Fujita, M., Ikeda, Y. Clin. Pharmacol. Ther. (1999) [Pubmed]
  8. Role of coagulation factor Xa and protease-activated receptor 2 in human mesangial cell proliferation. Tanaka, M., Arai, H., Liu, N., Nogaki, F., Nomura, K., Kasuno, K., Oida, E., Kita, T., Ono, T. Kidney Int. (2005) [Pubmed]
  9. Different antithrombotic properties of factor Xa inhibitor and thrombin inhibitor in rat thrombosis models. Furugohri, T., Shiozaki, Y., Muramatsu, S., Honda, Y., Matsumoto, C., Isobe, K., Sugiyama, N. Eur. J. Pharmacol. (2005) [Pubmed]
  10. Differential effects of DX-9065a, argatroban, and synthetic pentasaccharide on tissue thromboplastin inhibition test and dilute Russell's viper venom test. Gerbutavicius, R., Iqbal, O., Messmore, H.L., Wehrmacher, W.H., Hoppensteadt, D.A., Gerbutaviciene, R., Griniute, R., Fareed, J. Clin. Appl. Thromb. Hemost. (2003) [Pubmed]
  11. Effects of ZK-807834, a novel inhibitor of factor Xa, on arterial and venous thrombosis in rabbits. Abendschein, D.R., Baum, P.K., Martin, D.J., Vergona, R., Post, J., Rumennik, G., Sullivan, M.E., Eisenberg, P.R., Light, D.R. J. Cardiovasc. Pharmacol. (2000) [Pubmed]
  12. First experience with direct, selective factor Xa inhibition in patients with non-ST-elevation acute coronary syndromes: results of the XaNADU-ACS Trial. Alexander, J.H., Yang, H., Becker, R.C., Kodama, K., Goodman, S., Dyke, C.K., Kleiman, N.S., Hochman, J.S., Berger, P.B., Cohen, E.A., Lincoff, A.M., Burton, J.R., Bovill, E.G., Kawai, C., Armstrong, P.W., Harrington, R.A. J. Thromb. Haemost. (2005) [Pubmed]
  13. DX-9065a inhibition of factor Xa and the prothrombinase complex: mechanism of inhibition and comparison with therapeutic heparins. Rezaie, A.R. Thromb. Haemost. (2003) [Pubmed]
  14. Antithrombotic and hemorrhagic effects of DX-9065a, a direct and selective factor Xa inhibitor: comparison with a direct thrombin inhibitor and antithrombin III-dependent anticoagulants. Morishima, Y., Tanabe, K., Terada, Y., Hara, T., Kunitada, S. Thromb. Haemost. (1997) [Pubmed]
  15. DX-9065a, a new synthetic, potent anticoagulant and selective inhibitor for factor Xa. Hara, T., Yokoyama, A., Ishihara, H., Yokoyama, Y., Nagahara, T., Iwamoto, M. Thromb. Haemost. (1994) [Pubmed]
  16. Contribution of lysosomes to concentrative uptake of DX-9065a into rat liver. Murayama, N., Nakaoka, M., Sudo, K. Journal of pharmaceutical sciences. (2006) [Pubmed]
  17. Factor Xa-inhibitor (DX-9065a) modulates the leukocyte-endothelial cell interaction in endotoxemic rat. Iba, T., Kidokoro, A., Fukunaga, M., Fuse, S., Suda, M., Kunitada, S., Hara, T. Shock (2002) [Pubmed]
  18. Vascular endothelial tissue factor pathway inhibitor kinetics in culture following exposure to DX-9065a--a selective and direct factor Xa inhibitor. Becker, R.C., Alexander, J.H., Li, Y., Robertson, T., Kunitada, S., Spencer, F.A., Yang, H., Harrington, R.A. J. Thromb. Thrombolysis (2004) [Pubmed]
  19. Indoline derivatives I: synthesis and factor Xa (FXa) inhibitory activities. Noguchi, T., Tanaka, N., Nishimata, T., Goto, R., Hayakawa, M., Sugidachi, A., Ogawa, T., Asai, F., Matsui, Y., Fujimoto, K. Chem. Pharm. Bull. (2006) [Pubmed]
  20. Anti-Xa and anti-IIa drugs alter international normalized ratio measurements: potential problems in the monitoring of oral anticoagulants. Tobu, M., Iqbal, O., Hoppensteadt, D., Neville, B., Messmore, H.L., Fareed, J. Clin. Appl. Thromb. Hemost. (2004) [Pubmed]
  21. Management of thrombotic and cardiovascular disorders in the new millenium. Fareed, J., Hoppensteadt, D.A., Bick, R.L. Clin. Appl. Thromb. Hemost. (2003) [Pubmed]
  22. DX-9065a inhibits proinflammatory events induced by gingipains and factor Xa. Matsushita, K., Imamura, T., Tomikawa, M., Tancharoen, S., Tatsuyama, S., Maruyama, I. J. Periodont. Res. (2006) [Pubmed]
  23. Factor Xa releases matrix metalloproteinase-2 (MMP-2) from human vascular smooth muscle cells and stimulates the conversion of pro-MMP-2 to MMP-2: role of MMP-2 in factor Xa-induced DNA synthesis and matrix invasion. Rauch, B.H., Bretschneider, E., Braun, M., Schrör, K. Circ. Res. (2002) [Pubmed]
  24. Inhibition of factor Xa suppresses the expression of tissue factor in human monocytes and lipopolysaccharide-induced endotoxemia in rats. Akahane, K., Okamoto, K., Kikuchi, M., Todoroki, H., Higure, A., Ohuchida, T., Kitahara, K., Takeda, S., Itoh, H., Ohsato, K. Surgery (2001) [Pubmed]
  25. Thrombin and factor Xa enhance neutrophil chemoattractant production after ischemia/reperfusion in the rat liver. Yamaguchi, Y., Okabe, K., Liang, J., Ohshiro, H., Ishihara, K., Uchino, S., Zhang, J.L., Hidaka, H., Yamada, S., Ogawa, M. J. Surg. Res. (2000) [Pubmed]
  26. Radioimmunoassay method for DX-9065a, an anticoagulant agent. Development, evaluation and application to human plasma. Murayama, N., Tanaka, S., Kikuchi, T., Nakaoka, M., Sudo, K. Journal of pharmaceutical and biomedical analysis. (1996) [Pubmed]
  27. Global anticoagulant effects of a synthetic anti-factor Xa inhibitor (DX-9065a): implications for interventional use. Tobu, M., Iqbal, O., Ma, Q., Schultz, C., Jeske, W., Hoppensteadt, D., Lewis, B., Fareed, D., Fareed, J. Clin. Appl. Thromb. Hemost. (2003) [Pubmed]
  28. DX-9065a, a direct inhibitor of factor Xa. Kaiser, B. Cardiovascular drug reviews. (2003) [Pubmed]
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