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

• The results demonstrated that, in the presence of thrombomodulin, argatroban dose dependently accelerated fibrinolysis of the clots, whereas DX-9065a did not [6].
• Studies on the different modes of action of the anticoagulant protease inhibitors DX-9065a and Argatroban. II. Effects on fibrinolysis [6].
• The pharmacokinetics of DX-9065a in human subjects after intravenous dosing was linear [7].
• Factor Xa induced the activation of ERK in mesangial cells and this activation was also completely inhibited by DX-9065a, but not inhibited by PAR1 antagonist [8].
• In this study, therefore, we studied the role of factor Xa and its receptor, protease-activated receptor 2 (PAR2) in mesangial cell proliferation and fibrin deposition, and examined ant-proliferative effects of a specific factor Xa inhibitor, DX-9065a, in cultured human mesangial cells [8].

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

• DX-9065a also suppressed factor Xa-triggered fibrin deposition on mesangial cell surface [8].
• 7. In contrast, carrier-mediated systems did not play a significant role in the uptake of DX-9065a by hepatocytes [16].
• Contribution of lysosomes to concentrative uptake of DX-9065a into rat liver [16].
• In summary, the Factor Xa inhibitor DX-9065a showed a protective effect on the microcirculation of endotoxemic rats by attenuating leukocyte-endothelial interaction [17].
• METHODS/RESULTS: Human umbilical vein endothelial cells were grown to confluence and incubated with unfractionated heparin (1.0 U/mL), enoxaparin (1.5 U/mL), or DX-9065a at low (10 ng/ml), moderate (30 ng/ml), or high (90 ng/ml) concentrations [18].

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].

References