Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.21.6 (thromboplastin)
13,278 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibitory effects of 6-amidino-2-naphthyl-4-guanidinobenzoate X dimethanesulfonate (FUT-175) on the human Hageman factor fragment (HFf), factor Xa, thrombin, plasma kallikrein, and plasmin were studied. FUT-175 inhibited plasma kallikrein most (IC50 = 3.0 X 10(-9) M), followed by HFf (IC50 = 3.3 X 10(-7) M). FUT-175 was found to have an anticoagulant effect in the APTT and PT assay systems of human plasma. The concentration of FUT-175 for twofold increase in the clotting time in the APTT assay system was 5 X 10(-7) M.
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PMID:Inhibitory effect of a new synthetic protease inhibitor (FUT-175) on the coagulation system. 316 8

The effects of FUT-175 (6-amidino-2-naphthyl-4-guanidino benzoate-dimethanesulfonate), a new synthetic protease inhibitor, on endotoxin-induced experimental disseminated intravascular coagulation (DIC) were studied in rats. Experimental DIC was induced by a 4-hour sustained infusion of endotoxin at a dose of 100 mg/kg. The rats were infused continuously with FUT-175 at 0.001, 0.01, 0.1, 1.0 or 10.0 mg/kg into a femoral vein for 4 h. Simultaneously with the agent infusion, endotoxin (100 mg/kg/4 h) was administered into the contralateral femoral vein. A protective effect against DIC was noted in the rats treated with 0.01 or 0.1 mg/kg of FUT-175 in the following parameters: fibrinogen and fibrin degradation products, fibrinogen level, prothrombin time, partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi. These results demonstrated that FUT-175 reduces the extent of changes of the coagulation parameters caused by DIC.
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PMID:Effects of FUT-175, a new synthetic protease inhibitor on endotoxin-induced disseminated intravascular coagulation in rats. 666 5

Since activated factor X (FXa) is a coagulant enzyme that generates thrombin and participates in both intrinsic and extrinsic coagulation pathways, inhibition of FXa may be more effective than inactivation of thrombin for interrupting blood coagulation. To assess the possible effectiveness of FXa inhibition as an anticoagulant, we designed and synthesized 3-(amidinoaryl)-2-[4-[(3S)-3-pyrrolidinyloxy]phenyl]propanoi c acid derivatives as low molecular weight, nonpeptidic, orally active FXa inhibitors. These derivatives exhibited potent and highly selective anti-FXa activity in vitro and anticoagulant activity on oral administration. The most promising compound, (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]- 3-(7-amidino-2-naphthyl)propanoic acid hydrochloride pentahydrate (4,DX-9065a), inhibited 50% of FXa activity (IC50) at 0.07 microM, doubled plasma recalcification time (PRCT) at 0.5 microM, and significantly prolonged activated partial thromboplastin time (APTT) at a dose of 100 mg/kg on oral administration. In contrast with FXa inhibition, 4 showed no activity against thrombin (IC50 > 2000 microM).
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PMID:Dibasic (amidinoaryl)propanoic acid derivatives as novel blood coagulation factor Xa inhibitors. 816 62

Hypercoagulability is known to occur in the early phase of hemorrhagic shock. The prolongation of excessive clot formation after recovery from a shock state leads to the formation of microthrombi or disseminated intravascular coagulation which disturbs microcirculation, damaging organ function. The aim of the present study is to investigate the beneficial effect of a synthetic protease inhibitor, 6-amidino-2-naphthyl p-guanidinobenzoate dimethanesulfonate (nafamostat mesilate), in the attenuation of hypercoagulability in hemorrhagic shock. A model of hemorrhagic shock that simulates the clinical course of injured patients was created in anesthetized dogs. The animals were divided into two groups: a control group (group-C, n = 9) and an experimental group (group-E, n = 9). Animals received saline or 0.2 mg/kg of nafamostat mesilate respectively when their mean arterial pressure declined to 50 mmHg. The serum concentration of hydroxytryptamine (5-HT), prothrombin time (PT), and activated partial thromboplastin time (APTT) were determined as indicators of platelet activity and blood coagulation. In group-C, serum 5-HT was elevated significantly at 60 min after hemorrhagic shock but not so in group-E. The APTT at 30 and 60 min was shorter in group-C than in group-E. The PT at 30 min was also shorter in group-C. Plasma fibrin degradation products (FDP) increased at 60 min after the induction of shock in group-C. The results indicate that inadequate tissue perfusion in shock stimulates blood coagulation and that nafamostat mesilate might be beneficial in decreasing excessive blood coagulation.
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PMID:Nafamostat mesilate, a synthetic protease inhibitor, attenuated hypercoagulability in a canine model of hemorrhagic shock. 911 59

(+)-2S-2-[4-[[(3S)-1-Acetimidoyl-3- pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride pentahydrate (DX-9065a) is an antithrombin III (AT III)-independent and selective inhibitor of activated blood coagulation factor X (FXa). The aim of the present study was to compare the antithrombotic and hemorrhagic effects of DX-9065a with a direct thrombin inhibitor and AT III-dependent anticoagulants in rat models of thrombosis and bleeding. Rats were administered intravenously DX-9065a (0.1-1 mg/kg/h), argatroban (0.1-1 mg/k/h), low molecular weight heparin (25-100 anti-XaU/kg/h), unfractionated heparin (25-100 anti-XaU/kg/h) or Orgaran (30-300 anti-XaU/kg/h) for 1 h. DX-9065a dose-dependently inhibited both thrombus formation and elevation in plasma thrombin-AT III complex (TAT) level in a copper wire-inserted arteriovenous (AV) shunt model in rats. The dose required for 50% inhibition of thrombus formation was 0.27 mg/kg/h. DX-9065a did not prolong transection bleeding time up to 7.78 mg/kg/h. Argatroban and AT III-dependent anticoagulants also inhibited both thrombus formation and TAT elevation, but prolonged bleeding time at a slightly higher dose than the effective dose. 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.
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PMID: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. 940 21

The photodegradation reaction of (2S)-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3- (7-amidino-2-naphthyl) propanoic acid hydrochloride pentahydrate (DX-9065a), a new factor Xa inhibitor, was investigated in aqueous solution at various pH values (1.1-8.0) at 25 degrees C. The photodegradation of DX-9065a followed apparent first-order kinetics under artificial sunlight in a fairly good manner. The photodegradation rates of DX-9065a in a neutral solution were higher than those in acidic solution. The log k-pH profile indicated that the photodegradation rate of DX-9065a was related to the dissociation of the carboxyl group and suggested that the main photo-labile species was the carboxylate form. Further kinetic study showed that the carboxylate form of DX-9065a underwent decarboxylation quantitatively to produce D41-1077, the photodecarboxylation product, on irradiation, while the carboxylic acid form of DX-9065a did not perform any photodecarboxylation. Moreover, the photodecarboxylation mechanism was discussed in relation to the kinetics and photodegradation pathway.
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PMID:Photodecarboxylation of DX-9065a, a new factor Xa inhibitor, in aqueous solution. 946 45

In an in vitro study, anticoagulant and antiplatelet effects of the synthetic, direct factor Xa inhibitor DX-9065a, (+)-2S-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-a midino-2-naphthyl]propanoic acid hydrochloride pentahydrate, which shows a high affinity and selectivity towards the enzyme, were investigated. Anticoagulant actions of DX-9065a were studied in human plasma using global clotting assays [prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT) and Heptest]. The effect on thrombin generation was measured in whole blood by determining the plasma concentration of prothrombin fragment F1.2. The influence on agonist-induced platelet activation in whole blood was studied using flow cytometric analysis. DX-9065a caused a concentration-dependent prolongation of clotting times in the PT and APTT assay, whereas Heptest was less affected and TT was not influenced. Furthermore, DX-9065a strongly inhibited the generation of thrombin without and after coagulation activation. The factor Xa inhibitor did not affect platelet activation mediated by either thrombin receptor activating peptide, arachidonic acid or y-thrombin, but prevented tissue factor- and factor Xa-induced activation of platelets in a concentration-dependent manner. Inactivation of factor Xa by a highly effective and selective inhibitor, and the resulting inhibition of thrombin generation leads to strong anticoagulant and antiplatelet actions. The interference with the coagulation system at the early level of factor Xa is expected to be an effective approach for a successful anticoagulant/antithrombotic therapy.
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PMID:Inactivation of factor Xa by the synthetic inhibitor DX-9065a causes strong anticoagulant and antiplatelet actions in human blood. 1063 61

Sepimostat mesilate (FUT-187: 6-amidino-2-naphthyl 4-[(4,5-dihydro-1H-imidazol-2-yl) amino] benzoate dimethane sulfonate) is a newly synthesized serine protease inhibitor. In the present study, the oral administration of FUT-187 inhibited stasis-induced venous thrombosis in rats. We supposed that such effect of this compound was caused by its inhibitory effect on coagulation. However, the dose of FUT-187 that was effective at inhibiting thrombosis (10 and 30 mg/kg, po) had no effect on the plasma recalcification time (PRCT), activated partial thromboplastin time (APTT) and prothrombin time (PT) in rats. Therefore, we investigated the fibrinolytic activity of FUT-187 in rat plasma. The results revealed that rat plasma after FUT-187 administration exhibited increased amidolytic activity for a plasmin-, tissue-type plasminogen activator (t-PA)-, urokinase-type plasminogen activator (u-PA)-, factor Xa-, factor XIa- and factor XIIa-sensitive synthetic peptide substrate. On the other hand, the inhibitory effect of FUT-187 in the thrombosis model was not affected by additional treatment with epsilon-amino-n-caproic acid (EACA), a plasmin-mediated fibrinolysis inhibitor. These results suggest that even if FUT-187 enhanced fibrinolysis, it would be independent of a plasmin-mediated fibrinolytic pathway. To characterize the fibrinolytic activity, which might reduce the thrombus weight in the thrombosis model administered FUT-187, we carried out fibrinogen zymography, and clarified that FUT-187 enhanced the formation of a 20-kDa fibrinolytic fragment. Interestingly, this fragment was not affected by t-PA. Consequently, we consider that the inhibitory effect of FUT-187 on venous thrombosis model is caused by fibrinolysis, which is attributable to the 20-kDa fragment, rather than by inhibition of thrombus formation.
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PMID:Effect of sepimostat mesilate on experimental venous thrombosis in rats. 1122 42

Based on DuPont Pharmaceuticals' monobenzamidine lead structure SN429, we have designed the biphenyl 1-(2-naphthyl)-1H-pyrazole-5-carboxylamides as a novel series of non-basic factor Xa inhibitors. We have discovered that the displacement of the benzamidine moiety with substituted 2-naphthyl structures not only results in highly potent factor Xa inhibitors, but also significantly increases their enzyme specificity and oral bioavailability.
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PMID:Design, synthesis and biological activity of novel non-amidine factor Xa inhibitors. Part 1: P(1) structure-activity relationships of the substituted 1-(2-Naphthyl)-1H-pyrazole-5-carboxylamides. 1203 83

Effects of DX-9065a ((+)-2S-2-[4-[[(3S)-1-acetimidoyl-3-pyrrolidinyl]oxy]phenyl]-3-[7-amidino-2-naphthyl]propanoic acid hydrochloride pentahydrate), a dibasic propanoic acid and an inhibitor of factor Xa, were compared with those of argatroban, a low molecular weight thrombin inhibitor, on the ellagic acid-induced plantar skin thrombosis in the rats treated with tetrodotoxin and N(omega)-nitro-L-arginine. Plantar skin blood flow was measured with laser Doppler flow meters, and skin temperature of the hindlimb was monitored simultaneously. In order to induce thrombus in plantar skin vasculature, ellagic acid (300 microg, i.a.) was injected into a branch of femoral artery. The formation of thrombus in femoral and plantar vessels was assessed by light microscopy. Ellagic acid decreased plantar skin blood flow and skin temperature. Intravenous injections of DX-9065a (3 mg/kg) and argatroban (1-3 mg/kg) significantly inhibited the ellagic acid-induced disturbance of plantar skin blood flow and lowering skin temperature without affecting bleeding time. The oral administration of DX-9065a (30-100 mg/kg) significantly prevented the decrease in skin temperature induced by ellagic acid, but it partially inhibited the disturbance of plantar skin blood flow. DX-9065a and argatroban also prolonged prothrombin time in a dose-dependent manner. These results suggest that DX-9065a effectively prevented thrombosis produced by ellagic acid in the skin circulation without a risk of bleeding.
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PMID:Effects of DX-9065a, an inhibitor of factor Xa, on ellagic acid-induced plantar skin thrombosis assessed in tetrodotoxin- and N(omega)-nitro-L-arginine-treated rats. 1271 61


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