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

---

Query: EC:3.4.21.5 (thrombin)
33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of heparin and the synthetic irreversible antithrombin D-phenylalanyl-L-prolyl-L-arginyl chloromethyl ketone (FPRCH2Cl) was studied on FeCl3-induced thrombotic occlusion of rat carotid arteries. Thrombocytopenia prevented occlusion in five of 7 rats for the 60 min observation period after FeCl3 injury demonstrating platelet dependence in this model of thrombosis. Intravenous injection of heparin (250 units/kg) followed by continuous infusion (250 units/kg/hr) failed to prevent occlusion in four of 6 rats whereas intravenous FPRCH2Cl infusion prevented occlusion at a dose of 200 nmol/kg/min during infusion in 6/6 rats. These findings indicate that thrombin plays a principle role in the platelet-dependent process of arterial thrombosis in FeCl3-damaged rat carotid arteries. Neutralization of the thrombogenic stimulus in this model by the thrombin inhibitor FPRCH2Cl suggests selective thrombin inhibition may be useful in the treatment of arterial thrombosis.
...
PMID:The effect of thrombin inhibition in a rat arterial thrombosis model. 178 27

Fluorinated ketone thrombin inhibitors based on the peptide sequence methyl-(D)-Phe-Pro-Arg-CF2R were synthesized: MDL 73,446 (1, R = F); MDL 73,775 (2, R = CF3); and MDL 75,579 (3, R = CH2CH2CH3). These were shown to be highly effective, slow binding inhibitors of thrombin. Anticoagulant activity was dose-dependent with 3 > 2 > 1 at doubling thrombin time and APTT, respectively. Anticoagulant activity corresponded with efficacy in a platelet-dependent (FeCl3-induced) rat carotid artery thrombosis model. Arterial occlusion was dose-dependently prolonged with 3 > 2 > 1 at doubling the occlusion time.
...
PMID:Synthesis and comparison of tripeptidylfluoroalkane thrombin inhibitors. 758 79

Endogenous nitric oxide (NO, endothelium-derived relaxing factor) was stimulatory for histamine- and suppressive for serotonin-induced paw edema of mice. This action was mediated by guanosine 3',5'-cyclic monophosphate production. Local injection of superoxide dismutase (SOD), catalase, NG-monomethyl-L-arginine (L-NMMA), methylene blue and Desferal (iron chelator) mixed with mediator suppressed histamine-induced edema at doses between 0.1 and 100 micrograms/kg and showed no or little stimulatory effect at higher doses. L-arginine reversed the effect of L-NMMA. Serotonin edema was enhanced by a high dose of these drugs. Their effect became suppressive as the histamine ratio was increased in edema induced by a histamine-serotonin mixture. This suggested that serotonin-induced vascular permeability decreased with a greater production of either O2- or NO. Cimetidine (H2-antagonist) was not effective in histamine edema of normal mice, but became suppressive (ED50 = 70 micrograms/kg) when 10 mg/kg L-NMMA was coinjected. SOD and methylene blue also rendered this edema sensitive to cimetidine. A simultaneous decrease in sensitivity to mepyramine (H1-antagonist) indicated that NO and oxyradicals kept H1-receptors activated. L-NMMA had no effect on bradykinin edema, but suppressed thrombin-, acetylcholine-, platelet-activating factor-, substance P- and FeCl3-induced paw edemata. Nitroprusside (NO donator) suppressed serotonin edema. N-Acetylcysteine and cytochrome c, but not ascorbate and hydroxyl radical scavengers suppressed histamine edema.
...
PMID:Opposite effect of superoxide dismutase, L-arginine analogues, methylene blue and desferal: suppression of histamine-induced and stimulation of serotonin-induced paw edema in mice. 835 90

As part of an effort to prepare efficacious and orally bioavailable analogs of the previously reported thrombin inhibitors 1a, b, we have synthesized a series of compounds that utilize 3,3-disubstituted propionic acid derivatives as P3 ligands. By removing the N-terminal amino group, the general oral bioavailability of this class of compounds was enhanced without excessively increasing the lipophilicity of the compounds. The overall properties of the molecules could be drastically altered depending on the nature of the groups substituted onto the 3-position of the P3 propionic acid moiety. A number of the compounds exhibited good oral bioavailability in rats and dogs, and numerous compounds were efficacious in a rat FeCl3-induced model of arterial thrombosis. Compound 7, the 3,3-diphenylpropionic acid derivative, showed the best overall profile of in vivo and in vitro activity. Molecular modeling studies suggest that these compounds bind in the thrombin active site in a manner essentially identical to that previously reported for compound 1a.
...
PMID:Synthesis of a series of potent and orally bioavailable thrombin inhibitors that utilize 3,3-disubstituted propionic acid derivatives in the P3 position. 935 36

The relation between the antithrombotic effect in vivo, and the inhibition constant (Ki) and the association rate constant (k(on)) in vitro was investigated for eight different thrombin inhibitors. The carotid arteries of anaesthetized rats were exposed to FeCl3 for 1 h, and the thrombus size was determined from the amount of incorporated 125I-fibrinogen. The thrombin inhibitors were given intravenously, and complete concentration- and/or dose-response curves were constructed. Despite a 50,000-fold difference between the Ki-values comparable plasma concentrations of hirudin and melagatran were needed (0.14 and 0.12 micromol l(-1), respectively) to obtain a 50% antithrombotic effect (IC50) in vivo. In contrast, there was a comparable in vitro (Ki-value) and in vivo (IC50) potency ratio for melagatran and inogatran, respectively. These results can be explained by the concentration of thrombin in the thrombus and improved inhibition by the low-molecular-weight compounds. For all eight thrombin inhibitors tested, there was an inverse relationship between k(on)-values in vitro and the slope of the dose response curves in vivo. Inhibitors with k(on)-values of < 1 x 10(7) M(-1) s(-1) gave steep dose response curves with a Hill coefficient > 1. The association time for inhibition of thrombin for slow-binding inhibitors will be too long to give effective antithrombotic effects at low plasma concentrations, but at increasing concentrations the association time will decrease, resulting in a steeper dose-response curve and thereby a more narrow therapeutic interval.
...
PMID:The importance of enzyme inhibition kinetics for the effect of thrombin inhibitors in a rat model of arterial thrombosis. 936 99

Current therapeutic use of heparin as an adjunct to thrombolytic therapy for myocardial infarction is suboptimal with respect to efficacy and bleeding risk. In a rat carotid arterial thrombolysis model (FeCl3-induced injury) we evaluated the combined effect of tPA (2.0 mg/kg/30 min) with our potent injectable direct thrombin inhibitor, BCH-2763 (Ki 0.11 nM; MW 1.5 kDa), which, unlike heparin, inhibits bound and free thrombin; comparisons were with standard heparin (SH), other direct thrombin inhibitors, r-hirudin (MW 6.5 kDa) and hirulog (MW 2.3 kDa), or tPA alone. Time to lysis (TL), patency time (PT), aPTT (fold increase) and bleeding time (BT) were determined. ED100 (100% of rats reperfused) for BCH-2763, hirulog or r-hirudin was 1, 3 or 2 mg/kg/60 min, respectively; 67% of rats reperfused with SH at the highest dose tested (220 U/kg/60 min) and 43% with tPA alone. At these doses, TL (min) was shorter (p < 0.01) with BCH-2763 (0.5 +/- 0.1), hirulog (3.3 +/- 2.3) or r-hirudin (2.3 +/- 1.0) than SH (66.3 +/- 30.8) or tPA alone (93.4 +/- 21.4). The aPTT fold increase after 15 min infusion was markedly greater (p < 0.001) for SH (32.0 +/- 0.8) than BCH-2763 (3.7 +/- 0.5), hirulog (5.2 +/- 0.3) or r-hirudin (4.5 +/- 0.8) in combination with tPA or tPA alone (1.1 +/- 0.1). In addition, the BT (min) for BCH-2763 (3.0 +/- 0.4) was similar to tPA alone (1.6 +/- 0.3), but prolonged (p < 0.05) for hirulog (7.5 +/- 2.7), r-hirudin (6.6 +/- 0.8) or SH (7.3 +/- 1.8). Comparisons at same aPTT fold increase revealed that in combination with tPA, BCH-2763 required a lower anticoagulant level to shorten the TL and prolong the PT than hirulog, r-hirudin or SH. Thus, in this rat arterial thrombolysis model direct thrombin inhibitors are more effective than SH as antithrombotic adjuncts to tPA. BCH-2763 is effective at a lower gravimetric dose and more modest aPTT fold increase than hirulog or r-hirudin with less alteration in haemostasis, which may confer an improved safety index.
...
PMID:Effective use of BCH-2763, a new potent injectable direct thrombin inhibitor, in combination with tissue plasminogen activator (tPA) in a rat arterial thrombolysis model. 968 8

Vitronectin (VN) binds to plasminogen activator inhibitor-1 (PAI-1) and integrins and may play an important role in the vascular response to injury by regulating fibrinolysis and cell migration. However, the role of VN in the earliest response to vascular injury, thrombosis, is not well characterized. The purpose of this study was to test the hypothesis that variation in vitronectin expression alters the thrombotic response to arterial injury in mice. Ferric chloride (FeCl3) injury was used to induce platelet-rich thrombi in mouse carotid arteries. Wild-type (VN +/+, n = 14) and VN-deficient (VN -/-, n = 15) mice, matched for age and gender, were studied. Time to occlusion after FeCl3 injury was determined by application of a Doppler flowprobe to the carotid artery. Occlusion times of VN -/- mice were significantly shorter than those of VN +/+ mice (6.0 +/- 1.2 minutes v 17.8 +/- 2.3 minutes, respectively, P < .001). Histologic analysis of injured arterial segments showed that thrombi from VN +/+ and VN -/- mice consisted of dense platelet aggregates. In vitro studies of murine VN +/+ and VN -/- platelets showed no significant differences in ADP-induced aggregation, but a trend towards increased thrombin-induced aggregation in VN -/- platelets. Purified, denatured VN inhibited thrombin-induced platelet aggregation, whereas native VN did not. Thrombin times of plasma from VN -/- mice (20.5 +/- 2.1 seconds, n = 4) were significantly shorter than those of VN +/+ mice (34.2 +/- 6.7 seconds, n = 4, P < .01), and the addition of purified VN to VN -/- plasma prolonged the thrombin time into the normal range, suggesting that VN inhibits thrombin-fibrinogen interactions. PAI-1-deficient mice (n = 6) did not demonstrate significantly enhanced arterial thrombosis compared with wild-type mice (n = 6), excluding a potential indirect antithrombin function of VN mediated by interactions with PAI-1 as an explanation for the accelerated thrombosis observed in VN -/- mice. These results suggest that vitronectin plays a previously unappreciated antithrombotic role at sites of arterial injury and that this activity may be mediated, at least in part, by inhibiting platelet-platelet interactions and/or thrombin procoagulant activity.
...
PMID:Vitronectin inhibits the thrombotic response to arterial injury in mice. 1006 53

The endothelial cell Protein C receptor (EPCR) functions to enhance activation of anticoagulant Protein C (PC) by the thrombin/ thrombomodulin (Tm) complex on the surface of the endothelium. This overall system functions in anticoagulation, profibrinolytic, and antiinflammatory responses. Mice with a severe targeted deficiency of this receptor have been generated by integration of exogenous DNA elements into the 5'-untranslated region of the EPCR gene. Despite the retention of the entire endogenous EPCR coding sequence in the altered EPCR gene locus, only very low EPCR message contents were detected in mice by quantitative RT-PCR during embryogenesis and up to at least early adulthood. Immunohistochemical analysis of various regions of the arterial tree of mice up to 4 months of age, employing an anti-murine EPCR antibody, confirmed that undetectable levels of this protein were present in arterial regions during these periods. Despite this, these mice are not more prone to arterial thrombosis after challenge in a FeCl3 carotid artery thrombosis model. Small amounts (<10% of wild-type) of this protein were found in other tissues. Matings of mice homozygous for this deficiency led to normal births and survival of the offspring, in contrast to results by others demonstrating early embryonic lethality of a total EPCR deficiency. These data further show that minimal levels of EPCR are able to support male and female virility, as well as embryonic development, birth, and survival to adulthood.
...
PMID:Mice with a severe deficiency of the endothelial protein C receptor gene develop, survive, and reproduce normally, and do not present with enhanced arterial thrombosis after challenge. 1235 77

The antiplatelet and antithrombotic effects of FR171113, 3-(4-chlorophenyl)-2-(2,4-dichlorobenzoylimino)-5-(methoxycarbonyl methylene)-1,3-thiazolidin-4-one, a non-peptide protease-activated receptor 1 (PAR1) antagonist, were evaluated in guinea pigs. FR171113 inhibited Ser-Phe-Leu-Leu-Arg-Asn-NH2 (a synthetic PAR1 agonist peptide)-induced and thrombin-induced aggregation of guinea pig platelets in a concentration-dependent manner in vitro (IC50=1.5 and 0.35 microM, respectively). Subcutaneous administration of FR171113 (0.1-3.2 mg/kg) produced a dose-dependent inhibition of platelet aggregation ex vivo. The ED50 value of FR171113 for platelet aggregation was 0.49 mg/kg s.c. However, FR171113 did not have an inhibitory effect on ADP- or collagen-induced platelet aggregation in vitro and ex vivo. One hour after FR171113 treatment at 1.0 mg/kg s.c., significant inhibition of arterial thrombosis without a prolongation of thrombin time or coagulation time was seen in the FeCl3-induced carotid artery thrombosis model in guinea pigs. Furthermore, FR171113 did not prolong bleeding time even at 32 mg/kg s.c., which is a much higher dose than that required in the thrombosis model. These observations indicate that FR171113 has desirable antiplatelet effects both in vitro and in vivo and that its in vivo antithrombotic activity is efficacious without causing a prolongation of bleeding time.
...
PMID:Inhibition of arterial thrombosis by a protease-activated receptor 1 antagonist, FR171113, in the guinea pig. 1289 34

The roles that the various platelet collagen receptors play in initial platelet adhesion and thrombus growth remain controversial. Here we summarize some of the pertinent data and discuss some recent studies of the initiation and propagation of platelet accumulation into thrombi and the initiation and propagation of thrombin generation. Mice lacking platelet surface glycoprotein VI (GPVI) form normal thrombi in the laser injury model but have a diminished thrombotic response to severe FeCl3 injury. We hypothesize that the paths to thrombus formation in these two models are different with interaction of GPVI and collagen predominant early after severe FeCl3-induced injury but platelet activation by thrombin predominant after laser-induced injury. Understanding of the response to insult in thrombosis models deepens our understanding of the process and provides a firm foundation for evaluation of anti-thrombotic therapy in these models.
...
PMID:Tissue factor pathway vs. collagen pathway for in vivo platelet activation. 1651 78


1 2 3 4 Next >>

---