Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P35237 (thrombin inhibitor)
 2,012 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Thrombin-induced platelet activation involves cleavage of protease-activated receptors (PARs) 1 and 4, and interaction, via glycoprotein (Gp)Ibalpha, with the platelet GpIb/IX/V complex. This study investigated inhibition of platelet activation by thrombin inhibitors with different modes of action: two reversible direct thrombin inhibitors, melagatran and inogatran; hirudin, a tightly binding direct thrombin inhibitor; and two indirect thrombin inhibitors, heparin and dalteparin. Up-regulation of P-selectin (CD62P) and PAR-1 cleavage was measured in human whole blood, by flow cytometry. The thrombin concentration that induced 50% of maximum (EC50 ) PAR-1 cleavage was 0.028 nmol/l, while that of platelet activation (CD62P) was over two-fold higher (0.64 nmol/l). The EC50 of a PAR-1-independent component, defined as a further activating effect of thrombin on top of the maximum PAR-1-activating peptide (AP) effect, was 3.2 nmol/l. All anticoagulants were concentration-dependent inhibitors of thrombin-induced platelet activation and PAR-1 cleavage, but none inhibited PAR-1-AP or PAR-4-AP induced activation. Melagatran and inogatran were more potent inhibitors of CD62P up-regulation than of PAR-1 cleavage; conversely, hirudin, heparin and dalteparin were more potent inhibitors of PAR-1 cleavage.Thus, reversible direct thrombin inhibitors, such as melagatran, are potent inhibitors of thrombin-induced platelet activation, acting mainly by inhibition of a PAR-1-independent component.
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PMID:Thrombin-induced platelet activation and its inhibition by anticoagulants with different modes of action. 1263 26

The Tissue Factor/Factor VIIa (TF/FVIIa) complex is an attractive target for pharmacological interruption of thrombin generation and hence blood coagulation, as this complex is the initiation point of the extrinsic pathway of coagulation. TF is a cell membrane-associated protein that interacts with soluble FVIIa to activate factors IX and X resulting in a cascade of events that leads to thrombin generation and eventual fibrin deposition. The goal of this non-randomized study was to evaluate XK1, a specific protein inhibitor of TF/FVIIa, and compare antithrombotic efficacy and bleeding propensity to a previously described Factor Xa (FXa) inhibitor (SC-83157/SN429) and a direct-acting thrombin inhibitor (SC-79407/L-374087) in an acute rat model of arterial thrombosis. All saline-treated animals experienced occlusion of the carotid artery due to acute thrombus formation within 20 minutes. Rats treated with XK1 exhibited a dose-dependent inhibition of thrombus formation with full antithrombotic efficacy and no change in bleeding time or total blood loss at a dose of 4.5 mg/kg, i.v. administered over a 60 minute period. FXa inhibition with SC-83157 resulted in complete inhibition of thrombus formation at a dose of 1.2 mg/kg, i.v.; however, this effect was associated with substantial blood loss. Thrombin inhibition with SC-79407 also afforded complete protection from thrombus formation and occlusion at a dose of 2.58 mg/kg, i.v., and like SC-83157, was associated with substantial blood loss. These data imply that TF/FVIIa inhibition confers protection from acute thrombosis without concomitant changes in bleeding, indicating that this target (TF/FVIIa) may provide improved separation of efficacy vs. bleeding side-effects than interruption of coagulation by directly inhibiting either FXa or thrombin.
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PMID:Pharmacological intervention at disparate sites in the coagulation cascade: comparison of anti-thrombotic efficacy vs bleeding propensity in a rat model of acute arterial thrombosis. 1271 30

Thrombin-specific inhibitors directly diminish thrombin-induced coagulation and cellular activities without the side effects of heparin. Hirudin is the most potent natural thrombin-specific inhibitor. Recombinant hirudins (such as desirudin) have been shown to be effective in the treatment of heparin-induced thrombocytopenia (HIT) and in the prevention of thrombotic complications after hip or knee surgery. The application of recombinant hirudin has been limited mainly by hemorrhagic complications. Synthetic thrombin-specific inhibitors, including oligopeptides, tripeptides and non-peptide low molecular weight (LMW) thrombin inhibitors, have been designed according to their interactions with the active sites of thrombin. Bivalirudin (an anti-thrombin oligopeptide) has been approved for preventing thrombosis in unstable angina patients following angioplasty in adjunct to aspirin. Argotroban (a tripeptide thrombin inhibitor) has been used for the treatment of HIT, peripheral and cerebral thrombotic diseases. The benefit of using thrombin-specific inhibitors alone in acute myocardial infarction or unstable angina remains uncertain. A number of LMW thrombin-specific inhibitors have been developed. Some of them can be administrated orally, and cause less increase in bleeding time than other thrombin inhibitors. The efficacy, safety, stability and oral bioavailability of the thrombin inhibitors may be considerably improved through structural optimization. Most of the LMW thrombin inhibitors are currently being tested in animal models or at early stages of clinical trials. In this review, we will present an overview of recent advances in thrombin-specific inhibitors.
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PMID:Development and current applications of thrombin-specific inhibitors. 1276 63

With advances in therapy of acute coronary syndromes, repetitive exposure to heparin has become commonplace. Consequently, the incidence of heparin-induced thrombocytopenia has risen. Limited strategies for management exist, and new thrombin inhibitors may provide safe alternatives to heparin. Two patients with documented heparin-induced thrombocytopenia underwent revascularization using a new thrombin inhibitor (Bivalirudin [Angiomax, Medicines Co, Cambridge, MA]) for anticoagulation. Both patients had uneventful perioperative hospitalizations. Thrombin inhibition with Bivalirudin (Angiomax) may provide a safe reliable alternative to heparin use in cardiac surgery [corrected].
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PMID:Bivalirudin use in off-pump myocardial revascularization in patients with heparin-induced thrombocytopenia [corrected]. 1284 58

Thrombin, a crucial enzyme in the blood coagulation, has been a target for antithrombotic therapy. Orally active thrombin inhibitors would provide effective and safe prophylaxis for venous and arterial thrombosis. We conducted optimization of a highly efficacious benzamidine-based thrombin inhibitor LB30812 (3, K(i) = 3 pM) to improve oral bioavailability. Of a variety of arylamidines investigated at the P1 position, 2,5-thienylamidine effectively replaced the benzamidine without compromising the thrombin inhibitory potency and oral absorption. The sulfamide and sulfonamide derivatization at the N-terminal position in general afforded highly potent thrombin inhibitors but with moderate oral absorption, while the well-absorbable N-carbamate derivatives exhibited limited metabolic stability in S9 fractions. The present work culminated in the discovery of the N-carboxymethyl- and 2,5-thienylamidine-containing compound 22 that exhibits the most favorable profiles of anticoagulant and antithrombotic activities as well as oral bioavilability (K(i) = 15 pM; F = 43%, 42%, and 15% in rats, dogs, and monkeys, respectively). This compound on a gravimetric basis was shown to be more effective than a low molecular weight heparin, enoxaparin, in the venous thrombosis models of rat and rabbit. Compound 22 (LB30870) was therefore selected for further preclinical and clinical development.
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PMID:Efficacious and orally bioavailable thrombin inhibitors based on a 2,5-thienylamidine at the P1 position: discovery of N-carboxymethyl-d-diphenylalanyl-l-prolyl[(5-amidino-2-thienyl)methyl]amide. 1290 65

The physiologic function of the serpin heparin cofactor II (HCII) is not fully understood. We have hypothesized that HCII functions as an extravascular inhibitor of thrombin. Thrombin formed at a site of injury has been hypothesized to contribute to migration and proliferation of fibroblasts and smooth muscle cells involved in wound healing. To begin to test our hypothesis, we examined the immunohistochemical localization of HCII in human skin and compared it to that of the closely related serpin, antithrombin (ATIII). In skin specimens with acute wounds, there was diffuse HCII and ATIII staining in areas of hemorrhage. In healing skin wounds ATIII was primarily associated with mast cells, while HCII was associated with mononuclear phagocytes in the dermis. Blood monocytes isolated from healthy donors also stained for HCII protein. However, in situ hydridization and RT-PCR studies failed to show significant HCII mRNA expression either in macrophages in wounded skin or in peripheral blood leukocytes. HCII localization is not due to nonspecific uptake of plasma proteins, since ATIII had a very different distribution in wounded skin. These findings support the notion that HCII could function as an extravascular thrombin inhibitor and might play a role in the regulation of wound healing.
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PMID:Localization of heparin cofactor II in injured human skin: a potential role in wound healing. 1451 71

Most tumors have constitutively active tissue factor on their surface, capable of generating thrombin in the surrounding environment, and thrombosis is associated with cancer. Thrombin is known to induce a malignant phenotype by enhancing tissue adhesion and cell growth in vitro and in vivo in mice. Because tumors require angiogenesis for growth, we examined whether thrombin induces neoangiogenesis in a physiologically intact in vivo model. Thrombin (0.1 U mL-1) induced neoangiogenesis in the chick chorioallantoic membrane over a 24-72-h period by approximately 2-3-fold. This was inhibited by the potent thrombin inhibitor, hirudin and shown to have its mode of action by ligation of the thrombin protease-activated receptor, PAR-1. The thrombin receptor activation peptide, SFLLRNPNDKYEPF (200 microm) also enhanced neoangiogenesis c. 2-3-fold. Thrombin-induced neoangiogenesis was accompanied by the induction of vascular endothelial growth factor (VEGF) and angiopoietin-2 (Ang-2) mRNA at 24-48 h (approximately 2-fold) as determined by semi-quantitative reverse transcriptase-polymerase chain reaction. Thrombin-induced neoangiogenesis was inhibited to baseline level by the specific angiogenesis receptor inhibitors KDR-Fc (vs. VEGF) and Tie-2-Fc (vs. Ang-1 and Ang-2), as well as the non-specific angiogenesis inhibitor thrombospondin-1. Thrombin-induced neoangiogenesis was also inhibited to baseline level by agents known to inhibit thrombin receptor signaling in other cells: G-coupled protein receptor inhibitor, pertussis toxin (40 pg per egg), protein kinase C inhibitor, bisindolylmaleimide (1 microm per egg), MAP kinase inhibitor, PD980598 (10 microm per egg) and PI3 kinase inhibitor, LY294002 (0.25 microm per egg). Thus angiogenesis is stimulated by thrombosis, which could help explain the enhancement of experimental tumorigenesis by thrombin.
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PMID:Thrombin induces neoangiogenesis in the chick chorioallantoic membrane. 1452 87

Thrombin, a plasma serine protease, plays a key role not only in coagulation and hemostasis but in thrombosis, restenosis and atherosclerosis. Thrombin activates platelets, endothelium, inflammatory cells and smooth muscle cells. The cellular action of thrombin is mediated by specific G-protein coupled thrombin receptors called proteinase-activated receptors (protease-activated receptor or PARs). Among the three thrombin receptors, PAR1 is the primary thrombin receptor in human and animal cells with an exception of non-primate platelets. An increased thrombin generation and PAR1 expression are observed on cells within atherosclerotic plaque and thrombus and following vascular injury. Animal studies with PAR1 deficient mice and small molecule antagonists indicate an important role of PAR1 in thrombosis and restenosis and thus the therapeutic potential of a PAR1 antagonist in treating these diseases. Development of a thrombin receptor tethered ligand analog binding assay led to the discovery of several different series of potent, nonpeptide small molecular antagonists of PAR1. These antagonists are PAR1 selective and inhibit most of the cellular effects of thrombin. A PAR1 antagonist has an advantage over a direct thrombin inhibitor since it does not inhibit enzymatic action of thrombin in the coagulation cascade with the consequent minimal bleeding side-effects, unlike a direct thrombin inhibitor. In addition, the emerging evidence for the role of PAR1 in various inflammatory diseases suggests as yet unexplored therapeutic potentials of PAR1 antagonists in various inflammatory diseases.
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PMID:Development of proteinase-activated receptor 1 antagonists as therapeutic agents for thrombosis, restenosis and inflammatory diseases. 1452 96

Thrombin is a serine protease that plays a key role in the blood coagulation cascade. Compound I [2-[6-chloro-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-oxopyrazin-1(2H)-yl]-N-[(3-fluoropyridin-2-yl)methyl]acetamide] is a potent, selective, and orally bioavailable thrombin inhibitor that is being studied as a possible anticoagulant. Biotransformation studies in rats revealed that 84% of an i.v. dose of I was excreted in the form of two metabolites. Both metabolites were formed by metabolic activation of the pyrazinone ring in I and subsequent rearrangement leading to two novel dihydro-imidazole and imidazolidine derivatives. The structures of these metabolites and their mechanism of formation were elucidated by additional use of two 13C single labels in the pyrazinone ring of I in combination with mass spectrometry and NMR techniques. The metabolite structures described here illustrate the rich metabolic chemistry of the amino-pyrazinone heterocycle.
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PMID:Bioactivation of the 3-amino-6-chloropyrazinone ring in a thrombin inhibitor leads to novel dihydro-imidazole and imidazolidine derivatives: structures and mechanism using 13C-labels, mass spectrometry, and NMR. 1457 Jul 77

In addition to its central role in hemostasis, thrombin may play a role in inflammation and remodeling. To investigate the contribution of thrombin to allergic airway inflammation in asthma, we used an enzymatic assay to determine thrombin activity in bronchoalveolar lavage fluid obtained from 19 subjects with atopic asthma before (Day 0) and 48 hours after (Day 2) segmental bronchoprovocation with antigen. Thrombin activity increased from 0 (0, 2.9) on Day 1 to 41.1 (0.3, 75.6) U x 10(-3)/ml on Day 2 (p = 0.002) and correlated with total protein levels in lavage fluid on Day 2 (r = 0.885, p < 0.001). After antigen challenge, thrombin activity also showed significant correlations with interleukin-5 (r = 0.66, p = 0.002), transforming growth factor beta1 (r = 0.70, p < 0.001), fibronectin (r = 0.85, p < 0.001) and tissue factor (r = 0.55, p = 0.03) levels in lavage fluid. Furthermore, Day 2, but not Day 0 lavage fluid, induced proliferation of human airway fibroblasts. This mitogenic effect was significantly reduced with hirudin, a specific thrombin inhibitor. Taken together, our findings suggest that allergen-driven airway inflammation in asthma is associated with enhanced potential for fibroblast proliferation that is related, at least in part, to increased thrombin activity. We propose that enhanced thrombin activity provides a potential link between allergic inflammation and initiation of airway remodeling.
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PMID:Increased thrombin activity after allergen challenge: a potential link to airway remodeling? 1463 Jun 20


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