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

Quercetin and 12 other natural flavonoid aglycones inhibit washed human platelet aggregation and secretion of serotonin induced by ADP, collagen or thrombin. The inhibitory effect of flavonoids is of the same order of magnitude as IBMX and dipyridamole. The structural features required for a flavonoid to inhibit human platelet function are similar to those previously reported by us to inhibit cyclic nucleotide phosphodiesterase. The inhibitory effect of flavonoids on human platelet function was diminished by saturation of the C-2, C-3 double bond, lack of the C-4 carbonyl, glycosylation at C-3 and a high number of hydroxyl substituents.
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PMID:Inhibition of aggregation and secretion of human platelets by quercetin and other flavonoids: structure-activity relationships. 618 78

Ioxaglate causes a dose dependent prolongation of thrombin time, thrombin coagulase time, partial thromboplastin time and calcium thromboplastin time. A substantial activation of fibrinolysis, assayed by a dose dependent decrease of plasminogen concentrations, does not take place. Higher concentration of ioxaglate (more than 25 mg iodine/ml) cause a complement activation. No C-3 split products could be detected by two-dimensional immunoelectrophoresis. Ioxaglate induced changes of global coagulation tests are interpreted as being caused by interference of fibrin polymerization. The demonstration of complement activation by high concentrations of ioxaglate has no practical consequences.
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PMID:[The in-vitro-effects of loxaglate (Hexabrix) on coagulation, fibrinolysis and complement system (author's transl)]. 645 60

A series of 3-(3-guanidinopropyl)-azetidin-2-one derivatives was prepared and evaluated as inhibitors of cleavage of synthetic substrates in vitro by the serine proteases thrombin, trypsin and plasmin. The N-unsubstituted, 4-phenethyl derivative 9a demonstrated weak inhibition of these enzymes but acetylation of the beta-lactam N atom afforded 9b, an effective, time-dependent inhibitor of thrombin and a potent inhibitor of plasmin. Variation of the 4-position of the beta-lactam ring was examined in conjunction with different N-substituents to provide a series of potent, time-dependent inhibitors of thrombin. A C-4 substituent was essential for good inhibitory properties and, in general, polar C-4 substituents enhanced the selectivity of inhibition for thrombin compared to plasmin. A trans relationship between the C-4 and C-3 substituents was found to be superior to a cis disposition whilst homologation of the guanidinopropyl side chain to that of a guanidinobutyl moiety reduced activity. Several compounds were effective inhibitors of thrombin-induced clot formation in human plasma in vitro but activity in this assay did not correlate well with inhibition of thrombin-induced cleavage of a synthetic substrate, presumably a consequence of inherent chemical instability and degradation in plasma.
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PMID:Azetidin-2-one derivatives as inhibitors of thrombin. 758 85

In an effort to increase the thrombin inhibitory activity of a novel series of inhibitors (i.e., 1a), substituents were incorporated at the C-3" position of the C-3 aryl ring (2). Consistent with the X-ray crystallography studies, small hydrophobic groups at the C-3" site (Br and Me) enhanced thrombin inhibitory activity by 8-fold. However, a few more hydrophilic substituents (NO2 and OMe) also enhanced the potency of the series. The biological results are discussed in terms of molecular modeling studies.
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PMID:Dibasic benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 2. Exploring interactions at the proximal (S2) binding site. 987 74

When human platelets are stimulated with collagen or thrombin, the asymmetric distribution of membrane lipids is disrupted as phosphatidylserine and phosphatidylethanolamine translocate from the inner monolayer to the outer monolayer. Coincident with the stimulus-dependent rearrangement of membrane phospholipids is a rapid redistribution of cholesterol from the outer to the inner membrane monolayer. This redistribution of cholesterol was observed when the stimulus was collagen or ADP. The data presented here show that epinephrine stimulation does not promote cholesterol translocation but does potentiate collagen-promoted movement of cholesterol. To investigate the process of cholesterol translocation, experiments were performed to determine whether collagen stimulated reverse cholesterol movement; i.e. from the inner to the outer monolayer. For this study, the fluorescent sterol cholestatrienol (C-3) was incorporated into platelet membranes by exchange from cholesterol-containing phosphatidylcholine small unilamellar vesicles. C-3 was then removed selectively from the outer monolayer by treatment of the platelets with bovine serum albumin (BSA). During the subsequent incubation of BSA-treated platelets, C-3 moved spontaneously into the outer from the inner monolayer. This translocation had an apparent half-time of approximately 25 min and was unaltered by the presence of collagen. These results suggest that collagen treatment of platelets selectively facilitates the inward movement of the sterol. We have hypothesized that cholesterol translocation may be thermodynamically driven as a result of an unfavorable entropy, resulting in cholesterol translocation out of an environment becoming enriched in phosphatidylethanolamine. The unidirectional nature of collagen-promoted cholesterol movement from the phosphatidylethanolamine-rich outer monolayer is consistent with this interpretation.
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PMID:Collagen-stimulated unidirectional translocation of cholesterol in human platelet membranes. 991 52

A systematic investigation of the structure-activity relationships of the C-3 side chain of the screening hit 1a led to the identification of the potent thrombin inhibitors 23c, 28c, and 31c. Their activities (1240, 903, and 1271 x 10(6) L/mol, respectively) represent 2200- and 2900-fold increases in potency over the starting lead 1a. This activity enhancement was accomplished with an increase of thrombin selectivity. The in vitro anticoagulant profiles of derivatives 28c and 31c were determined, and they compare favorably with the clinical agent H-R-1-[4aS, 8aS]perhydroisoquinolyl-prolyl-arginyl aldehyde (D-Piq-Pro-Arg-H; 32). The more potent members of this series have been studied in an arterial/venous shunt (AV shunt) model of thrombosis and were found to be efficacious in reducing clot formation. However, their efficacy is currently limited by their rapid and extensive distribution following administration.
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PMID:Diamino benzo[b]thiophene derivatives as a novel class of active site directed thrombin inhibitors. 5. Potency, efficacy, and pharmacokinetic properties of modified C-3 side chain derivatives. 1069 91

The crystal structures of four active site-directed thrombin inhibitors, 1-4, in a complex with human alpha-thrombin have been determined and refined at up to 2.0 A resolution using X-ray crystallography. These compounds belong to a structurally novel family of inhibitors based on a 2,3-disubstituted benzo[b]thiophene structure. Compared to traditional active-site directed inhibitors, the X-ray crystal structures of these complexes reveal a novel binding mode. Unexpectedly, the lipophilic benzo[b]thiophene nucleus of the inhibitor appears to bind in the S1 specificity pocket. At the same time, the basic amine of the C-3 side chain of the inhibitor interacts with the mostly hydrophobic proximal, S2, and distal, S3, binding sites. The second, basic amine side chain at C-2 was found to point away from the active site, occupying a location between the S1 and S1' sites. Together, the aromatic rings of the C-2 and C-3 side chains sandwich the indole ring of Trp60D contained in the thrombin S2 insertion loop defined by the sequence "Tyr-Pro-Pro-Trp." [The thrombin residue numbering used in this study is equivalent to that reported for chymotrypsinogen (Hartley BS, Shotton DM, 1971, The enzymes, vol. 3. New York: Academic Press. pp 323-373).] In contrast to the binding mode of more classical thrombin inhibitors (D-Phe-Pro-Arg-H, NAPAP, Argatroban), this novel class of benzo[b]thiophene derivatives does not engage in hydrogen bond formation with Gly216 of the thrombin active site. A detailed analysis of the three-dimensional structures not only provides a clearer understanding of the interaction of these agents with thrombin, but forms a foundation for rational structure-based drug design. The use of the data from this study has led to the design of derivatives that are up to 2,900-fold more potent than the screening hit 1.
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PMID:The crystal structures of human alpha-thrombin complexed with active site-directed diamino benzo[b]thiophene derivatives: a binding mode for a structurally novel class of inhibitors. 1073 44

Discoveries that lead to ZK 807834 (CI-1031, 2a), a potent and selective factor Xa (fXa) inhibitor currently in clinical testing as an intravenous antithrombotic, were initiated by the identification of the potent (Z,Z)-isomer of BABCH (1c). A structure-activity relationship (SAR) was established with a series of analogues of BABCH. This SAR database, combined with computer modeling, demonstrated that binding of the second basic group in the S3/S4 pocket provided fXa potency and that a carboxylic acid group on the opposite side of the molecule resulted in selectivity versus thrombin. Simple substitution of a cyclic urea for the unsaturated ketone structure of BABCH gave disappointing results, but discovery of the bisphenoxy-pyridine analogues provided a template that could be readily optimized. The SAR established for this template is described and compared with computer modeling, REDOR NMR and X-ray crystallography studies. Inhibitor binding to fXa was increased by the introduction of a hydroxyl group on the proximal phenylamidine ring and by the introduction of fluorine atoms at C-3 and C-5 of the pyridine ring. Pharmacokinetic parameters were improved by balancing the contributions from the substituents on the distal ring and the central pyridine ring. The optimal combination was a methyl-(2H)-imidazoline group on the distal ring and a sarcosine at C-4 of the pyridine ring. The promising preclinical database for CI-1031 is described. This review relates the SAR leading to the discovery of the clinical candidate, CI-1031 directly to our best understanding of how this potent inhibitor interacts with the fXa active site.
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PMID:Discovery of the factor Xa inhibitor, ZK 807834 (CI-1031). 1189 48

A polysaccharide was isolated from marine green algae Monostroma latissimum, and its chemical characteristic and anticoagulant activity were investigated. The results demonstrated that the polysaccharide was high rhamnose-containing sulfated polysaccharide, and was mainly composed of 1,2-linked l-rhamnose residues with sulfate groups substituted at positions C-3 and/or C-4. The sulfated polysaccharide exhibited high anticoagulant activities by assays of the activated partial thromboplastin time (APTT) and thrombin time (TT). The anticoagulant property of the sulfated polysaccharide was mainly attributed to powerful potentiation thrombin by heparin cofactor II.
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PMID:Chemical characteristic and anticoagulant activity of the sulfated polysaccharide isolated from Monostroma latissimum (Chlorophyta). 1900 6

A stereoselective synthesis of enantiopure aeruginosin 205B aglycon confirms the presence of a (3R,2S)-3-chloroleucine amide residue and a (6R)-hydroxy (3aS,7aS)-octahydroindole-(2S)-2-carboxamide [corrected] (Choi) subunit instead of a 6-chloro-substituted core (Ccoi). Enzyme inhibitory tests against thrombin revealed an IC(50) of 0.31 microM. The total synthesis of the presumed aeruginosin 205B shows that the alpha-d-xylopyranosyl unit carries a sulfate group at C-4' (and not at C-3'). Comparison of NMR data leads to the same revision of aeruginosin 205A.
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PMID:Total synthesis and structural revision of the presumed aeruginosins 205A and B. 1969 54


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