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Solid-phase synthesis of thrombin inhibitors - …

Fasudil, another inhibitor of Rho-kinase, suppressed thrombin-stimulated IL-6 synthesis.

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Active site-directed synthetic thrombin inhibitors: synthesis, ..

N2 - Dansylarginine N-(3-ethyl-1,5-pentanediyl)amide is a specific and potent inhibitor of thrombin. The apparent avidity and specificity of the inhibitor coupled with the fluorescence properties of the dansyl moiety suggested to us that the compound could be extremely useful as a probe for the study of thrombin and its interactions. The synthesis of the inhibitor was accomplished by coupling 4-ethylpiperidine to dansylarginine previously activated with N,N′-carbonyl-diimidazole. Although the compound is not susceptible to hydrolysis catalyzed by thrombin, it competitively inhibits the thrombin-catalyzed hydrolysis of either synthetic substrates or fibrinogen with an apparent Ki of about 10-7 M. When the inhibitor is bound to thrombin, marked changes in the fluorescence properties of the dansyl moiety are observed, including a threefold increase in intensity and lifetime and a decrease in the depolarization of the excitation signal. Using measurements of fluorescence intensity and polarization to study binding, a dissociation constant of 4.3 × 10-8 M and a stoichiometry of 1 mol of inhibitor per mol of thrombin were found. The enhancement of fluorescence intensity concomitant with binding provides a continuous monitor of the conversion of prothrombin to thrombin as catalyzed by the "prothrombinase" complex. This permits the precise analysis of the kinetics of thrombin formation. In addition, thrombin-catalyzed feedback reactions which can occur during prothrombin activation are inhibited, and therefore the inter-pretation of the kinetics of the activation process are greatly simplified. In general the present results indicate that dansylarginine N-(3-ethyl-1,5-pentanediyl)amide is an ideal probe of the catalytic function and numerous interactions of thrombin.

The convergent solid-phase synthesis of thrombin inhibitors is reported

L-Mevalonic acid is the distant precursor of cholesterol, in contrast to cholesterol, L-mevalonic acid, its distant precursor gives rise to farnesyl and geranylgeranyl pyrophosphates in relatively few metabolic steps. These isoprenyl pyrophophates covalently conjugate with specific G-proteins and serve as membrane anchors enabling them to carry out their function. Although farnesyl-proteins may participate in signal transduction, geranylgeranyl-proteins (e.g., Rho GTP binding proteins) are well known to downregulate signaling pathways by inhibiting L-mevalonic acid synthesis. Such inhibitors include 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, drugs (statins) and isoprenoids of dietary origins, where Rho protein activation appears to be necessary for cellular-mediated thrombin generation. Thrombin and other proteases (e.g., coagulation factor Xa, tryptase) upregulate protease-activated receptor (PAR) synthesis and PAR activation promotes synthesis and expression of other proteins [e.g., tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)]. With the PAR-1 activating peptide SSFLRNP, we found that either cerivastatin or atorvastatin mitigated platelet stimulation in a time-and dose-dependent manner, as predicted if a statin-mediated Rho pathway is required. We also found that simvastatin decreased prothrombin fragments F1+2 in plasma from type 2 diabetics, demonstrating that statins downregulate thrombin generation. Thus, independent of cholesterol, statins and dietary isoprenoids behave as inhibitors of TF-dependent thrombin generation. Because thrombin has multiple physiological functions, the 20 pleiotropic effects reported for statins may reflect a common mechanism for downregulation of thrombin-mediated events, in particular at the cellular level.

Design and synthesis of thrombin inhibitors - …

Dansylarginine N-(3-ethyl-1,5-pentanediyl)amide is a specific and potent inhibitor of thrombin. The apparent avidity and specificity of the inhibitor coupled with the fluorescence properties of the dansyl moiety suggested to us that the compound could be extremely useful as a probe for the study of thrombin and its interactions. The synthesis of the inhibitor was accomplished by coupling 4-ethylpiperidine to dansylarginine previously activated with N,N′-carbonyl-diimidazole. Although the compound is not susceptible to hydrolysis catalyzed by thrombin, it competitively inhibits the thrombin-catalyzed hydrolysis of either synthetic substrates or fibrinogen with an apparent Ki of about 10-7 M. When the inhibitor is bound to thrombin, marked changes in the fluorescence properties of the dansyl moiety are observed, including a threefold increase in intensity and lifetime and a decrease in the depolarization of the excitation signal. Using measurements of fluorescence intensity and polarization to study binding, a dissociation constant of 4.3 × 10-8 M and a stoichiometry of 1 mol of inhibitor per mol of thrombin were found. The enhancement of fluorescence intensity concomitant with binding provides a continuous monitor of the conversion of prothrombin to thrombin as catalyzed by the "prothrombinase" complex. This permits the precise analysis of the kinetics of thrombin formation. In addition, thrombin-catalyzed feedback reactions which can occur during prothrombin activation are inhibited, and therefore the inter-pretation of the kinetics of the activation process are greatly simplified. In general the present results indicate that dansylarginine N-(3-ethyl-1,5-pentanediyl)amide is an ideal probe of the catalytic function and numerous interactions of thrombin.

N2 - L-Mevalonic acid is the distant precursor of cholesterol, in contrast to cholesterol, L-mevalonic acid, its distant precursor gives rise to farnesyl and geranylgeranyl pyrophosphates in relatively few metabolic steps. These isoprenyl pyrophophates covalently conjugate with specific G-proteins and serve as membrane anchors enabling them to carry out their function. Although farnesyl-proteins may participate in signal transduction, geranylgeranyl-proteins (e.g., Rho GTP binding proteins) are well known to downregulate signaling pathways by inhibiting L-mevalonic acid synthesis. Such inhibitors include 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, drugs (statins) and isoprenoids of dietary origins, where Rho protein activation appears to be necessary for cellular-mediated thrombin generation. Thrombin and other proteases (e.g., coagulation factor Xa, tryptase) upregulate protease-activated receptor (PAR) synthesis and PAR activation promotes synthesis and expression of other proteins [e.g., tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)]. With the PAR-1 activating peptide SSFLRNP, we found that either cerivastatin or atorvastatin mitigated platelet stimulation in a time-and dose-dependent manner, as predicted if a statin-mediated Rho pathway is required. We also found that simvastatin decreased prothrombin fragments F1+2 in plasma from type 2 diabetics, demonstrating that statins downregulate thrombin generation. Thus, independent of cholesterol, statins and dietary isoprenoids behave as inhibitors of TF-dependent thrombin generation. Because thrombin has multiple physiological functions, the 20 pleiotropic effects reported for statins may reflect a common mechanism for downregulation of thrombin-mediated events, in particular at the cellular level.

Synthesis of Thrombin Inhibitor DuP 714 - The Journal …

AB - L-Mevalonic acid is the distant precursor of cholesterol, in contrast to cholesterol, L-mevalonic acid, its distant precursor gives rise to farnesyl and geranylgeranyl pyrophosphates in relatively few metabolic steps. These isoprenyl pyrophophates covalently conjugate with specific G-proteins and serve as membrane anchors enabling them to carry out their function. Although farnesyl-proteins may participate in signal transduction, geranylgeranyl-proteins (e.g., Rho GTP binding proteins) are well known to downregulate signaling pathways by inhibiting L-mevalonic acid synthesis. Such inhibitors include 3-hydroxy-3-methylglutaryl CoA reductase inhibitors, drugs (statins) and isoprenoids of dietary origins, where Rho protein activation appears to be necessary for cellular-mediated thrombin generation. Thrombin and other proteases (e.g., coagulation factor Xa, tryptase) upregulate protease-activated receptor (PAR) synthesis and PAR activation promotes synthesis and expression of other proteins [e.g., tissue factor (TF) and plasminogen activator inhibitor-1 (PAI-1)]. With the PAR-1 activating peptide SSFLRNP, we found that either cerivastatin or atorvastatin mitigated platelet stimulation in a time-and dose-dependent manner, as predicted if a statin-mediated Rho pathway is required. We also found that simvastatin decreased prothrombin fragments F1+2 in plasma from type 2 diabetics, demonstrating that statins downregulate thrombin generation. Thus, independent of cholesterol, statins and dietary isoprenoids behave as inhibitors of TF-dependent thrombin generation. Because thrombin has multiple physiological functions, the 20 pleiotropic effects reported for statins may reflect a common mechanism for downregulation of thrombin-mediated events, in particular at the cellular level.

While SP600125, an inhibitor of SAPK/JNK, failed to reduce IL-6 synthesis, PD98059, a specific inhibitor of MEK, and SB203580 and BIRB0796, potent inhibitors of p38 MAP kinase, suppressed the IL-6 synthesis induced by thrombin.

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  • 08/07/2014 · Thrombin inhibitor synthesis ..

    Design and Synthesis of Potent and Highly Selective Thrombin Inhibitors.

  • Direct Thrombin Inhibitors — NEJM

    We have designed, synthesized, and tested in vitro a novel class of noncovalent thrombin inhibitors

  • - both direct inhibitor of thrombin (IIa)

    Indirect thrombin inhibitors - University of Minnesota …

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Anticoagulants / Indirect thrombin inhibitors

AB - Dansylarginine N-(3-ethyl-1,5-pentanediyl)amide is a specific and potent inhibitor of thrombin. The apparent avidity and specificity of the inhibitor coupled with the fluorescence properties of the dansyl moiety suggested to us that the compound could be extremely useful as a probe for the study of thrombin and its interactions. The synthesis of the inhibitor was accomplished by coupling 4-ethylpiperidine to dansylarginine previously activated with N,N′-carbonyl-diimidazole. Although the compound is not susceptible to hydrolysis catalyzed by thrombin, it competitively inhibits the thrombin-catalyzed hydrolysis of either synthetic substrates or fibrinogen with an apparent Ki of about 10-7 M. When the inhibitor is bound to thrombin, marked changes in the fluorescence properties of the dansyl moiety are observed, including a threefold increase in intensity and lifetime and a decrease in the depolarization of the excitation signal. Using measurements of fluorescence intensity and polarization to study binding, a dissociation constant of 4.3 × 10-8 M and a stoichiometry of 1 mol of inhibitor per mol of thrombin were found. The enhancement of fluorescence intensity concomitant with binding provides a continuous monitor of the conversion of prothrombin to thrombin as catalyzed by the "prothrombinase" complex. This permits the precise analysis of the kinetics of thrombin formation. In addition, thrombin-catalyzed feedback reactions which can occur during prothrombin activation are inhibited, and therefore the inter-pretation of the kinetics of the activation process are greatly simplified. In general the present results indicate that dansylarginine N-(3-ethyl-1,5-pentanediyl)amide is an ideal probe of the catalytic function and numerous interactions of thrombin.

the first oral direct thrombin inhibitor; search

We have designed, synthesized, and tested in vitro a novel class of noncovalent thrombin inhibitors. The main feature of these inhibitors is a 6,5-fused bicyclic core structure that fills the S2 pocket of the active site of thrombin. The bicycle introduces conformational constraint into the ligand and locks the Xaa−Pro amide bond into the desired trans configuration. Among the known ring systems, we selected by molecular modeling the 7-thiaindolizidinones (BTD) as our basic template. The influence of several structural features was analyzed: the length of the argininal side chain, the stereochemistry at C6, and the importance of making optimal use of the S3 pocket. Finally, an X-ray crystal structure of inhibitor 15 bound to thrombin was obtained at a resolution of 2.3 Å. These designed thrombin inhibitors, which were prepared by an efficient synthesis, showed high selectivity over trypsin and other serine proteases. Further derivation based on the information obtained by X-ray crystallography should certainly allow to improve the potency.

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