Synthetic Inhibitors of Thrombin and Factor Xa

Hauptmann, J.; Stürzebecher, Jörg

doi:10.1016/s0049-3848(98)00192-3

Cited by 125 publications

(67 citation statements)

References 234 publications

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“…As for the latter, the concentrations effective in doubling the respective plasma clotting times (IC 200 ) in the thrombin time, partial thromboplastin times, and prothrombin time assays in vitro have the typical ratio of Ϸ1:10:20, which is known for a variety of selective thrombin inhibitors with low or moderate serum protein binding (8).…”

Section: Resultsmentioning

confidence: 99%

Thrombin inhibitors identified by computer-assisted multiparameter design

Riester

Wirsching

Salinas

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Here, we present a series of thrombin inhibitors that were generated by using powerful computer-assisted multiparameter optimization process. The process was organized in design cycles, starting with a set of randomly chosen molecules. Each cycle combined combinatorial synthesis, multiparameter characterization of compounds in a variety of bioassays, and algorithmic processing of the data to devise a set of compounds to be synthesized in the next cycle. The identified lead compounds exhibited thrombin inhibitory constants in the lower nanomolar range. They are by far the most selective synthetic thrombin inhibitors, with selectivities of >100,000-fold toward other proteases such as Factor Xa, Factor XIIa, urokinase, plasmin, and Plasma kallikrein. Furthermore, these compounds exhibit a favorable profile, comprising nontoxicity, high metabolic stability, low serum protein binding, good solubility, high anticoagulant activity, and a slow and exclusively renal elimination from the circulation in a rat model. Finally, x-ray crystallographic analysis of a thrombin-inhibitor complex revealed a binding mode with a neutral moiety in the S1 pocket of thrombin.crystallographic structure ͉ drug design ͉ early adsorption ͉ toxicity ͉ genetic algorithm

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Section: Resultsmentioning

confidence: 99%

Thrombin inhibitors identified by computer-assisted multiparameter design

Riester

Wirsching

Salinas

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…23 By directly and specifically interacting with the active site of thrombin, univalent DTIs such as dabigatran inactivate fibrin-bound thrombin. 40 Thrombin is also the most potent physiological agonist of platelet activation and aggregation. 23 Dabigatran competitively inhibits human thrombin in a concentration-dependent manner, 41 displaying highly selective and rapid but reversible binding to thrombin.…”

Section: Mechanisms Of Action Of Dabigatranmentioning

confidence: 99%

Antithrombotic Therapy in Atrial Fibrillation - Evaluation and Positioning of New Oral Anticoagulant Agents -

Ogawa

Koretsune

Yasaka

et al. 2011

Circ J

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“…15,16) In particular, recombinant antistasin has shown equal or superior efficacy to that achieved by heparin for the inhibition of thrombin. 17,18) Despite this clinical potency as an FXa inhibitor, its strong immunogenicity has been a fatal defect. An alternative approach introduced the most potent synthetic peptide derived from antistasin.…”

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confidence: 99%

Inhibition of Coagulation Activation and Inflammation by a Novel Factor Xa Inhibitor Synthesized from the Earthworm Eisenia andrei

Joo

Won

Kim

et al. 2009

Biological & Pharmaceutical Bulletin

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We have cloned an earthworm-derived Factor Xa (FXa) inhibitor, with an excellent inhibitory specificity from the midgut of the Eisenia andrei. We designate this inhibitor eisenstasin. An eisenstasin-derived small peptide (ESP) was synthesized and we examined whether ESP played an essential role in FXa inhibition. Compared to antistasin-derived small peptides (ASP) originating from leech, ESP primarily exhibited a high level of FXa inhibition in chromogenic peptide substrate assays and revealed an approximately 2-fold greater inhibition of FXa cleavage of a target protein than ASP. This suggests that ESP could be an effective anti-coagulant that targets FXa during the propagation step of coagulation. ESP also inhibited proteinase-activated receptor 2-mediated FXa activation, which may trigger endothelial inflammation. Endothelial nitric oxide (NO) was significantly reduced by ESP (pϽ0.0001), indicating that protease-activated receptor-2 (PAR-2) was effectively inactivated. We also found that ESP reduced the expressions of pro-inflammatory cytokines (IL-1a a, IL-1b b, IL-8, IL-16, MCP-1, MIP-1a a and MIP-1b b) by cultured cells treated with both ESP and FXa. Our results provide the first evidence that ESP might interrupt coagulation cascades by inhibiting FXa, and thereby may effectively control the bidirectional alternation between coagulation and inflammation.

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Synthetic Inhibitors of Thrombin and Factor Xa

Cited by 125 publications

References 234 publications

Thrombin inhibitors identified by computer-assisted multiparameter design

Thrombin inhibitors identified by computer-assisted multiparameter design

Antithrombotic Therapy in Atrial Fibrillation - Evaluation and Positioning of New Oral Anticoagulant Agents -

Inhibition of Coagulation Activation and Inflammation by a Novel Factor Xa Inhibitor Synthesized from the Earthworm Eisenia andrei

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