Pharmacologic Aspects of the Development of Selective Synthetic Thrombin Inhibitors as Anticoagulants

Hauptmann, J.; Markwardt, Fritz

doi:10.1055/s-2007-1002426

Cited by 50 publications

(34 citation statements)

References 89 publications

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“…Short amino acid sequences with a C-terminal arginine show high affinity for thrombin. 9,10 Furthermore, proline precedes arginine in the cleavage sites of many thrombin sensitive proteins including prothrombin and factor XIII. A variety of inhibitors based on the sequence (D)Phe-ProArg, including esters, aldehydes, and chloromethyl ketones have been synthesized and tested for antithrombin activity.…”

Section: Introductionmentioning

confidence: 99%

Peptide modified gold-coated polyurethanes as thrombin scavenging surfaces

Sun

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Tengvall

et al. 2000

J. Biomed. Mater. Res.

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Thin layers of gold were deposited on polyurethane film and chemisorbed with three peptides having an N-terminal cysteine: Cys-Pro-Arg, Cys-(L)Phe-Pro-Arg, and Cys-(D)Phe-Pro-Arg. The ability of these surfaces to act as thrombin scavengers was evaluated. The peptides are related to the known thrombin inhibitor Phe-Pro-Arg chloromethyl ketone and were shown to have significant thrombin inhibitory activity in solution. Attachment of the peptides to gold was confirmed by water contact angle and X-ray photoelectron spectroscopy measurements. Thrombin adsorption from a buffer and plasma was investigated, and chromogenic substrate assays were carried out for thrombin activity on the surfaces and in the supernatant following adsorption. The data suggest that the peptide-modified surfaces are able to adsorb thrombin with high affinity from a buffer and that thrombin is taken up selectively from plasma. The Cys-(D)Phe-Pro-Arg modified surfaces showed particularly high affinity for thrombin. It was also found that the activity of thrombin adsorbed on the peptide surfaces was inhibited, and inhibition was greatest on the Cys-(D)Phe-Pro-Arg surface. We concluded that the peptide surfaces may have potential as antithrombogenic materials via their ability to scavenge and inhibit thrombin generated as a result of blood-material contact.

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Section: Introductionmentioning

confidence: 99%

Peptide modified gold-coated polyurethanes as thrombin scavenging surfaces

Sun

Sheardown

Tengvall

et al. 2000

J. Biomed. Mater. Res.

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“…Thrombin inhibitors with guanidine and amidine moieties in P-1 have been associated with poor oral absorption, hypotension and other side effects. 1,2 The potent noncovalent thrombin inhibitor 1a 3 (Chart 1) illustrates the importance of a basic P-1 amino group for binding potency. Deletion of the amino group results in a 700 times reduction in potency (1b).…”

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confidence: 99%

Design of Novel, Potent, Noncovalent Inhibitors of Thrombin with Nonbasic P-1 Substructures: Rapid Structure−Activity Studies by Solid-Phase Synthesis

et al. 1998

J. Med. Chem.

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Study of surface representations of the inhibitor-bound thrombin P-1 pocket revealed a lipophilic recess in this pocket which is not occupied by any known inhibitor. Solid-phase synthesis was used to generate benzylamides of D-diphenylAlaPro by aminolysis of Boc dipeptide Kaiser resin. The resulting amides inhibited thrombin in the range IC50 = 3-13,000 nM, and the structure-activity relationships and molecular modeling suggest a unique fit of the benzyl side chain into P-1 with the meta substituent occupying the recess.

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“…However, seen from the point of pharmacological control of blood coagulation, only a few compounds among the numerous synthetic low-molecular thrombin inhibitors described have proved to be suitable for use as an antithrombotic drug and have reached the stage of early clinical trials (for a review, see Hauptmann and Markwardt 64 ).…”

Section: Resultsmentioning

confidence: 99%

Hirudin As Alternative Anticoagulant- A Historical Review

Markwardt¹

2002

Semin Thromb Hemost

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113

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Advances in separation techniques and biotechnology have contributed to the development of anticoagulant agents from hematophagous animals. The most potent known natural thrombin inhibitor from blood-sucking leeches ( Hirudo medicinalis), hirudin has served as a standard for designing the natural coagulation inhibitors as an anticoagulant drug. The search for the development of hirudin from leech extract to genetically engineered products as an alternative anticoagulant has been resumed. The pharmacological profiling of the isolated thrombin inhibitor has shown that native hirudin is an antithrombotic agent of high quality. However, its clinical use has remained limited, because the substance has not been available in adequate amounts. The progress in molecular biology has stimulated the interest in the structure and function of hirudin. This development resulted in the production of recombinant hirudins (r-hirudins) through gene technology. The biological properties of hirudin combined with the ready availability of recombinant forms make the specific thrombin inhibitor well-suited for use as an antithrombotic drug. Its use should lead to a decisive progress in the management of thromboembolic diseases of both arterial and venous origin. Clinical trials, especially in diseases in which thrombin plays a crucial role, are in progress.

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Pharmacologic Aspects of the Development of Selective Synthetic Thrombin Inhibitors as Anticoagulants

Cited by 50 publications

References 89 publications

Peptide modified gold-coated polyurethanes as thrombin scavenging surfaces

Peptide modified gold-coated polyurethanes as thrombin scavenging surfaces

Design of Novel, Potent, Noncovalent Inhibitors of Thrombin with Nonbasic P-1 Substructures: Rapid Structure−Activity Studies by Solid-Phase Synthesis

Hirudin As Alternative Anticoagulant- A Historical Review

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