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Related Experiment Videos

Thrombin inhibitor design

P E Sanderson1, A M Naylor-Olsen

  • 1Department of Medicinal Chemistry, West Point, PA 19486, USA.

Current Medicinal Chemistry
|July 21, 1998
PubMed
Summary
This summary is machine-generated.

Researchers developed new oral direct thrombin inhibitors, offering a potential alternative to warfarin. These compounds show improved selectivity and bioavailability, addressing limitations of earlier direct thrombin inhibitors.

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Area of Science:

  • Pharmacology
  • Medicinal Chemistry
  • Drug Discovery

Background:

  • Direct thrombin inhibitors administered intravenously (IV) are safe and effective alternatives to heparin.
  • The development of an orally active direct thrombin inhibitor is a significant goal, potentially improving upon warfarin therapy with predictable pharmacokinetics and dosing convenience.
  • Efegatran, a prototype inhibitor, had deficiencies that needed to be addressed for successful oral drug development.

Purpose of the Study:

  • To develop orally active direct thrombin inhibitors with improved selectivity, efficacy, and pharmacokinetic properties.
  • To overcome the limitations of previous direct thrombin inhibitors, such as efegatran.
  • To identify compounds suitable for once or twice-daily oral dosing.

Main Methods:

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  • Structure-based design and empirical structure optimization were employed to identify more selective compounds.
  • Modifications included altering the P1 group and incorporating different peptidomimetic P2/P3 scaffolds.
  • Development focused on potent and selective non-covalent inhibitors to avoid issues associated with serine traps.

Main Results:

  • Selective compounds were identified through structural modifications.
  • Potent and selective non-covalent inhibitors were developed, bypassing serine trap liabilities.
  • Oral bioavailability was achieved by incorporating less basic P1 groups, maintaining selectivity and efficacy.

Conclusions:

  • Oral direct thrombin inhibitors have been successfully developed by addressing deficiencies in prototype compounds.
  • The new inhibitors demonstrate improved selectivity and oral bioavailability, representing a significant advance in anticoagulant therapy.
  • Further optimization of the duration of action is required, but the development of non-peptide templates and uncharged P1 groups shows promise.