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Identification and SAR for a selective, nonpeptidyl thrombin inhibitor
A M Naylor-Olsen1, G S Ponticello, S D Lewis
1Department of Molecular Design and Diversity, Merck Research Laboratories, West Point, PA 19486, USA.
Bioorganic & Medicinal Chemistry Letters
|January 5, 1999
Summary
Researchers discovered a new nonpeptidyl thrombin inhibitor, L-636,619, through database searching. Modifications improved its potency and stability, with Analog 9 showing the most promise.
Area of Science:
- Medicinal Chemistry
- Biochemistry
- Structural Biology
Background:
- Thrombin is a key enzyme in blood coagulation.
- Development of novel anticoagulants is crucial for treating thrombotic disorders.
- Nonpeptidyl inhibitors offer an alternative to peptide-based therapeutics.
Purpose of the Study:
- To identify and characterize novel nonpeptidyl thrombin inhibitors.
- To elucidate the binding interactions of inhibitors with thrombin.
- To optimize inhibitor properties through chemical modification.
Main Methods:
- Topological similarity searching of a corporate sample database.
- X-ray crystallography for determining ligand-enzyme geometry.
- Structure-activity relationship studies via chemical modification.
Main Results:
- Identification of a novel nonpeptidyl thrombin inhibitor, L-636,619.
- Determination of the binding mode of L-636,619 within the thrombin active site.
- Chemical modifications at P1 and P3 positions enhanced inhibitor potency and stability.
- Analog 9 emerged as a highly promising lead compound.
Conclusions:
- L-636,619 represents a structurally novel class of thrombin inhibitors.
- Structural insights guided the optimization of inhibitor potency and chemical properties.
- Further development of Analog 9 could lead to new anticoagulant therapies.
