Identification and SAR for a selective, nonpeptidyl thrombin inhibitor

A novel, nonpeptidyl thrombin inhibitor, L-636,619 ( 1), was identified via topological similarity searching over the Merck Corporate Sample Database. X-ray crystallographic studies determined the geometry for ligand binding to the enzyme. Chemical modification of the P1 and P3 segments of the ligan...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 1998-07, Vol.8 (13), p.1697-1702
Main Authors: Naylor-Olsen, Adel M., Ponticello, Gerald S., Lewis, S.Dale, Mulichak, Anne M., Chen, Zhonguo, Habecker, Charles N., Phillips, Brian T., Sanders, William M., Tucker, Thomas J., Shafer, Jules A., Vacca, Joseph P.
Format: Article
Language:English
Subjects:
Antithrombins - chemistry
Antithrombins - pharmacology
Binding Sites
Biological and medical sciences
Blood. Blood coagulation. Reticuloendothelial system
Crystallography
Medical sciences
Models, Molecular
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:A novel, nonpeptidyl thrombin inhibitor, L-636,619 ( 1), was identified via topological similarity searching over the Merck Corporate Sample Database. X-ray crystallographic studies determined the geometry for ligand binding to the enzyme. Chemical modification of the P1 and P3 segments of the ligand resulted in enhanced potency and improvement in the chemical stability of the lead. Analog 9 proved to be the most interesting lead from this structurally novel series. A series of novel, nonpeptidyl thrombin inhibitors, of the general form A, were identified and characterized via synthetic medicinal chemistry, biochemistry and X-ray crystallographic studies.
ISSN:0960-894X
1464-3405
DOI:10.1016/S0960-894X(98)00296-0