Novel non-covalent thrombin inhibitors incorporating P(1) 4,5,6,7-tetrahydrobenzothiazole arginine side chain mimetics
| Autor: | Jure Stojan, Alenka Trampuš Bakija, Danijel Kikelj, Gregor Mlinsek, Ales Krbavcic, Tomaz Solmajer, Mojca Stegnar, Petra Marinko |
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| Rok vydání: | 2003 |
| Předmět: |
Models
Molecular Arginine Peptidomimetic Stereochemistry Non covalent Crystallography X-Ray Substrate Specificity Structure-Activity Relationship Thrombin Biomimetic Materials Drug Discovery Side chain medicine Structure–activity relationship Humans Trypsin Enzyme Inhibitors Pharmacology Binding Sites biology Molecular Structure Chemistry Organic Chemistry Active site General Medicine Thiazoles Enzyme inhibitor biology.protein Discovery and development of direct thrombin inhibitors medicine.drug Protein Binding |
| Zdroj: | European journal of medicinal chemistry. 39(3) |
| ISSN: | 0223-5234 |
| Popis: | The design, synthesis and biological activity of a series of novel non-covalent D-Phe-Pro-Arg motif-based thrombin inhibitors incorporating 4,5,6,7-tetrahydrobenzothiazol-2-amine as a novel arginine surrogate are described. Compound 9, the most potent in the series of thrombin inhibitors, exhibited an in vitro K(i) of 128 nM and 342-fold selectivity against trypsin. The binding mode of this novel class of thrombin inhibitors in the enzyme active site, based on the X-ray crystal structure of compound 9 co-crystallized with human alpha-thrombin, is discussed. |
| Databáze: | OpenAIRE |
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