Synthesis and biological activity of ketomethylene pseudopeptide analogs as thrombin inhibitors
| Autor: | Vijay V. Kakkar, Leifeng Cheng, Christopher A. Goodwin, Goran Claeson, Michael F. Schully |
|---|---|
| Rok vydání: | 1992 |
| Předmět: |
chemistry.chemical_classification
Dipeptide biology Plasmin Stereochemistry Thrombin Stereoisomerism Biological activity Tripeptide Amino acid Structure-Activity Relationship chemistry.chemical_compound chemistry Enzyme inhibitor Drug Discovery biology.protein medicine Molecular Medicine Peptides medicine.drug Discovery and development of direct thrombin inhibitors |
| Zdroj: | Journal of Medicinal Chemistry. 35:3364-3369 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | Ketomethylene pseudopeptide analogues Aa-Pro-Arg psi (COCH2) Gly-pip, 1, where Aa are D- or L-amino acids (Dpa, beta, beta-diphenylalanine; alpha Nal, alpha-naphthylalanine; beta Nal, beta-naphthylalanine; Fgl, fluorenylglycine) with highly lipophilic side chains and psi (COCH2) is a ketomethylene pseudopeptide bond, have been synthesized through a modified Dakin-West reaction under very mild conditions with a high yield using tripeptide 4 with a labile functional group directly on the side chain. Their enzymatic assay of thrombin inhibition has been carried out. The structure-activity relationship study indicated that a lipophilic side chain on the amino acid in the P3 position is very important for binding to the apolar site of thrombin. Compound 1a with D-Dpa at the P3 position has a Ki of 0.2 microM and it doubles thrombin clotting time at only 3 times higher concentration. These values are about 7 times better than those of the corresponding D-Phe analogues. Furthermore, 1a shows poor inhibitory activity against plasmin, factor Xa, urokinase, and kallikrein. Preliminary in vivo testing (3-4-kg rabbit as the animal model) shows no observable side effect (change of blood pressure and accumulation of blood platelet in lungs) at a dose of 1 mg/kg. |
| Databáze: | OpenAIRE |
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