Peptide-derived transition state analogue inhibitors of thrombin; synthesis, activity and selectivity.

hexapeptide) yields thrombin inhibitors of high potency and selectivity. The effects of these two alterations reinforce each other indicating a synergistic effect. This might be rationalized by entropy factors. -->
Substance Nomenclature: 0 (Antithrombins)
0 (Factor Xa Inhibitors)
0 (Indicators and Reagents)
0 (Oligopeptides)
EC 3.4.21.5 (Thrombin)
Entry Date(s): Date Created: 19950801 Date Completed: 19951218 Latest Revision: 20190830
Update Code: 20240829
DOI: 10.1016/0968-0896(95)00102-m
PMID: 7582983
Autor: Jetten M; N.V. Organon, Oss, The Netherlands., Peters CA, Visser A, Grootenhuis PD, van Nispen JW, Ottenheijm HC
Jazyk: angličtina
Zdroj: Bioorganic & medicinal chemistry [Bioorg Med Chem] 1995 Aug; Vol. 3 (8), pp. 1099-114.
DOI: 10.1016/0968-0896(95)00102-m
Abstrakt: In a study to combine the transition state analogue concept with the principle of catalytic site spanning, a series of peptide-derived transition state analogue (TSA) inhibitors of thrombin has been synthesized and tested. In the sequence H-D-Phe-Pro-Arg-Gly-OH (2) the Arg-Gly amide bond has been replaced by three classes of transition state analogues, being the ketomethylene, the hydroxyethylene and the hydroxymethylene amide bond replacements. Compound 12a, in which the amide bond has been replaced by the ketomethylene group, was found to be the most potent thrombin inhibitor of the series studied. Subsequently, penta- and hexapeptide sequences with good affinity for thrombin were developed, i.e. H-D-Phe-Pro-Arg-Gly-Phe-OH (16) and H-D-Phe-Pro-Arg-Gly-Phe-Lys-OH (26). In these sequences the Arg-Gly amide bond was then replaced by the ketomethylene group. The resulting compounds 43a and 47a, respectively, were evaluated in vitro as inhibitors of thrombin and factor Xa. Compound 47a was found to be the most potent thrombin inhibitor of the series studied (Ki = 29 nM). The combination of the transition state analogue concept and the principle of peptide elongation (tetrapeptide-->hexapeptide) yields thrombin inhibitors of high potency and selectivity. The effects of these two alterations reinforce each other indicating a synergistic effect. This might be rationalized by entropy factors.
Databáze: MEDLINE
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