Abstract
The thrombin inhibitory tripeptide d-Phe-Pro-Arg has been mimicked using either cyclopentenedicarboxylic derivatives or a cyclohexenedicarboxylic derivative as surrogate for the P2 proline. In the P3 position, tertiary amides were optimized as d-Phe P3 replacements. The P1 arginine was, in all compounds, substituted with the more rigid and biocompatible 4-aminomethylbenzamidine. One of the novel inhibitors was cocrystallized with alpha-thrombin and subjected to X-ray analysis. From analysis of the X-ray crystal structure, new ligands were designed leading to significantly improved binding affinity, the lead candidate exhibiting an in vitro IC(50) of 49 nM.
MeSH terms
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Amides / chemical synthesis*
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Amides / chemistry
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Benzamides / chemical synthesis*
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Benzamides / chemistry
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Crystallography, X-Ray
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Cyclohexanes / chemical synthesis*
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Cyclohexanes / chemistry
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Cyclopentanes / chemical synthesis*
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Cyclopentanes / chemistry
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Dicarboxylic Acids / chemical synthesis*
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Dicarboxylic Acids / chemistry
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Ligands
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Models, Molecular
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Molecular Mimicry
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Oligopeptides / chemistry
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / chemistry
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Structure-Activity Relationship
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Thrombin / antagonists & inhibitors*
Substances
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Amides
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Benzamides
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Cyclohexanes
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Cyclopentanes
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Dicarboxylic Acids
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Ligands
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Oligopeptides
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Serine Proteinase Inhibitors
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cyclopent-2-ene-1,2-dicarboxylic acid 1-(4-carbamimidoylbenzylamide) 2-(cyclohexyl(2,5-dimethoxyphenyl)amide)
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phenylalanyl-prolyl-arginine
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Thrombin