Synthesis of novel thrombin inhibitors. Use of ring-closing metathesis reactions for synthesis of P2 cyclopentene- and cyclohexenedicarboxylic acid derivatives

J Med Chem. 2003 Mar 27;46(7):1165-79. doi: 10.1021/jm021065a.

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

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Benzamides / chemical synthesis*
  • Benzamides / chemistry
  • Crystallography, X-Ray
  • Cyclohexanes / chemical synthesis*
  • Cyclohexanes / chemistry
  • Cyclopentanes / chemical synthesis*
  • Cyclopentanes / chemistry
  • Dicarboxylic Acids / chemical synthesis*
  • Dicarboxylic Acids / chemistry
  • Ligands
  • Models, Molecular
  • Molecular Mimicry
  • Oligopeptides / chemistry
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / chemistry
  • Structure-Activity Relationship
  • Thrombin / antagonists & inhibitors*

Substances

  • Amides
  • Benzamides
  • Cyclohexanes
  • Cyclopentanes
  • Dicarboxylic Acids
  • Ligands
  • Oligopeptides
  • Serine Proteinase Inhibitors
  • cyclopent-2-ene-1,2-dicarboxylic acid 1-(4-carbamimidoylbenzylamide) 2-(cyclohexyl(2,5-dimethoxyphenyl)amide)
  • phenylalanyl-prolyl-arginine
  • Thrombin