New proline mimetics: synthesis of thrombin inhibitors incorporating cyclopentane- and cyclopentenedicarboxylic acid templates in the P2 position. Binding conformation investigated by X-ray crystallography

J Med Chem. 2000 May 4;43(9):1705-13. doi: 10.1021/jm990557t.

Abstract

With the aim to prepare nonpeptidic thrombin inhibitors, the amino acids of the thrombin-inhibiting tripeptide chain D-Phe-Pro-Arg were replaced with isosteres. Arg was replaced with the more rigid P1 truncated p-amidinobenzylamine (Pab), Pro with either cyclopentane-1, 2-dicarboxylic acid or cyclopentene-1,5-dicarboxylic acid, and D-Phe with a series of readily available lipophilic amines. One of the most potent compounds (25, pIC(50) = 6.01) in these series was cocrystallized with thrombin where the X-ray crystal structure provide insight to the structure-activity relationship (SAR).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anticoagulants / chemical synthesis*
  • Anticoagulants / chemistry
  • Anticoagulants / pharmacology
  • Blood Coagulation / drug effects
  • Crystallography, X-Ray
  • Cyclopentanes / chemistry*
  • Cyclopentanes / pharmacology
  • Humans
  • In Vitro Techniques
  • Indicators and Reagents
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Proline / pharmacology*
  • Protein Binding
  • Protein Conformation
  • Stereoisomerism
  • Structure-Activity Relationship
  • Templates, Genetic
  • Thrombin / antagonists & inhibitors*
  • Thrombin / chemistry

Substances

  • Anticoagulants
  • Cyclopentanes
  • Indicators and Reagents
  • cyclopentenedicarboxylic acid
  • Proline
  • Thrombin