Stereospecific synthesis of 5-substituted 2-bisarylthiocyclopentane carboxylic acids as specific matrix metalloproteinase inhibitors

J Med Chem. 2003 Aug 28;46(18):3840-52. doi: 10.1021/jm0307638.

Abstract

The synthesis and structure-activity relationship (SAR) studies of a series of cyclopentane carboxylic acid matrix metalloproteinase (MMP) inhibitors are described. Potent and specific MMP-2, -3, -9, -13 inhibitors were obtained by regio- and stereoselective substitutions at positions 2 and 5 on the cyclopentane ring. Compounds 2a and 2e are active in the mouse B16-F10 metastasis model and display very good pharmacokinetic parameters.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Biological Availability
  • Caco-2 Cells
  • Cyclopentanes / chemical synthesis*
  • Cyclopentanes / chemistry
  • Cyclopentanes / pharmacology
  • Humans
  • In Vitro Techniques
  • Matrix Metalloproteinase Inhibitors*
  • Matrix Metalloproteinases / chemistry
  • Melanoma, Experimental / drug therapy
  • Melanoma, Experimental / pathology
  • Mice
  • Microsomes, Liver / drug effects
  • Microsomes, Liver / metabolism
  • Models, Molecular
  • Molecular Conformation
  • Neoplasm Metastasis
  • Permeability
  • Phthalimides / chemical synthesis*
  • Phthalimides / chemistry
  • Phthalimides / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / pharmacology
  • Stereoisomerism
  • Structure-Activity Relationship
  • Triazines / chemical synthesis*
  • Triazines / chemistry
  • Triazines / pharmacology

Substances

  • 2-(2-(4'-chlorobiphenylthio))-5-(2-(4-oxo-4H-benzo(d)(1,2,3)triazin-3-ylmethyl))cyclopentanecarboxylic acid
  • 2-(2-(4'-fluorobiphenyl)ethylthio)-5-(phthalimidomethyl)cyclopentanecarboxylic acid
  • Antineoplastic Agents
  • Cyclopentanes
  • Matrix Metalloproteinase Inhibitors
  • Phthalimides
  • Protease Inhibitors
  • Triazines
  • Matrix Metalloproteinases