Substituted tetrahydrofuroyl-1-phenylalanine derivatives as potent and specific VLA-4 antagonists

Bioorg Med Chem Lett. 2002 Jun 3;12(11):1501-5. doi: 10.1016/s0960-894x(02)00211-1.

Abstract

A series of substituted tetrahydrofuroyl-1-phenylalanine derivatives was prepared and evaluated as VLA-4 antagonists. Substitution of the alpha carbon of the tetrahydrofuran with aryl groups increased the specificity for VLA-4 versus alpha(4)beta(7) while amide substitution increased the potency of the series without increasing the specificity. Substitution of the beta carbon of the tetrahydrofuran with keto or amino groups slightly improved the specificity for VLA-4 versus alpha(4)beta(7) but with a significant loss in binding affinity for VLA-4.

MeSH terms

  • Administration, Oral
  • Animals
  • Furans / chemical synthesis
  • Furans / chemistry
  • Furans / pharmacokinetics
  • Furans / pharmacology
  • Humans
  • Inhibitory Concentration 50
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Ligands
  • Molecular Weight
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / chemical synthesis
  • Phenylalanine / pharmacokinetics
  • Phenylalanine / pharmacology
  • Rats
  • Stereoisomerism
  • Structure-Activity Relationship
  • Substrate Specificity
  • Sulfonamides / blood
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacokinetics*
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Furans
  • Integrin alpha4beta1
  • Ligands
  • Sulfonamides
  • Vascular Cell Adhesion Molecule-1
  • tetrahydrofuran
  • Phenylalanine