N-(3-phenylsulfonyl-3-piperidinoyl)-phenylalanine derivatives as potent, selective VLA-4 antagonists

Bioorg Med Chem Lett. 2003 Mar 10;13(5):885-90. doi: 10.1016/s0960-894x(02)01077-6.

Abstract

The SAR of 1-sulfonyl-cyclopentyl carboxylic acid amides, ligands for the VLA-4 integrin, was investigated. This effort resulted in the identification of N-(3-phenylsulfonyl-3-piperidinoyl)-(L)-4-(2',6'-dimethoxyphenyl)phenylalanine 52 as a potent, selective VLA-4 antagonist (IC(50)=90 pM). Expansion of the SAR demonstrated that this structural unit can be used to identify a diverse series of sub-nanomolar antagonists.

MeSH terms

  • Amides / chemistry
  • Amides / metabolism
  • Amides / pharmacology
  • Cell Adhesion Molecules
  • Humans
  • Immunoglobulins
  • Inhibitory Concentration 50
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Integrin alpha4beta1 / metabolism
  • Jurkat Cells
  • Mucoproteins / antagonists & inhibitors
  • Phenylalanine / analogs & derivatives*
  • Phenylalanine / pharmacokinetics
  • Phenylalanine / pharmacology*
  • Radioligand Assay
  • Receptors, Lymphocyte Homing / antagonists & inhibitors
  • Structure-Activity Relationship
  • Vascular Cell Adhesion Molecule-1 / metabolism

Substances

  • Amides
  • Cell Adhesion Molecules
  • Immunoglobulins
  • Integrin alpha4beta1
  • MADCAM1 protein, human
  • Mucoproteins
  • Receptors, Lymphocyte Homing
  • Vascular Cell Adhesion Molecule-1
  • Phenylalanine