Substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl-phenylalanine analogues as potent VLA-4 antagonists

Bioorg Med Chem Lett. 2002 Feb 25;12(4):637-40. doi: 10.1016/s0960-894x(01)00821-6.

Abstract

A series of substituted N-(3,5-dichlorobenzenesulfonyl)-L-prolyl- and alpha-methyl-L-prolyl-phenylalanine derivatives was prepared as VLA-4/VCAM antagonists. The compounds showed excellent potency with a wide variety of neutral, polar, electron withdrawing or donating groups on the phenylalanine ring (IC50 approximately 1 nM). Heteroaryl ring substitution for phenylalanine was also well tolerated. Pharmacokinetic studies in rat were performed on a representative set of compounds in both series.

MeSH terms

  • Animals
  • Biological Availability
  • Dipeptides / chemical synthesis
  • Dipeptides / chemistry
  • Dipeptides / pharmacokinetics*
  • Dogs
  • Haplorhini
  • Inhibitory Concentration 50
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Metabolic Clearance Rate
  • Phenylalanine
  • Rats
  • Rats, Sprague-Dawley
  • Sheep
  • Structure-Activity Relationship
  • Sulfones
  • Vascular Cell Adhesion Molecule-1 / drug effects

Substances

  • Dipeptides
  • Integrin alpha4beta1
  • Sulfones
  • Vascular Cell Adhesion Molecule-1
  • Phenylalanine
  • benzenesulfonyl chloride