Arylsulfonamide pyrimidines as VLA-4 antagonists

Bioorg Med Chem Lett. 2013 May 15;23(10):3070-4. doi: 10.1016/j.bmcl.2013.03.010. Epub 2013 Mar 15.

Abstract

A series of (S)-2-(2-(diethylamino)-5-(N-alkyl-N-sulfonamido)pyrimidin-4-ylamino)-3-(4-(carbamoyloxy)phenyl)propanoic acid is discovered as orally available VLA-4 antagonists. Representative compounds 11b and 11p showed efficacy in multiple in vivo animal models. The in vitro selectivity of 11p is also described.

MeSH terms

  • Animals
  • Antirheumatic Agents / administration & dosage
  • Antirheumatic Agents / chemical synthesis
  • Antirheumatic Agents / pharmacology*
  • Arthritis, Experimental / drug therapy
  • Asthma / drug therapy
  • Cell Adhesion / drug effects
  • Collagen Type II / antagonists & inhibitors
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Female
  • Fibronectins / chemistry
  • Humans
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Molecular Conformation
  • Multiple Sclerosis / drug therapy
  • Pyrimidines / administration & dosage
  • Pyrimidines / chemical synthesis
  • Pyrimidines / pharmacology*
  • Rats
  • Rats, Inbred Lew
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship
  • Sulfonamides / administration & dosage
  • Sulfonamides / chemical synthesis
  • Sulfonamides / pharmacology*

Substances

  • Antirheumatic Agents
  • Collagen Type II
  • Fibronectins
  • Integrin alpha4beta1
  • Pyrimidines
  • Sulfonamides