4-(Pyrrolidinyl)methoxybenzoic acid derivatives as a potent, orally active VLA-4 antagonist

Chem Pharm Bull (Tokyo). 2006 Nov;54(11):1515-29. doi: 10.1248/cpb.54.1515.

Abstract

A novel series of benzoic acid derivatives as VLA-4 antagonists were synthesized. Optimization, focusing on activity and lipophilicity needed for cell permeability, resulted in the identification of 15b and 15e with good activity (IC50 = 1.6 nM each) and moderate lipophilicity (Log D = 2.0, 1.8). Furthermore, 15e demonstrated efficacy in murine asthma model by an oral dose of 30 mg/kg.

MeSH terms

  • Administration, Oral
  • Animals
  • Asthma / drug therapy*
  • Benzoates / administration & dosage*
  • Benzoates / chemistry
  • Benzoates / pharmacokinetics*
  • Cell Membrane Permeability / drug effects
  • Disease Models, Animal
  • Dogs
  • Drug Evaluation, Preclinical
  • Enzyme Activation / drug effects
  • Hydroxybenzoate Ethers
  • Integrin alpha4beta1 / antagonists & inhibitors*
  • Kidney / cytology
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Molecular Conformation
  • Pyrrolidines / chemistry*
  • Pyrrolidinones / administration & dosage*
  • Pyrrolidinones / chemistry
  • Pyrrolidinones / pharmacokinetics*
  • Rats
  • Rats, Sprague-Dawley
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • 4-(Pyrrolidinyl)methoxybenzoic acid
  • Benzoates
  • Hydroxybenzoate Ethers
  • Integrin alpha4beta1
  • Pyrrolidines
  • Pyrrolidinones