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