Synthesis and biological evaluation of benzoic acid derivatives as potent, orally active VLA-4 antagonists

Abstract

A series of benzoic acid derivatives was synthesized as VLA-4 antagonists. Introduction of chlorine or bromine into the 3-position on the central benzene of the diphenylurea portion as in lead compound 2 led to improvement in the pharmacokinetic properties. In particular, 12l demonstrated an acceptable plasma clearance and bioavailability in mice and rats as well as dogs (mice, CL = 18.5 ml/min/kg, F = 28 % ; rats, CL = 5.2 ml/min/kg, F = 36 % ; dogs, CL = 3.6 ml/min/kg, F = 55 % ). Additionally, 12l exhibited potent activity with an IC 50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model.