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

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, 121 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, 121 exhibited potent activity with an IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model. (c) 2006 Elsevier Ltd. All rights reserved.