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

Add time:07/14/2019    Source:sciencedirect.com

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=18.5ml/min/kg,F=28%; rats, CL=5.2ml/min/kg,F=36%; dogs, CL=3.6ml/min/kg,F=55%). Additionally, 12l 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.

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