RESUMO
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 IC50 value of 0.51 nM and efficacy by oral administration at a dosage of 10 mg/kg in a rat pleurisy model.
Assuntos
Benzoatos/síntese química , Benzoatos/farmacocinética , Integrina alfa4beta1/antagonistas & inibidores , Administração Oral , Animais , Benzoatos/farmacologia , Modelos Animais de Doenças , Cães , Inflamação/tratamento farmacológico , Concentração Inibidora 50 , Camundongos , Farmacocinética , Pleurisia/tratamento farmacológico , Ratos , Relação Estrutura-AtividadeRESUMO
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.