RESUMEN
We have focused on optimization of the inadequate pharmacokinetic profile of trans-4-substituted cyclohexanecarboxylic acid 5, which is commonly observed in many small molecule very late antigen-4 (VLA-4) antagonists. We modified the lipophilic moiety in 5 and found that reducing the polar surface area of this moiety results in improvement of the PK profile. Consequently, our efforts have led to the discovery of trans-4-[1-[[2,5-dichloro-4-(1-methyl-3-indolylcarboxamido)phenyl]acetyl]-(4S)-methoxy-(2S)-pyrrolidinylmethoxy]cyclohexanecarboxylic acid (14e) with potent activity (IC(50) = 5.4 nM) and significantly improved bioavailability in rats, dogs, and monkeys (100%, 91%, 68%), which demonstrated excellent oral efficacy in murine and guinea pig models of asthma. Based on its overall profile, compound 14e was progressed into clinical trails. In a single ascending-dose phase I clinical study, compound 14e exhibited favorable oral exposure as expected and had no serious adverse events.
Asunto(s)
Ácidos Ciclohexanocarboxílicos/química , Ácidos Ciclohexanocarboxílicos/farmacocinética , Indoles/farmacocinética , Integrina alfa4beta1/antagonistas & inhibidores , Pirrolidinas/farmacocinética , Administración Oral , Animales , Disponibilidad Biológica , Células CHO , Cricetinae , Cricetulus , Ácidos Ciclohexanocarboxílicos/síntesis química , Ácidos Ciclohexanocarboxílicos/farmacología , Perros , Cobayas , Haplorrinos , Humanos , Indoles/síntesis química , Indoles/química , Indoles/farmacología , Ratones , Pirrolidinas/síntesis química , Pirrolidinas/química , Pirrolidinas/farmacología , Ratas , Ratas Sprague-Dawley , Relación Estructura-ActividadRESUMEN
Optimization of benzoic acid derivatives by introducing substituents into the diphenyl urea moiety led to the identification of compound 20l as a potent VLA-4 antagonist. Compound 20l inhibited eosinophil infiltration into bronchial alveolar lavage fluid in a murine asthma model by oral dosing and its efficacy was comparable to anti-mouse alpha4 antibody (R1-2). Furthermore, this compound significantly blocked bronchial hyper-responsiveness in the model.
Asunto(s)
Benzoatos/farmacología , Integrina alfa4beta1/antagonistas & inhibidores , Pirroles/farmacología , Administración Oral , Animales , Antiinflamatorios/farmacología , Asma/tratamiento farmacológico , Benzoatos/administración & dosificación , Benzoatos/síntesis química , Células Cultivadas , Modelos Animales de Enfermedad , Perros , Femenino , Concentración 50 Inhibidora , Ratones , Ratones Endogámicos BALB C , Permeabilidad , Pirroles/administración & dosificación , Pirroles/síntesis química , RatasRESUMEN
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.
Asunto(s)
Benzoatos/síntesis química , Benzoatos/farmacocinética , Integrina alfa4beta1/antagonistas & inhibidores , Administración Oral , Animales , Benzoatos/farmacología , Modelos Animales de Enfermedad , Perros , Inflamación/tratamiento farmacológico , Concentración 50 Inhibidora , Ratones , Farmacocinética , Pleuresia/tratamiento farmacológico , Ratas , Relación Estructura-ActividadRESUMEN
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.