RESUMO
We have carried out the optimization of substituents at the C-3 or the C-5 position on the pyrrolidine ring of VLA-4 antagonist 3 with 2-(phenylamino)-7-fluorobenzoxazolyl moiety for the purpose of improving in vivo efficacy while maintaining good aqueous solubility. As a result, we successfully increased in vitro activity in the presence of 3% human serum albumin and achieved an exquisite lipophilic and hydrophilic balance of compounds suitable for oral administrative regimen. The modification resulted in the identification of zwitterionic compound 7n with (5S)-[methoxy(methyl)amino]methylpyrrolidine, which significantly alleviated bronchial hyper-responsiveness to acetylcholine chloride at 12.5mg/kg, p.o. in a murine asthma model and showed favorable aqueous solubility (JP1, 89 µg/mL; JP2, 462 µg/mL). Furthermore, this compound showed good oral bioavailability (F=54%) in monkeys.
Assuntos
Anti-Inflamatórios/química , Anti-Inflamatórios/uso terapêutico , Asma/tratamento farmacológico , Ácidos Cicloexanocarboxílicos/química , Ácidos Cicloexanocarboxílicos/uso terapêutico , Integrina alfa4beta1/antagonistas & inibidores , Administração Oral , Animais , Anti-Inflamatórios/administração & dosagem , Anti-Inflamatórios/farmacocinética , Asma/imunologia , Disponibilidade Biológica , Brônquios/efeitos dos fármacos , Brônquios/imunologia , Linhagem Celular , Ácidos Cicloexanocarboxílicos/administração & dosagem , Ácidos Cicloexanocarboxílicos/farmacocinética , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Haplorrinos , Humanos , Integrina alfa4beta1/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Pirrolidinas/administração & dosagem , Pirrolidinas/química , Pirrolidinas/farmacocinética , Pirrolidinas/uso terapêutico , Solubilidade , Água/químicaRESUMO
We have discovered imidazo[1,2-b]pyridazine derivatives that show suppressive activity of inflammation in arthritis models. We optimized the substructures of imidazo[1,2-b]pyridazine derivatives to combine potent IKKß inhibitory activity, TNFα inhibitory activity in vivo and excellent pharmacokinetics. The compound we have acquired, which had both potent activities and good pharmacokinetic profiles based on improved physicochemical properties, demonstrated efficacy on collagen-induced arthritis models in mice and rats.