RESUMO
Structural modification and cellular adhesion inhibition activities of pyridazinone-substituted phenylalanine amide alpha(4) integrin antagonists are described. Functionality requirements for the arylamide moiety and the carboxylic acid group were demonstrated. The study also revealed novel structure-activity relationships (SAR) for arylated pyridazinones. A correlation between bioavailability and permeability was also explored. A selected compound showed effectiveness in a mouse leukocytosis study.
Assuntos
Amidas/química , Amidas/farmacologia , Integrina alfa4/metabolismo , Fenilalanina/análogos & derivados , Piridazinas/química , Piridazinas/farmacologia , Amidas/síntese química , Amidas/farmacocinética , Animais , Disponibilidade Biológica , Células CACO-2 , Adesão Celular/efeitos dos fármacos , Humanos , Integrina alfa4/química , Absorção Intestinal , Leucocitose/tratamento farmacológico , Camundongos , Fenilalanina/síntese química , Fenilalanina/farmacocinética , Fenilalanina/farmacologia , Piridazinas/síntese química , Piridazinas/farmacocinética , Ratos , Relação Estrutura-AtividadeRESUMO
The design, synthesis, and biological activity of novel alpha(4)beta(1) and alpha(4)beta(7) integrin antagonists, containing a bridged azabicyclic nucleus, are reported. Conformational analysis of targets containing an azabicyclo[2.2.2]octane carboxylic acid and known integrin antagonists indicated that this azabicycle would be a suitable molecular scaffold. Variation of substituents on the pendant arylsulfonamide and phenylalanine groups resulted in potent alpha(4)beta(1)-selective and dual alpha(4)beta(1)/alpha(4)beta(7) antagonists. Potent compounds 11i, 11h, and 14 were effective in the antigen-sensitized sheep model of asthma.