RESUMO
3-(S)-Pyrimidin-5-yl-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5e) and 3-(S)-(methylpyrimidin-5-yl)-9-(5,6,7,8-tetrahydro-[1,8]naphthyridin-2-yl)-nonanoic acid (5f) were identified as potent and selective antagonists of the alpha(v)beta(3) receptor. These compounds have excellent in vitro profiles (IC(50) = 0.07 and 0.08 nM, respectively), significant unbound fractions in human plasma (6 and 4%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in an in vivo model of bone turnover following once-daily oral administration, these two compounds were selected for clinical development for the treatment of osteoporosis.
Assuntos
Integrinas/antagonistas & inibidores , Naftiridinas/farmacologia , Osteoporose/tratamento farmacológico , Receptores de Vitronectina/antagonistas & inibidores , Administração Oral , Animais , Disponibilidade Biológica , Densidade Óssea/efeitos dos fármacos , Reabsorção Óssea/tratamento farmacológico , Cães , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Feminino , Humanos , Concentração Inibidora 50 , Integrinas/metabolismo , Macaca mulatta , Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacocinética , Osteoporose/prevenção & controle , Ovariectomia , Ratos , Ratos Sprague-Dawley , Receptores de Vitronectina/metabolismo , Relação Estrutura-AtividadeRESUMO
Potent non-peptidic alpha(v)beta(3) antagonists have been prepared incorporating various beta-amino acids as aspartic acid mimetics. Modification of the beta-alanine 3-substituents alters the potency and physicochemical properties of these receptor antagonists and in some cases provides orally bioavailable alpha(v)beta(3) inhibitors.
