RESUMEN
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.
Asunto(s)
Integrinas/antagonistas & inhibidores , Naftiridinas/farmacología , Osteoporosis/tratamiento farmacológico , Receptores de Vitronectina/antagonistas & inhibidores , Administración Oral , Animales , Disponibilidad Biológica , Densidad Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Perros , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Humanos , Concentración 50 Inhibidora , Integrinas/metabolismo , Macaca mulatta , Modelos Moleculares , Naftiridinas/química , Naftiridinas/farmacocinética , Osteoporosis/prevención & control , Ovariectomía , Ratas , Ratas Sprague-Dawley , Receptores de Vitronectina/metabolismo , Relación Estructura-ActividadRESUMEN
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.