RESUMEN
3(S)-(6-methoxypyridin-3-yl)-3-[2-oxo-3-[3-(5,6,7,8-tetrahydro-[1,8]-naphthyridin-2-yl)propyl]imidazolidin-1-yl]propionic acid 6 was identified as a potent and selective antagonist of the alpha(v)beta(3) receptor. This compound has an excellent in vitro profile (IC(50) = 0.08 nM), a significant unbound fraction in human plasma (12%), and good pharmacokinetics in rat, dog, and rhesus monkey. On the basis of the efficacy shown in three in vivo models of bone turnover, the compound was selected for clinical development. To support the ongoing metabolism and safety studies, a novel strategy was employed in which a series of oxidized derivatives of 6 were prepared by exposure of 6 (or the methyl ester) to chemical oxidizing agents. These products proved useful in the identification of active metabolites generated by either in vitro or in vivo metabolism.
Asunto(s)
Integrina alfaVbeta3/antagonistas & inhibidores , Naftiridinas/síntesis química , Osteoporosis , Propionatos/síntesis química , Animales , Densidad Ósea/efectos de los fármacos , Resorción Ósea/tratamiento farmacológico , Resorción Ósea/etiología , Resorción Ósea/metabolismo , Perros , Femenino , Humanos , Macaca mulatta , Masculino , Naftiridinas/química , Naftiridinas/farmacología , Osteoporosis/tratamiento farmacológico , Osteoporosis/prevención & control , Ovariectomía , Oxidación-Reducción , Propionatos/química , Propionatos/farmacología , Ratas , Ratas Sprague-Dawley , Estereoisomerismo , Relación Estructura-ActividadRESUMEN
Mimetics of the RGD tripeptide are described that are potent, selective antagonists of the integrin receptor, alpha(v)beta(3). The use of the 5,6,7,8-tetrahydro[1,8]naphthyridine group as a potency-enhancing N-terminus is demonstrated. Two 3-substituted-3-amino-propionic acids previously contained in alpha(IIb)beta(3) antagonists were utilized to enhance binding affinity and functional activity for the targeted receptor. Further affinity increases were then achieved through the use of cyclic glycyl amide bond constraints.