RESUMEN
Ovariectomy-induced osteopenia in the rat produces skeletal responses similar to that in a post-menopausal woman. In the ovariectomized (ovx) rat, high bone turnover, and subsequent bone loss, like in the human post-menopausal condition, can be prevented by estrogen replacement. Because of the striking resemblance of skeletal responses in humans and rats in the state of estrogen deficiency, the ovx rat is considered to be a gold standard model for evaluating drugs for prevention and reversal of osteoporosis. This chapter describes the procedure for performing ovariectomy on the rat and the utility of the ovx rat model we have utilized over the last two decades in our laboratory.
Asunto(s)
Evaluación Preclínica de Medicamentos , Osteoporosis , Ovariectomía , Animales , Densidad Ósea , Conservadores de la Densidad Ósea/uso terapéutico , Fuerza Compresiva , Modelos Animales de Enfermedad , Estrógenos/deficiencia , Femenino , Humanos , Osteoporosis/tratamiento farmacológico , Osteoporosis/fisiopatología , Ratas , Columna Vertebral/anatomía & histología , Columna Vertebral/metabolismo , Tibia/anatomía & histología , Tibia/químicaRESUMEN
A high-throughput screening campaign to discover small molecule leads for the treatment of bone disorders concluded with the discovery of a compound with a 2-aminopyrimidine template that targeted the Wnt beta-catenin cellular messaging system. Hit-to-lead in vitro optimization for target activity and molecular properties led to the discovery of (1-(4-(naphthalen-2-yl)pyrimidin-2-yl)piperidin-4-yl)methanamine (5, WAY-262611). Compound 5 has excellent pharmacokinetic properties and showed a dose dependent increase in the trabecular bone formation rate in ovariectomized rats following oral administration.