RESUMEN
Structure-activity relationship studies are described, which led to the discovery of novel selective estrogen receptor modulators (SERMs) for the potential treatment of uterine fibroids. The SAR studies focused on limiting brain exposure and were guided by computational properties. Compounds with limited impact on the HPO axis were selected using serum estrogen levels as a biomarker for ovarian stimulation.
Asunto(s)
Leiomioma/tratamiento farmacológico , Ovario/efectos de los fármacos , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Encéfalo/metabolismo , Relación Dosis-Respuesta a Droga , Diseño de Fármacos , Estrógenos/sangre , Femenino , Humanos , Modelos Químicos , Ovario/metabolismo , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/química , Programas Informáticos , Relación Estructura-ActividadRESUMEN
The design of a novel selective estrogen receptor modulator (SERM) for the potential treatment of uterine leiomyoma is described. 16 (LY2066948-HCl) binds with high affinity to estrogen receptors alpha and beta (ERalpha and ERbeta, respectively) and is a potent uterine antagonist with minimal effects on the ovaries as determined by serum biomarkers and histologic evaluation.
Asunto(s)
Receptor alfa de Estrógeno/antagonistas & inhibidores , Receptor beta de Estrógeno/antagonistas & inhibidores , Leiomioma/tratamiento farmacológico , Naftalenos/síntesis química , Ovario/efectos de los fármacos , Piperidinas/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Neoplasias Uterinas/tratamiento farmacológico , Útero/efectos de los fármacos , Animales , Sitios de Unión , Disponibilidad Biológica , Línea Celular , Proliferación Celular , Estradiol/sangre , Receptor alfa de Estrógeno/agonistas , Receptor alfa de Estrógeno/química , Receptor beta de Estrógeno/agonistas , Femenino , Humanos , Glándulas Mamarias Animales/citología , Glándulas Mamarias Animales/efectos de los fármacos , Modelos Moleculares , Naftalenos/química , Naftalenos/farmacología , Tamaño de los Órganos/efectos de los fármacos , Ovario/anatomía & histología , Ovario/metabolismo , Piperidinas/química , Piperidinas/farmacología , Ratas , Ratas Sprague-Dawley , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Relación Estructura-Actividad , Útero/anatomía & histología , Útero/citología , Útero/metabolismoRESUMEN
The use of selective estrogen receptor modulators for the treatment of estrogen-dependent diseases in premenopausal women has been hindered by undesirable ovarian stimulation and associated risks of ovarian cysts. We have identified a selective estrogen receptor modulator compound (LY2066948) that is a strong estrogen antagonist in the uterus yet has minimal effects on the ovaries of rats. LY2066948 binds with high affinity to both estrogen receptors and has potent estrogen antagonist activity in human uterine and breast cancer cells. Oral administration of LY2066948 to immature rats blocked uterine weight gain induced by ethynyl estradiol with an ED50 of 0.07 mg/kg. Studies in mature rats demonstrated that LY2066948 decreases uterine weight by 51% after 35 d treatment, confirming potent uterine antagonist activity over several estrous cycles. This strong uterine response contrasted with the minimal effects on the ovaries: serum estradiol levels remained within the normal range, whereas histologic evaluation showed granulosa cell hyperplasia in few of the rats. Bone studies demonstrated that LY2066948 prevented ovariectomy-induced bone loss and treatment of ovary-intact rats caused no bone loss, confirming estrogen receptor agonist skeletal effects. Collectively, these data show that LY2066948 exhibits a tissue-specific profile consistent with strong antagonist activity in the uterus, agonist activity in bone, and minimal effects in the ovaries.
