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 synthesis and biological evaluation of novel tetrahydroisoquinoline, tetrahydroquinoline, and tetrahydroazepine antagonists of the human and rat H(3) receptors are described. The substitution around these rings as well as the nature of the substituent on nitrogen is explored. Several compounds with high affinity and selectivity for the human and rat H(3) receptors are reported.
Asunto(s)
Azepinas , Receptores Histamínicos H3/efectos de los fármacos , Tetrahidroisoquinolinas/síntesis química , Animales , Azepinas/síntesis química , Azepinas/química , Azepinas/farmacología , Evaluación Preclínica de Medicamentos , Humanos , Estructura Molecular , Ratas , Relación Estructura-Actividad , Tetrahidroisoquinolinas/química , Tetrahidroisoquinolinas/farmacologíaRESUMEN
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.
