RESUMEN
As part of a program aimed at the development of selective estrogen receptor modulators (SERMs), novel chromene scaffolds, benzopyranobenzoxapanes, were discovered. Many compounds showed binding affinity as low as 1.6-200 nM, displayed antagonist behaviors in the MCF-7 human breast adenocarcinoma cell line as well in Ishikawa cell line with IC(50) values in the range 0.2-360 nM. On the basis of the side chain substitution, various compounds demonstrated strong inhibitory activity in anti-uterotropic assay. Compound 7-(R) and its major metabolites 5-(R) and 6-(R) were evaluated in several in vivo models of estrogen action. Relative to a full estrogen agonist (ethynyl estradiol) and the SERM raloxifene, 7-(R) was found to be a potent SERM that behaved as antagonist in the uterus and exhibited estrogen agonistic activity on bone, plasma lipids, hot flush, and vagina. The overall pharmacokinetic profile and stability were significantly improved compared to those of the phase 2 development compound 9-(R).
Asunto(s)
Benzopiranos/química , Benzopiranos/farmacología , Posmenopausia/efectos de los fármacos , Receptores de Estrógenos/metabolismo , Moduladores Selectivos de los Receptores de Estrógeno/química , Moduladores Selectivos de los Receptores de Estrógeno/farmacología , Animales , Benzopiranos/síntesis química , Benzopiranos/uso terapéutico , Resorción Ósea/tratamiento farmacológico , Línea Celular Tumoral , Colesterol/sangre , Evaluación Preclínica de Medicamentos , Estabilidad de Medicamentos , Células Epiteliales/efectos de los fármacos , Células Epiteliales/patología , Femenino , Sofocos/tratamiento farmacológico , Humanos , Tamaño de los Órganos/efectos de los fármacos , Ovariectomía , Posmenopausia/sangre , Ratas , Moduladores Selectivos de los Receptores de Estrógeno/síntesis química , Moduladores Selectivos de los Receptores de Estrógeno/uso terapéutico , Relación Estructura-Actividad , Especificidad por Sustrato , Útero/patología , Vagina/efectos de los fármacos , Vagina/metabolismoRESUMEN
A novel SERM (selective estrogen receptor modulators), 1-(R), a chromene-derived bisbenzopyran, was discovered to alleviate hot flushes and effectively increase vaginal fluidity in rats. Moreover, 1-(R) was found to have beneficial effects on plasma cholesterol and bone metabolism while maintaining antiestrogenic activity in the uterus. The biological profile of its enantiomer 1-(S) was also evaluated.