RESUMO
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).
Assuntos
Benzopiranos/química , Benzopiranos/farmacologia , Pós-Menopausa/efeitos dos fármacos , Receptores de Estrogênio/metabolismo , Moduladores Seletivos de Receptor Estrogênico/química , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Benzopiranos/síntese química , Benzopiranos/uso terapêutico , Reabsorção Óssea/tratamento farmacológico , Linhagem Celular Tumoral , Colesterol/sangue , Avaliação Pré-Clínica de Medicamentos , Estabilidade de Medicamentos , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/patologia , Feminino , Fogachos/tratamento farmacológico , Humanos , Tamanho do Órgão/efeitos dos fármacos , Ovariectomia , Pós-Menopausa/sangue , Ratos , Moduladores Seletivos de Receptor Estrogênico/síntese química , Moduladores Seletivos de Receptor Estrogênico/uso terapêutico , Relação Estrutura-Atividade , Especificidade por Substrato , Útero/patologia , Vagina/efeitos dos fármacos , Vagina/metabolismoRESUMO
Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.