Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERß Activity.
J Med Chem
; 61(2): 514-534, 2018 01 25.
Article
em En
| MEDLINE
| ID: mdl-28426931
ABSTRACT
Estrogen receptor α (ERα) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). Three series of ER-ligands based on the benzoxepin scaffold structure were synthesized series I containing an acrylic acid, series II with an acrylamide, and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERα selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERα and ERß expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ERß. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, while compound 22 will be a useful experimental probe for helping to elucidate the role of ERß in cancer cells.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzoxepinas
/
Moduladores Seletivos de Receptor Estrogênico
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Receptor alfa de Estrogênio
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Receptor beta de Estrogênio
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article