Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity

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 ERβ expression in MCF-7 breast cancer cells. Interestingly,
from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated
ERβ. 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 ERβ
in cancer cells.