Estrogen receptor a (ERa) is an important target for the design of drugs such as tamoxifen and fulvestrant. Three series of ER-ligands based on the benzoxepin scaffold structure were synthesised – 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 ERa selective. In particular, a compound (1) featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERa and ERb expression in MCF-7 breast cancer cells. Interestingly, from series III, a phenoxybutyric acid derivative compound (2) was not antiproliferative and selectively downregulated ERb. A docking study of the benzoxepin ligands was undertaken. Compound 1 is a promising lead for development as a clinically relevant SERD, whilst compound 2 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.