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

Niamh M O'Boyle, Irene Barrett, Lisa M Greene, Miriam Carr, Darren Fayne, Brendan Twamley, Andrew J S Knox, Niall O Keely, Daniela M Zisterer, Mary J Meegan

Journal of medicinal chemistry 2018 Jan 25

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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.

Citation

Niamh M O'Boyle, Irene Barrett, Lisa M Greene, Miriam Carr, Darren Fayne, Brendan Twamley, Andrew J S Knox, Niall O Keely, Daniela M Zisterer, Mary J Meegan. Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity. Journal of medicinal chemistry. 2018 Jan 25;61(2):514-534