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

• Published in: Journal of medicinal chemistry 2018-01, Vol.61 (2), p.514-534
• Main Authors: O’Boyle, Niamh M, Barrett, Irene, Greene, Lisa M, Carr, Miriam, Fayne, Darren, Twamley, Brendan, Knox, Andrew J. S, Keely, Niall O, Zisterer, Daniela M, Meegan, Mary J
• Format: Article
• Language: English
• Subjects: Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Benzoxepins - chemistry; Crystallography, X-Ray; Estrogen Receptor alpha - chemistry; Estrogen Receptor alpha - metabolism; Estrogen Receptor beta - chemistry; Estrogen Receptor beta - metabolism; Humans; Ligands; MCF-7 Cells; Models, Molecular; Molecular Docking Simulation; Proteolysis - drug effects; Selective Estrogen Receptor Modulators - chemical synthesis; Selective Estrogen Receptor Modulators - chemistry; Selective Estrogen Receptor Modulators - pharmacology; Structure-Activity Relationship
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b01917

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.