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

  • J Med Chem. 2018 Jan 25;61(2):514-534. doi: 10.1021/acs.jmedchem.6b01917.
Niamh M O'Boyle  1  2 ,  Irene Barrett  1 ,  Lisa M Greene  2 ,  Miriam Carr  1 ,  Darren Fayne  2 ,  Brendan Twamley  3 ,  Andrew J S Knox  2 ,  Niall O Keely  1 ,  Daniela M Zisterer  2 ,  Mary J Meegan  1
Affiliations
  • 1. School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2 D02 R590, Ireland.
  • 2. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2 D02 R590, Ireland.
  • 3. School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin , 152-160 Pearse Street, Dublin 2 D02 R590, Ireland.
PMID: 28426931 DOI: 10.1021/acs.jmedchem.6b01917
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 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.