Characterization of the pharmacophore properties of novel selective estrogen receptor downregulators (SERDs)

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Abstract

Selective estrogen receptor (ER) down-regulators (SERDs) reduce ERα protein levels as well as block ER activity and therefore are promising therapeutic agents for the treatment of hormone refractory breast cancer. Starting with the triarylethylene acrylic acid SERD 4, we have investigated how alterations in both the ligand core structure and the appended acrylic acid substituent affect SERD activity. The new ligands were based on high affinity, symmetrical cyclofenil or bicyclo[3.3.1]nonane core systems, and in these, the position of the carboxyl group was extended from the ligand core, either retaining the vinylic linkage of the substituent or replacing it with an ether linkage. Although most structural variants showed binding affinities for ERα and ERβ higher than that of 4, only the compounds preserving the acrylic acid side chain retained SERD activity, although they could possess varying core structures. Hence, the acrylic acid moiety of the ligand is crucial for SERD-like blockade of ER activities.

Original languageEnglish (US)
Pages (from-to)3320-3329
Number of pages10
JournalJournal of Medicinal Chemistry
Volume53
Issue number8
DOIs
StatePublished - Apr 22 2010

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ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Characterization of the pharmacophore properties of novel selective estrogen receptor downregulators (SERDs). / Kieser, Karen J.; Kim, Dong Wook; Carlson, Kathryn E.; Katzenellenbogen, Benita S.; Katzenellenbogen, John A.

In: Journal of Medicinal Chemistry, Vol. 53, No. 8, 22.04.2010, p. 3320-3329.

Research output: Contribution to journalArticle