2. Academic Validation
  3. Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators

Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators

  • J Med Chem. 2015 Apr 23;58(8):3522-33. doi: 10.1021/acs.jmedchem.5b00066.
Sébastien L Degorce 1 2,  Andrew Bailey 1,  Rowena Callis 3,  Chris De Savi 1,  Richard Ducray 2,  Gillian Lamont 1,  Philip MacFaul 1,  Mickael Maudet 2,  Scott Martin 1,  Rémy Morgentin 2,  Richard A Norman 3,  Aurélien Peru 2,  Jennifer H Pink 1,  Patrick A Plé 2,  Bryan Roberts 1,  James S Scott 1
Affiliations

Affiliations

  • 1 †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
  • 2 ‡Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
  • 3 §Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
PMID: 25790336 DOI: 10.1021/acs.jmedchem.5b00066
Abstract

A novel Estrogen Receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective Estrogen Receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.

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