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
  • 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.