title: Investigation of (E)-3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators.
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.
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.|‡Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors: Sébastien L
authors: SL
authors: Degorce
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Andrew
authors: A
authors: Bailey
authors: §Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Rowena
authors: R
authors: Callis
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Chris
authors: C
authors: De Savi
authors: ‡Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors: Richard
authors: R
authors: Ducray
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Gillian
authors: G
authors: Lamont
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Philip
authors: P
authors: MacFaul
authors: ‡Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors: Mickael
authors: M
authors: Maudet
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Scott
authors: S
authors: Martin
authors: ‡Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors: Rémy
authors: R
authors: Morgentin
authors: §Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Richard A
authors: RA
authors: Norman
authors: ‡Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors: Aurélien
authors: A
authors: Peru
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Jennifer H
authors: JH
authors: Pink
authors: ‡Oncology Innovative Medicines Unit, AstraZeneca, Centre de Recherches, Z.I. la Pompelle, BP1050, 51689 Reims Cedex 2, France.
authors: Patrick A
authors: PA
authors: Plé
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: Bryan
authors: B
authors: Roberts
authors: †Oncology Innovative Medicines Unit, AstraZeneca, Mereside, Alderley Park, Macclesfield, Cheshire SK10 4TG, United Kingdom.
authors: James S
authors: JS
authors: Scott
mesh_terms: D000284:Administration, Oral; D000818:Animals; D045744:Cell Line, Tumor; D003374:Coumarins / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D015536:Down-Regulation / Q000187:drug effects; D047628:Estrogen Receptor alpha / Q000032:analysis / Q000378:metabolism*; D006801:Humans; D062105:Molecular Docking Simulation; D051381:Rats; D014468:Umbelliferones / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D003374:Coumarins; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D014468:Umbelliferones; C031477:7-hydroxycoumarin; C030123:coumarin