2. Academic Validation
  3. Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist

Optimization of a Novel Binding Motif to (E)-3-(3,5-Difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic Acid (AZD9496), a Potent and Orally Bioavailable Selective Estrogen Receptor Downregulator and Antagonist

  • J Med Chem. 2015 Oct 22;58(20):8128-40. doi: 10.1021/acs.jmedchem.5b00984.
Chris De Savi 1 2,  Robert H Bradbury 1,  Alfred A Rabow 1,  Richard A Norman 3,  Camila de Almeida 1,  David M Andrews 1,  Peter Ballard 1,  David Buttar 1,  Rowena J Callis 3,  Gordon S Currie 1,  Jon O Curwen 1,  Chris D Davies 1,  Craig S Donald 1,  Lyman J L Feron 1,  Helen Gingell 3,  Steven C Glossop 1,  Barry R Hayter 1,  Syeed Hussain 3,  Galith Karoutchi 1,  Scott G Lamont 1,  Philip MacFaul 1,  Thomas A Moss 1,  Stuart E Pearson 1,  Michael Tonge 3,  Graeme E Walker 3,  Hazel M Weir 1,  Zena Wilson 1
Affiliations

Affiliations

  • 1 Oncology iMed, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
  • 2 Oncology iMed, AstraZeneca R&D Boston, 35 Gatehouse Drive, Waltham, Massachusetts 02451, United States.
  • 3 Discovery Sciences, AstraZeneca, Mereside, Alderley Park, Macclesfield SK10 4TG, U.K.
PMID: 26407012 DOI: 10.1021/acs.jmedchem.5b00984
Abstract

The discovery of an orally bioavailable selective Estrogen Receptor downregulator (SERD) with equivalent potency and preclinical pharmacology to the intramuscular SERD fulvestrant is described. A directed screen identified the 1-aryl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole motif as a novel, druglike ER ligand. Aided by crystal structures of novel ligands bound to an ER construct, medicinal chemistry iterations led to (E)-3-(3,5-difluoro-4-((1R,3R)-2-(2-fluoro-2-methylpropyl)-3-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indol-1-yl)phenyl)acrylic acid (30b, AZD9496), a clinical candidate with high oral bioavailability across preclinical species that is currently being evaluated in phase I clinical trials for the treatment of advanced Estrogen Receptor (ER) positive breast Cancer.

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