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
  • 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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