Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist

J Med Chem. 2020 Dec 10;63(23):14530-14559. doi: 10.1021/acs.jmedchem.0c01163. Epub 2020 Sep 29.


Herein we report the optimization of a series of tricyclic indazoles as selective estrogen receptor degraders (SERD) and antagonists for the treatment of ER+ breast cancer. Structure based design together with systematic investigation of each region of the molecular architecture led to the identification of N-[1-(3-fluoropropyl)azetidin-3-yl]-6-[(6S,8R)-8-methyl-7-(2,2,2-trifluoroethyl)-6,7,8,9-tetrahydro-3H-pyrazolo[4,3-f]isoquinolin-6-yl]pyridin-3-amine (28). This compound was demonstrated to be a highly potent SERD that showed a pharmacological profile comparable to fulvestrant in its ability to degrade ERα in both MCF-7 and CAMA-1 cell lines. A stringent control of lipophilicity ensured that 28 had favorable physicochemical and preclinical pharmacokinetic properties for oral administration. This, combined with demonstration of potent in vivo activity in mouse xenograft models, resulted in progression of this compound, also known as AZD9833, into clinical trials.

MeSH terms

  • Administration, Oral
  • Antineoplastic Agents / administration & dosage*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacokinetics
  • Biological Availability
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / pathology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Crystallography, X-Ray
  • Cyclization
  • Drug Discovery
  • Female
  • Humans
  • Lipids / chemistry
  • Molecular Structure
  • Selective Estrogen Receptor Modulators / administration & dosage*
  • Selective Estrogen Receptor Modulators / chemistry
  • Selective Estrogen Receptor Modulators / pharmacokinetics
  • Structure-Activity Relationship


  • Antineoplastic Agents
  • Lipids
  • Selective Estrogen Receptor Modulators