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Discovery of AZD9833, a Potent and Orally Bioavailable Selective Estrogen Receptor Degrader and Antagonist. 2020
James S Scott, and
Thomas A Moss, and
Amber Balazs, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
Paul R J Davey, and
Oona Delpuech, and
Stephen Fawell, and
David I Fisher, and
Sladjana Gagrica, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Kara Herlihy, and
Samantha Hughes, and
Thomas A Hunt, and
Hoan Huynh, and
Sophie L M Janbon, and
Tony Johnson, and
Stefan Kavanagh, and
Teresa Klinowska, and
Mandy Lawson, and
Andrew S Lister, and
Stacey Marden, and
Dermot F McGinnity, and
Christopher J Morrow, and
J Willem M Nissink, and
Daniel H O'Donovan, and
Bo Peng, and
Radoslaw Polanski, and
Darren S Stead, and
Stephen Stokes, and
Kumar Thakur, and
Scott R Throner, and
Michael J Tucker, and
Jeffrey Varnes, and
Haixia Wang, and
David M Wilson, and
Dedong Wu, and
Ye Wu, and
Bin Yang, and
Wenzhan Yang
Oncology R&D, AstraZeneca, Cambridge CB4 0WG, United Kingdom.
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 ERĪ± 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.
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Thomas A Moss, and
Amber Balazs, and
Bernard Barlaam, and
Jason Breed, and
Rodrigo J Carbajo, and
Elisabetta Chiarparin, and
Paul R J Davey, and
Oona Delpuech, and
Stephen Fawell, and
David I Fisher, and
Sladjana Gagrica, and
Eric T Gangl, and
Tyler Grebe, and
Ryan D Greenwood, and
Sudhir Hande, and
Holia Hatoum-Mokdad, and
Kara Herlihy, and
Samantha Hughes, and
Thomas A Hunt, and
Hoan Huynh, and
Sophie L M Janbon, and
Tony Johnson, and
Stefan Kavanagh, and
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Mandy Lawson, and
Andrew S Lister, and
Stacey Marden, and
Dermot F McGinnity, and
Christopher J Morrow, and
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Daniel H O'Donovan, and
Bo Peng, and
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Hoan Huynh, and
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Teresa Klinowska, and
Mandy Lawson, and
Andrew S Lister, and
Stacey Marden, and
Dermot F McGinnity, and
Christopher J Morrow, and
J Willem M Nissink, and
Daniel H O'Donovan, and
Bo Peng, and
Radoslaw Polanski, and
Darren S Stead, and
Stephen Stokes, and
Kumar Thakur, and
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Michael J Tucker, and
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Haixia Wang, and
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Ye Wu, and
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Oona Delpuech, and
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David I Fisher, and
Sladjana Gagrica, and
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Sudhir Hande, and
Holia Hatoum-Mokdad, and
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Hoan Huynh, and
Sophie L M Janbon, and
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Teresa Klinowska, and
Mandy Lawson, and
Andrew S Lister, and
Stacey Marden, and
Dermot F McGinnity, and
Christopher J Morrow, and
J Willem M Nissink, and
Daniel H O'Donovan, and
Bo Peng, and
Radoslaw Polanski, and
Darren S Stead, and
Stephen Stokes, and
Kumar Thakur, and
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Jeffrey Varnes, and
Haixia Wang, and
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Ye Wu, and
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Andrew S Lister, and
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Christopher J Morrow, and
J Willem M Nissink, and
Daniel H O'Donovan, and
Bo Peng, and
Radoslaw Polanski, and
Darren S Stead, and
Stephen Stokes, and
Kumar Thakur, and
Scott R Throner, and
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Wenzhan Yang
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Sudhir Hande, and
Holia Hatoum-Mokdad, and
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Hoan Huynh, and
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Dermot F McGinnity, and
Christopher J Morrow, and
J Willem M Nissink, and
Daniel H O'Donovan, and
Bo Peng, and
Radoslaw Polanski, and
Darren S Stead, and
Stephen Stokes, and
Kumar Thakur, and
Scott R Throner, and
Michael J Tucker, and
Jeffrey Varnes, and
Haixia Wang, and
David M Wilson, and
Dedong Wu, and
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ACS medicinal chemistry letters,
