| Autor: |
Haixia Wang, Stefan Kavanagh, Radoslaw Polanski, Eric Gangl, Michael J. Tucker, Jason Breed, Thomas Anthony Hunt, Paul R. J. Davey, Mandy Lawson, Darren Stead, Oona Delpuech, Ye Wu, J. Willem M. Nissink, Barlaam Bernard Christophe, Dedong Wu, Sudhir M. Hande, Amber Balazs, Dermot F. McGinnity, Wenzhan Yang, Thomas A. Moss, Bin Yang, Sladjana Gagrica, Kumar Thakur, Stacey Marden, Tyler Grebe, Daniel Hillebrand O'donovan, Teresa Klinowska, Samantha Jayne Hughes, Kara Herlihy, David I Fisher, Stephen Stokes, Holia Hatoum-Mokdad, Tony Johnson, James S. Scott, Elisabetta Chiarparin, Bo Peng, Sophie L. M. Janbon, Scott Throner, Ryan Greenwood, David Matthew Wilson, Andrew Lister, Stephen Fawell, Hoan Huynh, Jeffrey G. Varnes, Christopher J. Morrow, Rodrigo J. Carbajo |
| Rok vydání: |
2020 |
| Předmět: |
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| Zdroj: |
Journal of medicinal chemistry. 63(23) |
| ISSN: |
1520-4804 |
| Popis: |
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. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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