| Literature DB >> 32910656 |
James S Scott1, Thomas A Moss1, Amber Balazs2, Bernard Barlaam1, Jason Breed3, Rodrigo J Carbajo1, Elisabetta Chiarparin1, Paul R J Davey1, Oona Delpuech1, Stephen Fawell2, David I Fisher3, Sladjana Gagrica1, Eric T Gangl2, Tyler Grebe2, Ryan D Greenwood1, Sudhir Hande2, Holia Hatoum-Mokdad2, Kara Herlihy3, Samantha Hughes1, Thomas A Hunt1, Hoan Huynh2, Sophie L M Janbon4, Tony Johnson1, Stefan Kavanagh5, Teresa Klinowska1, Mandy Lawson1, Andrew S Lister1, Stacey Marden6, Dermot F McGinnity1, Christopher J Morrow1, J Willem M Nissink1, Daniel H O'Donovan1, Bo Peng2, Radoslaw Polanski3, Darren S Stead1, Stephen Stokes1, Kumar Thakur2, Scott R Throner2, Michael J Tucker1, Jeffrey Varnes2, Haixia Wang2, David M Wilson1, Dedong Wu6, Ye Wu2, Bin Yang2, Wenzhan Yang6.
Abstract
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.Entities:
Year: 2020 PMID： 32910656 DOI： 10.1021/acs.jmedchem.0c01163
Source DB: PubMed Journal: J Med Chem ISSN： 0022-2623 Impact factor: 7.446