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Tricyclic Indazoles—A Novel Class of Selective Estrogen Receptor Degrader Antagonists

2019; American Chemical Society; Volume: 62; Issue: 3 Linguagem: Inglês

10.1021/acs.jmedchem.8b01837

1520-4804

James S. Scott, Andrew Bailey, David Buttar, Rodrigo J. Carbajo, Jon Curwen, Paul R. J. Davey, Robert D. M. Davies, Sébastien L. Degorce, Craig S. Donald, Eric T. Gangl, Ryan Greenwood, Sam D. Groombridge, Tony Johnson, Scott G. Lamont, Mandy Lawson, Andrew Lister, Christopher J. Morrow, Tom Moss, Jennifer H. Pink, Radosław Polański,

Synthesis and Biological Evaluation

Herein, we report the identification and synthesis of a series of tricyclic indazoles as a novel class of selective estrogen receptor degrader antagonists. Replacement of a phenol, present in our previously reported tetrahydroisoquinoline scaffold, with an indazole group led to the removal of a reactive metabolite signal in an in vitro glutathione trapping assay. Further optimization, guided by X-ray crystal structures and NMR conformational work, varied the alkyl side chain and pendant aryl group and resulted in compounds with low turnover in human hepatocytes and enhanced chemical stability. Compound 9 was profiled as a representative of the series in terms of pharmacology and demonstrated the desired estrogen receptor α degrader-antagonist profile and demonstrated activity in a xenograft model of breast cancer.