Open AccessBuilding Bridges in a Series of Estrogen Receptor Degraders: An Application of Metathesis in Medicinal Chemistry
Author(s) -
James S. Scott,
J. Breed,
Rodrigo J. Carbajo,
Paul Davey,
Ryan Greenwood,
Hoan K. Huynh,
Teresa Klinowska,
Christopher J. Morrow,
Tom Moss,
Radosław Polański,
J. Willem M. Nissink,
Jeffrey Varnes,
Bin Yang
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00370
Subject(s) - metathesis , estrogen receptor , chemistry , molecule , combinatorial chemistry , receptor , stereochemistry , estrogen , biochemistry , organic chemistry , medicine , cancer , breast cancer , polymerization , polymer
Herein we report the use of metathesis to construct a novel tetracyclic core in a series of estrogen receptor degraders. This improved the chemical stability, as assessed using an NMR-MS based assay, and gave a molecule with excellent physicochemical properties and pharmacokinetics in rat. X-ray crystallography established minimal perturbation of the bridged compounds relative to the unbridged analogues in the receptor binding pocket. Unfortunately, despite retaining excellent binding to ERα, this adversely affected the ability of the compounds to degrade the receptor.