Discovery of a Potent and Orally Bioavailable Zwitterionic Series of Selective Estrogen Receptor Degrader-Antagonists

Herein, we report the optimization of a meta-substituted
series
of selective estrogen receptor degrader (SERD) antagonists for the
treatment of ER+ breast cancer. Structure-based design together with
the use of modeling and NMR to favor the bioactive conformation led
to a highly potent series of basic SERDs with promising physicochemical
properties. Issues with hERG activity resulted in a strategy of zwitterion
formation and ultimately in the identification of 38.
This compound was shown to be a highly potent SERD capable of effectively
degrading ERα in both MCF-7 and CAMA-1 cell lines. The low lipophilicity
and zwitterionic nature led to a SERD with a clean secondary pharmacology
profile and no hERG activity. Favorable physicochemical properties
resulted in good oral bioavailability in preclinical species and potent in vivo activity in a mouse xenograft model.