期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 -, 期 -, 页码 -出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c01964
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In this study, we optimized a series of selective estrogen receptor degrader (SERD) antagonists for the treatment of ER+ breast cancer. Through structure-based design and the use of modeling and NMR, we obtained a highly potent series of basic SERDs with promising physicochemical properties. By forming a zwitterion, we successfully eliminated hERG activity and identified compound 38 as a highly potent SERD capable of effectively degrading ER alpha.
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 ER alpha 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.
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