Structure–activity relationship study of diphenylamine-based estrogen receptor (ER) antagonists

• Published in: Bioorganic & medicinal chemistry Vol. 23; no. 4; pp. 861 - 867
• Main Authors: Ohta, Kiminori, Chiba, Yuki, Kaise, Asako, Endo, Yasuyuki
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 15-02-2015
• Subjects: Antagonist; Breast Neoplasms - drug therapy; Breast Neoplasms - metabolism; Cell Proliferation - drug effects; Diphenylamine; Diphenylamine - chemistry; Diphenylamine - pharmacology; Estrogen receptor; Estrogen Receptor alpha - metabolism; Estrogen Receptor Antagonists - chemistry; Estrogen Receptor Antagonists - pharmacology; Female; Humans; MCF-7 Cells; Privileged structure; Structure-Activity Relationship; Estrogen receptor; Antagonist; Diphenylamine; Privileged structure
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2014.12.022

[Display omitted]
We have reported the design and synthesis of novel estrogen receptor (ER) agonists with a diphenylamine skeleton, which has several advantages over the formerly used diphenylmethane skeleton for drug development. Here, we confirmed the versatility of the diphenylamine skeleton by designing and synthesizing ER antagonist candidates bearing a basic alkylamino side chain on one of the two phenol groups of the diphenylamine agonist core structure. Among the tested compounds, cyclic alkylamine-containing derivatives showed more potent ER-antagonistic activity than the corresponding acyclic derivatives in cell proliferation assay using the MCF-7 cell line. Compound 5e showed the most potent antiestrogenic activity (IC50: 1.3×10−7M), being 10times more potent than tamoxifen.