Discovery of two novel (4-hydroxyphenyl) substituted polycyclic carbocycles as potent and selective estrogen receptor beta agonists

被引：0
|
作者：
Wetzel, Edward A. [1 ]
Marks, Kylee J. [2 ]
Gleason, Alexandra A. [2 ]
Brown-Ford, Sandra [2 ]
Reid, Terry-Elinor [2 ]
Chaudhury, Subhabrata [1 ]
Lindeman, Sergey [1 ]
Sem, Daniel S. [2 ]
Donaldson, William A. [1 ]
机构：
[1] Marquette Univ, Dept Chem, PO Box 1881, Milwaukee, WI 53201 USA
[2] Concordia Univ Wisconsin, Ctr Struct based Drug Design & Dev, Sch Pharm, Mequon, WI 53097 USA
来源：
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2022年 / 73卷
关键词：
SERBA; Estrogen receptor agonist; Drug development; Docking; CARBORANE; ALPHA;
D O I：
10.1016/j.bmcl.2022.128906
中图分类号：
R914 [药物化学];
学科分类号：
100701 ;
摘要：
Two (4-hydroxyphenyl) substituted polycyclic carbocycles were prepared and assayed for estrogen receptor activity. 4-(4-Hydroxyphenyl)tricyclo[3.3.1.1(3,7)]decane-1-methanol (5a/b) and 7-(4-hydroxyphenyl)spiro[3.5] nonan-2-ol ((+/-)-11) were found to be potent ER beta agonists (1.9 +/- 0.4 nM and 6.2 +/- 1.4 nM respectively) in a cell -based functional assay. Furthermore, both 5a/b and 11 were highly selective for ER beta over ER alpha (377 and 1,100 -fold selective respectively). While neither compound inhibited CYP2D6 or CYP3A4 at concentrations up to 62.5 mu M, 5a/b did have weak binding to CYP2C9 with an IC50 of 10 +/- 0.5 mu M. Computational assessment of 5a/b and 11 predicted the most probable site of metabolism would be ortho to the phenolic hydroxyl group.
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页数：5
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