Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template.
J Med Chem
; 53(5): 2155-70, 2010 Mar 11.
Article
in En
| MEDLINE
| ID: mdl-20148564
Single agents against multiple drug targets are of increasing interest. Hormone-dependent breast cancer (HDBC) may be more effectively treated by dual inhibition of aromatase and steroid sulfatase (STS). The aromatase inhibitory pharmacophore was thus introduced into a known biphenyl STS inhibitor to give a series of novel dual aromatase-sulfatase inhibitors (DASIs). Several compounds are good aromatase or STS inhibitors and DASI 20 (IC(50): aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC(50): aromatase, 0.5 nM; STS, 5.5 nM) are examples that show exceptional dual potency in JEG-3 cells. Both biphenyls share a para-sulfamate-containing ring B and a ring A, which contains a triazol-1-ylmethyl meta to the biphenyl bridge and para to a nitrile. At 1 mg/kg po, 20 and 23 reduced plasma estradiol levels strongly and inhibited liver STS activity potently in vivo. 23 is nonestrogenic and potently inhibits carbonic anhydrase II (IC(50) 86 nM). A complex was crystallized and its structure was solved by X-ray crystallography. This class of DASI should encourage further development toward multitargeted therapeutic intervention in HDBC.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Triazoles
/
Biphenyl Compounds
/
Steryl-Sulfatase
/
Aromatase Inhibitors
Limits:
Animals
/
Female
/
Humans
Language:
En
Journal:
J Med Chem
Year:
2010
Document type:
Article