Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template

Reference:

Woo, L. .W. L., Jackson, T., Putey, A., Cozier, G., Leonard, P., Acharya, K. R., Chander, S. K., Purohit, A., Reed, M. J. and Potter, B. V. L., 2010. Highly potent first examples of dual aromatase-steroid sulfatase inhibitors based on a biphenyl template. Journal of Medicinal Chemistry, 53 (5), pp. 2155-2170.

Related documents:

Official URL:

http://dx.doi.org/10.1021/jm901705h

Abstract

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 (IC50: aromatase, 2.0 nM; STS, 35 nM) and its chlorinated congener 23 (IC50: 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 (IC50 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.

Export

Actions (login required)