Dual aromatase-steroid sulfatase inhibitors

Woo, L.W.L. and Bubert, C. and Sutcliffe, O.B. and Smith, A. and Chander, S.K. and Mahon, M.F. and Purohit, A. and Reed, M.J. and Potter, B.V.L. (2007) Dual aromatase-steroid sulfatase inhibitors. Journal of Medicinal Chemistry, 50 (15). pp. 3540-3560. ISSN 0022-2623 (http://dx.doi.org/10.1021/jm061462b)

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Abstract

By introducting the steroid sulfatase inhibitory pharmacophore into aromatase inhibitor 1 (YM511), two series of single agent dual aromatase-sulfatase inhibitors (DASIs) were generated. The best DASIs in vitro (JEG-3 cells) are 5, (IC50(aromatase) = 0.82 nM; IC50(sulfatase) = 39 nM), and 14, (IC50(aromatase) = 0.77 nM; IC50(sulfatase) = 590 nM). X-ray crystallography of 5, and docking studies of selected compounds into an aromatase homology model and the steroid sulfatase crystal structure are presented. Both 5 and 14 inhibit aromatase and sulfatase in PMSG pretreated adult female Wistar rats potently 3 h after a single oral 10 mg/kg dose. Almost complete dual inhibition is observed for 5 but the levels were reduced to 85% (aromatase) and 72% (sulfatase) after 24 h. DASI 5 did not inhibit aldosterone synthesis. The development of a potent and selective DASI should allow the therapeutic potential of dual aromatase-sulfatase inhibition in hormone-dependent breast cancer to be assessed.

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