Dual aromatase-steroid sulfatase inhibitors

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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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