Dual Targeting of Steroid Sulfatase and 17ß-Hydroxysteroid Dehydrogenase Type 1 by a Novel Drug-Prodrug Approach: A Potential Therapeutic Option for the Treatment of Endometriosis.

ABSTRACT

A novel approach for the dual inhibition of steroid sulfatase (STS) and 17ß-hydroxysteroid dehydrogenase type 1(17ß HSD1) by a single drug was explored, starting from in-house 17ß HSD1 inhibitors via masking their phenolic OH group with a sulfamate ester. The sulfamates were intentionally designed as drugs for the inhibition of STS and, at the same time, prodrugs for 17ß-HSD1 inhibition ("drug-prodrug approach"). The most promising sulfamates 13, 16, 18-20, 22-24, 36, and 37 showed nanomolar IC50 values for STS inhibition in a cellular assay and their corresponding phenols displayed potent 17ß-HSD1 inhibition in cell-free and cellular assays, high selectivity over 17ß-HSD2, reasonable metabolic stability, and low estrogen receptor α affinity. A close relationship was found between the liberation of the phenolic compound by sulfamate hydrolysis and 17ß-HSD1 inactivation. These results showed that the envisaged drug-prodrug concept was successfully implemented. The novel compounds constitute a promising class of therapeutics for the treatment of endometriosis and other estrogen-dependent diseases.