Dual Targeting\nof Steroid Sulfatase and 17β-Hydroxysteroid\nDehydrogenase Type 1 by a Novel Drug-Prodrug Approach: A Potential\nTherapeutic Option for the Treatment of Endometriosis

A novel approach for the dual inhibition of steroid sulfatase\n(STS)\nand 17β-hydroxysteroid dehydrogenase type 1(17β HSD1)\nby a single drug was explored, starting from in-house 17β HSD1\ninhibitors via masking their phenolic OH group with a sulfamate ester.\nThe sulfamates were intentionally designed as drugs for the inhibition\nof STS and, at the same time, prodrugs for 17β-HSD1 inhibition\n(“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\ncellular assay and their corresponding phenols displayed potent 17β-HSD1\ninhibition in cell-free and cellular assays, high selectivity over\n17β-HSD2, reasonable metabolic stability, and low estrogen receptor\nα affinity. A close relationship was found between the liberation\nof the phenolic compound by sulfamate hydrolysis and 17β-HSD1\ninactivation. These results showed that the envisaged drug-prodrug\nconcept was successfully implemented. The novel compounds constitute\na promising class of therapeutics for the treatment of endometriosis\nand other estrogen-dependent diseases.