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

A novel approach for the dual inhibition of steroid sulfatase
(STS)
and 17β-hydroxysteroid dehydrogenase type 1(17β HSD1)
by a single drug was explored, starting from in-house 17β 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 17β-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 17β-HSD1
inhibition in cell-free and cellular assays, high selectivity over
17β-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 17β-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.