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

Abstract

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.

Potent Dual Inhibitors of Steroid Sulfatase and 17β-Hydroxysteroid Dehydrogenase Type 1 with a Suitable Pharmacokinetic Profile for In Vivo Proof-of-Principle Studies in an Endometriosis Mouse Model

“…A designed multiple ligand approach using the merged pharmacophore strategy�that was previously reported 19 �was successfully applied. A newly developed metabolically stable 17β-HSD1 inhibitor class 20 (e.g., compound 3) was used to build the aryl sulfamate pharmacophore which is essential for STS inhibition. In the first step, the position of the sulfamate moiety on the benzoyl ring (ring B, see Figure 2) was aimed to be optimized, resulting in compounds 5 and 6, which were the first dual inhibitors of this class.…”

“…17 In a randomized phase I proof-of-principle clinical study, it was further found that STS inhibition has no effect on the levels of systemic E2. 18 In a recent work, our group introduced the idea of dual inhibition of both STS and 17β-HSD1 by designing multiple ligands 19 and via a drug−prodrug approach 20 as a novel treatment option for EDDs. Compound 1 (Table 1) had a promising profile, as it showed well-balanced intracellular activity against both target proteins, with IC 50 values of 15 and 22 nM for STS and 17β-HSD1, respectively, with an irreversible mode of action toward STS.…”

Targeting the formation of estrogens for treatment of hormone dependent diseases–current status

“…Therefore, the development of dual inhibitors targeting multiples steps in the intracrine network is a useful and promising approach. Effective molecules have been developed, like the dual aromatase-sulfatase inhibitor STX681 (Foster et al, 2008), and other inhibitors (Woo et al, 2010;Woo et al, 2011;Harrelson and Lee, 2016) and the sulfatase-HSD17B1 inhibitor (Mohamed et al, 2022). Also the approach of combining pre-receptor (or intracrine) drugs and receptor-blocking agents deserves attention in the future to obtain a complete shut down of the hormone signalling.…”