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.

中文翻译：

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类固醇硫酸酯酶和 17β-羟基类固醇脱氢酶 1 型的双重靶向药物-前药方法：治疗子宫内膜异位症的潜在治疗选择

探索了一种通过单一药物双重抑制类固醇硫酸酯酶 (STS) 和 17β-羟基类固醇脱氢酶 1 型 (17β HSD1) 的新方法，从内部 17β HSD1 抑制剂开始，通过用氨基磺酸酯掩盖其酚羟基基团。氨基磺酸盐被有意设计为抑制 STS 的药物，同时也是抑制 17β-HSD1 的前药（“药物-前药方法”）。最有希望的氨基磺酸盐 13、16、18-20、22-24、36和37显示出纳摩尔 IC ₅₀细胞试验中 STS 抑制及其相应酚类的值在无细胞试验和细胞试验中显示出有效的 17β-HSD1 抑制、比 17β-HSD2 高选择性、合理的代谢稳定性和低雌激素受体 α 亲和力。发现氨基磺酸盐水解释放酚类化合物与 17β-HSD1 失活之间存在密切关系。这些结果表明，设想的药物-前药概念得到了成功实施。这些新化合物构成了一类有前途的治疗子宫内膜异位症和其他雌激素依赖性疾病的疗法。