Potent Dual\nInhibitors of Steroid Sulfatase and 17β-Hydroxysteroid\nDehydrogenase Type 1 with a Suitable Pharmacokinetic Profile for In Vivo Proof-of-Principle Studies in an Endometriosis Mouse\nModel

Treating estrogen-dependent diseases like endometriosis\nwith drugs\nsuppressing local estrogen activation may be superior to existing\nendocrine therapies. Steroid sulfatase (STS) and 17β-hydroxysteroid\ndehydrogenase type 1 (17β-HSD1) are key enzymes of local estrogen\nactivation. We describe the rational design, synthesis, and biological\nprofilation of furan-based compounds as a novel class of dual STS/17β-HSD1\ninhibitors (DSHIs). In T47D cells, compound 5 showed\nirreversible inhibition of STS and potent, reversible inhibition of\n17β-HSD1. It was selective over 17β-HSD2 and displayed\nhigh metabolic stabilities in human and mouse liver S9 fractions.\nNo effect on cell viability was detected up to 31 μM (HEK293)\nand 23 μM (HepG2), respectively, and there was no activation\nof the aryl hydrocarbon receptor (AhR) up to 3.16 μM. Single\ndaily application to mice revealed steady-state plasma levels high\nenough to make this compound eligible for an in vivo proof-of-principle study in a mouse endometriosis model.