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

摘要

Treating estrogen-dependent diseases like endometriosiswith drugssuppressing local estrogen activation may be superior to existingendocrine therapies. Steroid sulfatase (STS) and 17 & beta;-hydroxysteroiddehydrogenase type 1 (17 & beta;-HSD1) are key enzymes of local estrogenactivation. We describe the rational design, synthesis, and biologicalprofilation of furan-based compounds as a novel class of dual STS/17 & beta;-HSD1inhibitors (DSHIs). In T47D cells, compound 5 showedirreversible inhibition of STS and potent, reversible inhibition of17 & beta;-HSD1. It was selective over 17 & beta;-HSD2 and displayedhigh metabolic stabilities in human and mouse liver S9 fractions.No effect on cell viability was detected up to 31 & mu;M (HEK293)and 23 & mu;M (HepG2), respectively, and there was no activationof the aryl hydrocarbon receptor (AhR) up to 3.16 & mu;M. Singledaily application to mice revealed steady-state plasma levels highenough to make this compound eligible for an in vivo proof-of-principle study in a mouse endometriosis model.