Lead Optimization of 17β-HSD1\nInhibitors of\nthe (Hydroxyphenyl)naphthol Sulfonamide Type for the Treatment of\nEndometriosis

The reduction of estrone to estradiol, the most potent\nestrogen\nin human, is catalyzed by 17β-hydroxysteroid dehydrogenase type\n1 (17β-HSD1). A promising approach for the treatment of estrogen-dependent\ndiseases is the reduction of intracellular estradiol formation by\ninhibition of 17β-HSD1. For the species-specific optimization\nof the (hydroxyphenyl)­naphthols, a combinatorial approach was applied\nand enhanced by a focused synthesis that resulted in the aromatic-substituted\n(hydroxyphenyl)­naphthol sulfonamides. Rigidification of 12 led to the 4-indolylsulfonamide 30, which is a highly\nactive and selective human 17β-HSD1 inhibitor, as well as a\nhighly potent and selective inhibitor of 17β-HSD1 from Callithrix jacchus. It shows no affinity to the estrogen\nreceptors α and β and good intracellular activity (T47D).\nThus, compound 30 shows good properties for further ADMET\nstudies and might be a candidate for the in vivo proof of concept\nin C. jacchus.