title: Lead optimization of 17β-HSD1 inhibitors of the (hydroxyphenyl)naphthol sulfonamide type for the treatment of endometriosis.
abstract: The reduction of estrone to estradiol, the most potent estrogen in human, is catalyzed by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). A promising approach for the treatment of estrogen-dependent diseases is the reduction of intracellular estradiol formation by inhibition of 17β-HSD1. For the species-specific optimization of the (hydroxyphenyl)naphthols, a combinatorial approach was applied and enhanced by a focused synthesis that resulted in the aromatic-substituted (hydroxyphenyl)naphthol sulfonamides. Rigidification of 12 led to the 4-indolylsulfonamide 30, which is a highly active and selective human 17β-HSD1 inhibitor, as well as a highly potent and selective inhibitor of 17β-HSD1 from Callithrix jacchus. It shows no affinity to the estrogen receptors α and β and good intracellular activity (T47D). Thus, compound 30 shows good properties for further ADMET studies and might be a candidate for the in vivo proof of concept in C. jacchus.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C2 3, D-66041 Saarbrücken, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Henn
authors.forename: Almuth
authors.initials: A
authors.lastname: Einspanier
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D002144:Callithrix; D045744:Cell Line, Tumor; D004715:Endometriosis / Q000188:drug therapy*; D004960:Estradiol Dehydrogenases / Q000037:antagonists & inhibitors*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D005260:Female; D006801:Humans; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010920:Placenta / Q000201:enzymology; D011247:Pregnancy; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D009284:Naphthols; D013449:Sulfonamides; D004960:Estradiol Dehydrogenases; C513331:HSD17B1 protein, human