title: Towards the evaluation in an animal disease model: Fluorinated 17β-HSD1 inhibitors showing strong activity towards both the human and the rat enzyme.
abstract: 17β-Estradiol (E2), the most potent human estrogen, is known to be involved in the etiology of estrogen-dependent diseases (EDD) like breast cancer and endometriosis. 17β-Hydroxysteroid dehydrogenase type 1 (17β-HSD1) catalyses the last step of E2 biosynthesis and is thus a promising target for the treatment of EDD. The previously described bicyclic substituted hydroxyphenylmethanones (BSHs) display high inhibitory potency towards human 17β-HSD1, but marginal activity towards rodent 17β-HSD1, precluding a proof of principle study in an animal endometriosis model. The aim of this work was to perform structural optimizations in the BSHs class to enhance inhibitory activity against rodent (mouse and rat) 17β-HSD1 while maintaining activity against the human enzyme. The introduction of fluorine atoms on the benzoyl moiety resulted in compounds with the desired properties. Molecular docking and homology modeling were applied to elucidate the binding mode and interspecies differences in activity. Compound 33 is the most potent inhibitor of both human and rat 17β-HSD1 up to date (IC₅₀ = 2 nM and 97 nM, respectively).
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany.
authors: Ahmed S
authors: AS
authors: Abdelsamie
authors: ElexoPharm GmbH, Campus A12, D-66123 Saarbrücken, Germany.
authors: Emmanuel
authors: E
authors: Bey
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany.
authors: Emanuele M
authors: EM
authors: Gargano
authors: ElexoPharm GmbH, Campus A12, D-66123 Saarbrücken, Germany.
authors: Chris J
authors: CJ
authors: van Koppen
authors: Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus C23, D-66123 Saarbrücken, Germany.
authors: Martin
authors: M
authors: Empting
authors: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany. Electronic address: m.frotscher@mx.uni-saarland.de.
authors: Martin
authors: M
authors: Frotscher
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D010636:Phenols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry
chemical_list: D004791:Enzyme Inhibitors; D010636:Phenols; D013449:Sulfonamides; D015067:17-Hydroxysteroid Dehydrogenases
keywords: 17β-Hydroxysteroid dehydrogenase type 1; Estrogen mimetics; Estrogen-dependent diseases; Interspecies differences; Non-steroidal inhibitors