title: Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC50for a proof-of-principle study.
abstract: Current endocrine therapeutics for the estrogen-dependent disease endometriosis often lead to considerable side-effects as they act by reducing estrogen action systemically. A more recent approach takes advantage of the fact that the weak estrogen estrone (E1) which is abundant in the plasma, is activated in the target cell to the highly estrogenic estradiol (E2) by 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1). 17β-HSD1 is overexpressed in endometriosis and thus a promising target for the treatment of this disease, with the prospect of less target-associated side-effects. Potent inhibitors from the class of bicyclic substituted hydroxyphenylmethanones with sulfonamide moiety recently described by us suffered from high molecular weight and low selectivity over 17βHSD2, the physiological adversary of 17β-HSD1. We describe the structural optimizations leading to the discovery of (5-(3,5-dichloro-4-methoxyphenyl)thiophen-2-yl)(2,6-difluoro-3-hydroxyphenyl)methanone 20, which displayed a sub-nanomolar IC50towards 17β-HSD1 as well as high selectivity over the type 2 enzyme, the estrogen receptors α and β and a range of hepatic CYP enzymes. The compound did neither show cellular toxicity, nor PXR activation nor mutagenicity in the AMES II assay. Additional favourable pharmacokinetic properties (rat) make 20 a suitable candidate for proof-of-principle studies using xenotransplanted immunodeficient rats.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany; Chemistry of Natural and Microbial Products Department, National Research Centre, Dokki, 12622 Cairo, Egypt.
authors.forename: Ahmed S
authors.initials: AS
authors.lastname: Abdelsamie
authors.affiliation: ElexoPharm GmbH, Campus A12, D-66123 Saarbrücken, Germany.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: van Koppen
authors.affiliation: ElexoPharm GmbH, Campus A12, D-66123 Saarbrücken, Germany.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bey
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Salah
authors.affiliation: PharmBioTec GmbH, Science Park 1, D-66123 Saarbrücken, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Börger
authors.affiliation: PharmBioTec GmbH, Science Park 1, D-66123 Saarbrücken, Germany.
authors.forename: Lorenz
authors.initials: L
authors.lastname: Siebenbürger
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University, D-66421, Homburg/Saar, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Laschke
authors.affiliation: Institute for Clinical and Experimental Surgery, Saarland University, D-66421, Homburg/Saar, Germany.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Menger
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, Campus C23, D-66123 Saarbrücken, Germany. Electronic address: m.frotscher@mx.uni-saarland.de.
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000199:Actins / Q000378:metabolism; D000818:Animals; D060326:Chemistry Techniques, Synthetic; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D051381:Rats; D013379:Substrate Specificity
chemical_list: C000603397:ACTL9 protein, human; D000199:Actins; D004791:Enzyme Inhibitors; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D015067:17-Hydroxysteroid Dehydrogenases
keywords: 17β-Hydroxysteroid dehydrogenase type 1; Enzyme inhibitor; Estrogen-dependent disease; Intracrinology; Steroidogenic enzymes