title: 6-Hydroxybenzothiophene ketones: potent inhibitors of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1) owing to favorable molecule geometry and conformational preorganization.
abstract: The inhibition of 17β-hydroxysteroid dehydrogenase type 1 (17β-HSD1), which catalyzes the conversion of estrone into the potent estrogen receptor agonist estradiol (E2), is discussed as a novel therapeutic approach for the treatment of estrogen-dependent diseases. Because the reduction of E2 would be basically limited to the target tissues, this approach is expected to cause fewer side effects than the currently employed antihormonal therapies. Recently, we reported on 6-hydroxybenzothiazole ketones as a new class of 17β-HSD1 inhibitors with a notable activity/selectivity profile. In an attempt to further optimize these parameters, we modified the benzothiazole core by a systematic bioisosteric replacement. Thus, we were able to identify a new 6-hydroxybenzothiophene derivative that displayed stronger inhibition of 17β-HSD1 (IC50 =13 nM) and that was also more selective than a benzothiazole analog. Using ab initio calculations, we found that the higher potency of the 6-hydroxybenzothiophene derivative was probably due to more favorable conformational preorganization of the scaffold for binding to the enzyme.
authors.affiliation: Pharmaceutical & Medicinal Chemistry, Universität des Saarlandes, Campus C23, 66123 Saarbrücken (Germany); Department of Medicinal Chemistry, School of Pharmacy, Hamedan University of Medical Sciences, Hamedan (Iran).
authors.forename: Parisa
authors.initials: P
authors.lastname: Miralinaghi
authors.forename: Christian
authors.initials: C
authors.lastname: Schmitt
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Matthias
authors.initials: M
authors.lastname: Engel
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D007659:Ketones / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation
chemical_list: D004791:Enzyme Inhibitors; D007659:Ketones; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase
keywords: 17β-hydroxysteroid dehydrogenase 1; antiestrogen agents; benzofurans; benzothiophenes; breast cancer; steroids