title: Substituted 6-phenyl-2-naphthols. Potent and selective nonsteroidal inhibitors of 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1): design, synthesis, biological evaluation, and pharmacokinetics.
abstract: 17beta-Estradiol (E2) is implicated in the genesis and the development of estrogen-dependent diseases. Its concentration is mainly regulated by 17beta-hydroxysteroid dehydrogenase type 1 (17beta-HSD1), which catalyzes the reduction of the weak estrogen estrone (E1) to the highly potent E2. This enzyme is thus an important target for the treatment of hormone-dependent diseases. Thirty-seven novel substituted 6-phenyl-2-naphthols were synthesized and evaluated for 17beta-HSD1 inhibition, selectivity toward 17beta-HSD2 and the estrogen receptors (ERs) alpha and beta, and pharmacokinetic properties. SAR studies revealed that the compounds most likely bind according to binding mode B to the active site, i.e., the 6-phenyl moiety mimicking the steroidal A-ring. While substitution at the phenyl ring decreased activity, introduction of substituents at the naphthol moiety led to highly active compounds, especially in position 1. The 1-phenyl compound 32 showed a very high inhibitory activity for 17beta-HSD1 (IC50 = 20 nM) and good selectivity (17beta-HSD2 and ERs) and pharmacokinetic properties after peroral application.
authors.affiliation: 8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041 Saarbrücken, Germany.
authors.forename: Sandrine
authors.initials: S
authors.lastname: Marchais-Oberwinkler
authors.forename: Patricia
authors.initials: P
authors.lastname: Kruchten
authors.forename: Martin
authors.initials: M
authors.lastname: Frotscher
authors.forename: Erika
authors.initials: E
authors.lastname: Ziegler
authors.forename: Alexander
authors.initials: A
authors.lastname: Neugebauer
authors.forename: Umadevi
authors.initials: U
authors.lastname: Bhoga
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Bey
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Vieira
authors.forename: Josef
authors.initials: J
authors.lastname: Messinger
authors.forename: Hubert
authors.initials: H
authors.lastname: Thole
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D015067:17-Hydroxysteroid Dehydrogenases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D002460:Cell Line; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009284:Naphthols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013256:Steroids / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D009284:Naphthols; D013256:Steroids; D015067:17-Hydroxysteroid Dehydrogenases; C044256:3 (or 17)-beta-hydroxysteroid dehydrogenase