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Substituted 6-Phenyl-2-naphthols. Potent and Selective Nonsteroidal Inhibitors of 17β-Hydroxysteroid Dehydrogenase Type 1 (17β-HSD1): Design, Synthesis, Biological Evaluation, and Pharmacokinetics

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journal contribution
posted on 2008-08-14, 00:00 authored by Sandrine Marchais-Oberwinkler, Patricia Kruchten, Martin Frotscher, Erika Ziegler, Alexander Neugebauer, Umadevi Bhoga, Emmanuel Bey, Ursula Müller-Vieira, Josef Messinger, Hubert Thole, Rolf W. Hartmann
17β-Estradiol (E2) is implicated in the genesis and the development of estrogen-dependent diseases. Its concentration is mainly regulated by 17β-hydroxysteroid dehydrogenase type 1 (17β-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 17β-HSD1 inhibition, selectivity toward 17β-HSD2 and the estrogen receptors (ERs) α and β, 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 17β-HSD1 (IC50 = 20 nM) and good selectivity (17β-HSD2 and ERs) and pharmacokinetic properties after peroral application.

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