Marchais-Oberwinkler Sandrine, Kruchten Patricia, Frotscher Martin, Ziegler Erika, Neugebauer Alexander, Bhoga Umadevi, Bey Emmanuel, Müller-Vieira Ursula, Messinger Josef, Thole Hubert, Hartmann Rolf W
8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 15 11 50, D-66041 Saarbrücken, Germany.
J Med Chem. 2008 Aug 14;51(15):4685-98. doi: 10.1021/jm800367k. Epub 2008 Jul 17.
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.
17β-雌二醇（E2）与雌激素依赖性疾病的发生和发展有关。其浓度主要由1型17β-羟基类固醇脱氢酶（17β-HSD1）调节，该酶催化弱雌激素雌酮（E1）还原为高效能的E2。因此，这种酶是治疗激素依赖性疾病的重要靶点。合成了37种新型取代的6-苯基-2-萘酚，并对其进行了17β-HSD1抑制活性、对17β-HSD2以及雌激素受体（ERs）α和β的选择性以及药代动力学性质的评估。构效关系研究表明，这些化合物最有可能按照结合模式B与活性位点结合，即6-苯基部分模拟甾体A环。虽然苯环上的取代降低了活性，但在萘酚部分引入取代基则产生了高活性化合物，尤其是在1位。1-苯基化合物32对17β-HSD1表现出非常高的抑制活性（IC50 = 20 nM），口服给药后具有良好的选择性（对17β-HSD2和ERs）和药代动力学性质。
