Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC50 for a proof-of-principle study
Treatment of estrogen-dependent diseases: Design, synthesis and profiling of a selective 17β-HSD1 inhibitor with sub-nanomolar IC50 for a proof-of-principle study
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DOI：
10.1016/j.ejmech.2016.11.004
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发表时间：
2017-02-15
影响因子：
6.7
通讯作者：
Frotscher, Martin
中科院分区：
文献类型：
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作者：
Abdelsamie, Ahmed S.;van Koppen, Chris J.;Frotscher, Martin
目前用于雌激素依赖性疾病子宫内膜异位症的内分泌治疗通常会导致相当大的副作用，因为它们通过降低全身雌激素的作用来起作用。最近的一种方法利用了血浆中丰富的弱雌激素雌酮（El）在靶细胞中被17 β -羟基类固醇脱氢酶1型（17 β - hsd1）激活为高雌激素雌二醇（E2）的事实。17 β - hsd1在子宫内膜异位症中过度表达，因此是治疗该疾病的一个有希望的靶标，具有较少靶标相关副作用的前景。我们最近描述的一类具有磺酰胺片段的双环取代羟基苯基甲烷类强效抑制剂对17 β - HSD2 （17 β - hsd1的生理对手）具有高分子量和低选择性。我们描述了结构优化导致发现（5-（3,5-二氯-4-甲氧基苯基）噻吩-2-基）（2,6-二氟-3-羟基苯基）甲烷酮20，它对17 β - hsd1具有亚纳摩尔的IC50，并且对2型酶，雌激素受体α和β以及一系列肝脏CYP酶具有高选择性。在AMES II试验中，该化合物既没有显示细胞毒性，也没有PXR激活和诱变性。其他有利的药代动力学特性（大鼠）使20成为使用异种移植免疫缺陷大鼠进行原理验证研究的合适候选者。(C) 2016 Elsevier Masson SAS。版权所有。
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 (El) which is abundant in the plasma, is activated in the target cell to the highly estrogenic estradiol (E2) by 17 beta-hydroxysteroid dehydrogenase type 1 (17 beta-HSD1). 17 beta-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 17 beta HSD2, the physiological adversary of 17 beta-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 subnanomolar IC50 towards 17 beta-HSD1 as well as high selectivity over the type 2 enzyme, the estrogen receptors alpha and beta 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. (C) 2016 Elsevier Masson SAS. All rights reserved.