Discovery of a new class of bicyclic substituted hydroxyphenylmethanones as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors for the treatment of osteoporosis.
Discovery of a new class of bicyclic substituted hydroxyphenylmethanones as 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) inhibitors for the treatment of osteoporosis.
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发现一类新的双环取代羟苯基甲酮作为 17β-羟基类固醇脱氢酶 2 型 (17β-HSD2) 抑制剂，用于治疗骨质疏松症
DOI：
10.1016/j.ejmech.2011.09.004
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发表时间：
2012
影响因子：
6.7
通讯作者：
Hartmann
中科院分区：
文献类型：
--
作者：
Wetzel;Gargano;Hinsberger;Marchais-Oberwinkler;Hartmann
老年人缺乏E2会直接影响骨骼并导致骨质疏松症。17β-羟基类固醇脱氢酶2（17β-hydroxysteroid dehydrogenase type 2，17β-HSD 2）催化活性17β-羟基类固醇雌二醇（estradiol，E2）和睾酮（testosterone，T）转化为活性较低的17 β-酮类类固醇，并已在骨骼中发现，17β-HSD 2抑制剂可能为骨质疏松症的发病提供新的途径。合成了双环取代的羟基苯基甲酮衍生物作为底物E2的类固醇模拟物，并评价了其对17 β-HSD 2的抑制作用及其对17β-HSD 1的选择性，催化雌酮（E1）转化为E2的逆反应。已鉴定出高选择性化合物（11、12、14、21和22），最有希望的化合物（12）显示出低纳摩尔范围（101 nM）的IC 50值和对17β-HSD 1的选择性因子13。这些结果使化合物12成为进一步生物学评价的感兴趣的候选物。
E2 deficiency in elderly people has directly an effect on the skeleton and can lead to osteoporosis. As 17β-hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyses the conversion between active 17β-hydroxysteroid estradiol (E2) and testosterone (T) into their less active 17-ketosteroid and has been found in bones, 17β-HSD2 inhibitor may provide a new approach in the onset of osteoporosis. Bicyclic substituted hydroxyphenylmethanone derivatives were synthesised as steroidomimetics of the substrate E2 and were evaluated for their 17β-HSD2 inhibition and their selectivity toward 17β-HSD1, catalysing the reverse reaction the conversion of estrone (E1) into E2. Highly selective compounds (11, 12, 14, 21 and 22) have been identified, the most promising one (12) showing an IC50value in the low nanomolar range (101 nM) and a selectivity factor of 13 toward 17β-HSD1. These results make compound 12 an interesting candidate for further biological evaluation.