Pharmaceutical and Medicinal Chemistry, Saarland University, Germany.
Eur J Med Chem. 2011 Dec;46(12):5978-90. doi: 10.1016/j.ejmech.2011.10.010. Epub 2011 Oct 10.
17β-Hydroxysteroid dehydrogenase type 2 (17β-HSD2) catalyzes the oxidation of the highly potent steroids: the estrogen estradiol (E2) and the androgen testosterone (T) to the less active estrone and androstenedione, respectively. Inhibition of this enzyme may help maintain the local E2 level in bone tissue when the circulating E2 level drops and is therefore a novel and promising approach for the treatment of osteoporosis. In this work, a series of new nonsteroidal and achiral 17β-HSD2 inhibitors, namely N-benzyl-diphenyl-3(or 4)-carboxamide and N-benzyl-5-phenyl-thiophene-2-carboxamide was designed and the compounds were synthesized in a two to three steps reaction. A small library was built applying parallel synthesis. Highly potent 17β-HSD2 inhibitors could be identified in the thiophene-2-carboxamide class with IC(50) in the low nanomolar range. These compounds also showed a good selectivity profile toward 17β-HSD1 and toward the estrogen receptors α and β. The most interesting 17β-HSD2 inhibitor identified in this study is the 5-(2-fluoro-3-methoxyphenyl)-N-(3-hydroxybenzyl)-N-methylthiophene-2-carboxamide 6w displaying an IC(50) of 61 nM and a selectivity factor of 73 toward 17β-HSD1.
17β-羟甾脱氢酶 2 型（17β-HSD2）催化高度有效的甾体：雌激素雌二醇（E2）和雄激素睾酮（T）分别氧化为活性较低的雌酮和雄烯二酮。抑制这种酶可能有助于在循环 E2 水平下降时维持骨组织中的局部 E2 水平，因此是治疗骨质疏松症的一种新的有前途的方法。在这项工作中，设计了一系列新的非甾体和无手性 17β-HSD2 抑制剂，即 N-苄基-二苯基-3（或 4）-甲酰胺和 N-苄基-5-苯基-噻吩-2-甲酰胺，并通过两步到三步反应合成了这些化合物。通过平行合成构建了一个小文库。在噻吩-2-甲酰胺类中可以鉴定出具有低纳摩尔范围 IC50 的高度有效的 17β-HSD2 抑制剂。这些化合物对 17β-HSD1 和雌激素受体α和β也表现出良好的选择性特征。在这项研究中鉴定出的最有趣的 17β-HSD2 抑制剂是 5-（2-氟-3-甲氧基苯基）-N-（3-羟基苄基）-N-甲基噻吩-2-甲酰胺 6w，其 IC50 为 61 nM，对 17β-HSD1 的选择性因子为 73。
