Dipartimento di Scienze Farmaceutiche, Università di Pisa, Via Bonanno 6, 56126 Pisa, Italy.
Eur J Med Chem. 2011 Jun;46(6):2453-62. doi: 10.1016/j.ejmech.2011.03.030. Epub 2011 Mar 23.
In a continuing effort to improve the subtype selectivity and agonist potency of estrogen receptor β (ERβ) ligands, we have designed and developed a thus far unexplored structural series obtained by molecular refinements of monoaryl-substituted salicylaldoximes (Salaldox B). The most interesting compounds in this series (2c, d) show remarkably high ERβ-binding affinities, with Ki values reaching the sub-nanomolar range (Ki=0.38 nM for 2c and 0.57 nM for 2d), and have very high levels of ERβ-subtype selectivity. Both compounds show a potent full agonist character on ERβ (EC50=0.23 nM for 2c and 1.3 nM for 2d). Furthermore, 2d shows a remarkable functional subtype selectivity, with a β/α transcription potency ratio 50-fold higher than that of estradiol.
为了不断提高雌激素受体 β (ERβ) 配体的亚型选择性和激动剂效力，我们设计并开发了一个迄今为止尚未探索的结构系列，该系列通过对单芳基取代水杨醛肟 (Salaldox B) 进行分子改进得到。该系列中最有趣的化合物（2c、d）显示出非常高的 ERβ 结合亲和力，Ki 值达到亚纳摩尔范围（2c 的 Ki 值为 0.38 nM，2d 的 Ki 值为 0.57 nM），并且具有非常高的 ERβ 亚型选择性。这两种化合物在 ERβ 上均表现出很强的完全激动剂特性（2c 的 EC50 为 0.23 nM，2d 的 EC50 为 1.3 nM）。此外，2d 还表现出显著的功能亚型选择性，其β/α转录效力比雌二醇高 50 倍。
