Pyrazolo[1,5-a]pyrimidines:: Estrogen receptor ligands possessing estrogen receptor β antagonist activity
Pyrazolo[1,5-a]pyrimidines:: Estrogen receptor ligands possessing estrogen receptor β antagonist activity
复制标题
DOI：
10.1021/jm049631k
复制
发表时间：
2004-11-18
影响因子：
7.3
通讯作者：
Katzenellenbogen, JA
中科院分区：
文献类型：
--
作者：
Compton, DR;Sheng, SB;Katzenellenbogen, JA
在寻找新型亚型选择性雌激素受体（ER）配体的过程中，我们研究了各种杂环单元作为核心结构元件。在这里，我们研究了融合的双环吡唑并[1,5-a]嘧啶核心，这是一个允许类似物以类似库的方式轻松组装的系统。这一系列吡唑并[1,5-a]嘧啶ER配体为我们提供了ER配体的新药理学特征：对两种ER都是被动的化合物，具有有利于ER的独特效力选择性。该系列中最独特的配体是 2-苯基-3-(4-羟基苯基)-5,7-双(三氟甲基)-吡唑并[1,5-a]嘧啶，其对 ER 的结合选择性是 36 倍。奇怪的是，根据分子模型，该系列化合物的 ER 结合选择性似乎源自它们在 ERα 与 ERβ 配体结合口袋中适应的不同方向。在转录测定中，这种吡唑并嘧啶作为 ERbeta 拮抗剂完全有效，而对 ERalpha 没有表现出显着的活性。因此，该配体作为一种效力和功效选择性的 ERβ 拮抗剂发挥作用，通过 ER 消除雌激素作用，同时通过 ERα 对其活性影响最小。因此，它可用于研究 ER 的生物学功能。
In our search for novel subtype-selective estrogen receptor (ER) ligands, we have examined various heterocyclic units as core structural elements. Here, we have investigated the fused, bicyclic pyrazolo[1,5-a]pyrimidine core, which is a system that allows for analogues to be readily assembled in a library-like fashion. This series of pyrazolo[1,5-a]pyrimidine ER ligands provided us with a new pharmacological profile for an ER ligand: compounds that are passive on both ERs, with a distinct potency selectivity in favor of ER. The most distinctive ligand in this series, 2-phenyl-3-(4-hydroxyphenyl)-5,7-bis(trifluoromethyl)-pyrazolo[1,5-a]pyrimidine, was 36-fold selective for ER in binding. Curiously, on the basis of molecular modeling, the ER binding selectivity of compounds in this series appears to be derived from differing orientations that they adapt in the ligand binding pockets of ERalpha vs ERbeta. In transcription assays this pyrazolopyrimidine was fully effective as an ERbeta antagonist while exhibiting no significant activity on ERalpha. Thus, this ligand functions as a potency- and efficacy-selective ERbeta antagonist that would abrogate estrogen action through ER with minimal effects on its activity through ERalpha; as such, it could be used to study the biological function of ER.