Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects
Identification of Highly Efficacious Glucocorticoid Receptor Agonists with a Potential for Reduced Clinical Bone Side Effects
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DOI：
10.1021/jm4019178
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发表时间：
2014-02-27
影响因子：
7.3
通讯作者：
Thomson, David S.
中科院分区：
文献类型：
--
作者：
Harcken, Christian;Riether, Doris;Thomson, David S.
报道了一系列非甾体糖皮质激素受体激动剂的合成及其构效关系。这些化合物含有“二氮吲哚”部分，并在体外显示不同的转录调控谱，并被认为是“解离”之间的基因反式阻遏和反式激活。本文中描述的先导优化工作特别关注限制导致骨副作用的基因的反式激活，并且在MG-63骨肉瘤细胞中对这些基因进行了体外评估，从而鉴定了（R）-18和（R）-21。这些化合物在小鼠胶原诱导的关节炎研究中保持了体内抗炎活性，但与广泛使用的合成糖皮质激素泼尼松龙2相比，对骨相关参数的影响降低。据我们所知，我们是第一个在临床前体内模型中报告选择性糖皮质激素配体减少骨丢失的人。
Synthesis and structure-activity relationship (SAR) of a series of nonsteroidal glucocorticoid receptor (GR) agonists are described. These compounds contain "diazaindole" moieties and display different transcriptional regulatory profiles in vitro and are considered "dissociated" between gene transrepression and transactivation. The lead optimization effort described in this article focused in particular on limiting the transactivation of genes which result in bone side effects and these were assessed in vitro in MG-63 osteosarcoma cells, leading to the identification of (R)-18 and (R)-21. These compounds maintained anti-inflammatory activity in vivo in collagen induced arthritis studies in mouse but had reduced effects on bone relevant parameters compared to the widely used synthetic glucocorticoid prednisolone 2 in vivo. To our knowledge, we are the first to report on selective glucocorticoid ligands with reduced bone loss in a preclinical in vivo model.