Department of Medicinal Chemistry, Department of Immunology and Inflammation, Department of Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc. , 900 Ridgebury Road, Ridgefield, Connecticut 06877, United States.
J Med Chem. 2014 Feb 27;57(4):1583-98. doi: 10.1021/jm4019178. Epub 2014 Feb 7.
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.
描述了一系列非甾体糖皮质激素受体 (GR) 激动剂的合成和构效关系 (SAR)。这些化合物含有“二氮杂吲哚”部分，在体外显示出不同的转录调节谱，被认为是基因转录抑制和转录激活之间的“分离”。本文所述的先导优化工作特别关注限制导致骨副作用的基因的转录激活，这些在体外在 MG-63 骨肉瘤细胞中进行了评估，导致了 (R)-18 和 (R)-21 的鉴定。这些化合物在胶原诱导性关节炎研究中在体内保持抗炎活性在小鼠中，但与广泛使用的合成糖皮质激素泼尼松龙 2 相比，对骨骼相关参数的影响较小。据我们所知，我们是第一个在临床前体内模型中报告具有降低骨丢失的选择性糖皮质激素配体的人。
