Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877, USA.
Bioorg Med Chem Lett. 2014 Apr 15;24(8):1934-40. doi: 10.1016/j.bmcl.2014.03.005. Epub 2014 Mar 12.
Synthesis and structure-activity relationship (SAR) of a series of alkyl and cycloalkyl containing non-steroidal dissociated glucocorticoid receptor (GR) agonists is reported. This series of compounds was identified as part of an effort to replace the CF3 group in a scaffold represented by 1a. The study culminated in the identification of compound 14, a t-butyl containing derivative, which has shown potent activity for GR, selectivity against the progesterone receptor (PR) and the mineralocorticoid receptor (MR), in vitro anti-inflammatory activity in an IL-6 transrepression assay, and dissociation in a MMTV transactivation counter-screen. In a collagen-induced arthritis mouse model, 14 displayed prednisolone-like efficacy, and lower impact on body fat and free fatty acids than prednisolone at an equivalent anti-inflammatory dose.
报道了一系列含烷基和环烷基的非甾体解离型糖皮质激素受体（GR）激动剂的合成和构效关系（SAR）。这一系列化合物是作为用 1a 代表的支架中 CF3 基团替代的努力的一部分而被鉴定出来的。该研究的最终成果是鉴定出了一种含有叔丁基的化合物 14，它对 GR 具有很强的活性，对孕激素受体（PR）和盐皮质激素受体（MR）具有选择性，在 IL-6 反式转录抑制测定中具有体外抗炎活性，并且在 MMTV 反式激活对照筛选中具有解离作用。在胶原诱导性关节炎小鼠模型中，化合物 14 表现出与泼尼松龙相当的疗效，并且在等效抗炎剂量下对体脂肪和游离脂肪酸的影响低于泼尼松龙。
