Department of Medicinal Chemistry, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, Ridgefield, CT 06877, USA.
Bioorg Med Chem Lett. 2011 Nov 15;21(22):6842-51. doi: 10.1016/j.bmcl.2011.09.018. Epub 2011 Sep 10.
We report a SAR of non-steroidal glucocorticoid mimetics that utilize indoles as A-ring mimetics. Detailed SAR is discussed with a focus on improving PR and MR selectivity, GR agonism, and in vitro dissociation profile. SAR analysis led to compound (R)-33 which showed high PR and MR selectivity, potent agonist activity, and reduced transactivation activity in the MMTV and aromatase assays. The compound is equipotent to prednisolone in the LPS-TNF model of inflammation. In mouse CIA, at 30 mg/kg compound (R)-33 inhibited disease progression with an efficacy similar to the 3 mg/kg dose of prednisolone.
我们报告了非甾体糖皮质激素类似物的 SAR 研究，该研究利用吲哚作为 A 环类似物。详细的 SAR 讨论侧重于提高 PR 和 MR 选择性、GR 激动剂活性以及体外解离谱。SAR 分析导致了化合物 (R)-33 的出现，该化合物表现出高 PR 和 MR 选择性、有效激动剂活性，并在 MMTV 和芳香酶测定中降低了反式激活活性。该化合物在 LPS-TNF 炎症模型中与泼尼松龙具有同等效力。在小鼠 CIA 中，在 30mg/kg 的剂量下，化合物 (R)-33 抑制疾病进展的疗效与 3mg/kg 泼尼松龙的疗效相似。
