Bristol-Myers Squibb Company, Research and Development, Princeton, New Jersey 08543-4000, United States.
J Med Chem. 2010 Dec 9;53(23):8241-51. doi: 10.1021/jm100957a. Epub 2010 Nov 12.
A series of 2,2-dimethyl-3,3-diphenyl-propanamides as novel glucocorticoid receptor modulators is reported. SAR exploration led to the identification of 4-hydroxyphenyl propanamide derivatives displaying good agonist activity in GR-mediated transrepression assays and reduced agonist activity in GR-mediated transactivation assays. Compounds 17 and 30 showed anti-inflammatory activity comparable to prednisolone in the rat carrageenan-induced paw edema model, with markedly decreased side effects with regard to increases in blood glucose and expression of hepatic tyrosine aminotransferase. A hypothetical binding mode accounting for the induction of the functional activity by a 4-hydroxyl group is proposed.
报告了一系列作为新型糖皮质激素受体调节剂的 2,2-二甲基-3,3-二苯基丙酰胺。SAR 探索导致了鉴定出的 4-羟基苯基丙酰胺衍生物在 GR 介导的转录抑制测定中显示出良好的激动剂活性，并且在 GR 介导的转录激活测定中降低了激动剂活性。化合物 17 和 30 在大鼠角叉菜胶诱导的爪肿胀模型中表现出与泼尼松龙相当的抗炎活性，并且在血糖升高和肝酪氨酸转氨酶表达方面的副作用明显降低。提出了一个假设的结合模式，解释了 4-羟基基团对功能活性的诱导。
