Draheim S E, Bach N J, Dillard R D, Berry D R, Carlson D G, Chirgadze N Y, Clawson D K, Hartley L W, Johnson L M, Jones N D, McKinney E R, Mihelich E D, Olkowski J L, Schevitz R W, Smith A C, Snyder D W, Sommers C D, Wery J P
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA.
J Med Chem. 1996 Dec 20;39(26):5159-75. doi: 10.1021/jm960487f.
The preceding papers of this series detail the development of functionalized indole-3-acetamides as inhibitors of hnps-PLA2. We describe here the extension of the structure-activity relationship to include a series of indole-3-glyoxamide derivatives. Functionalized indole-3-glyoxamides with an acidic substituent appended to the 4- or 5-position of the indole ring were prepared and tested as inhibitors of hnps-PLA2. It was found that the indole-3-glyoxamides with a 4-oxyacetic acid substituent had optimal inhibitory activity. These inhibitors exhibited an improvement in potency over the best of the indole-3-acetamides, and LY315920 (6m) was selected for evaluation clinically as an hnps-PLA2 inhibitor.
本系列之前的论文详细介绍了功能化吲哚-3-乙酰胺作为人中性粒细胞磷脂酶A2（hnps-PLA2）抑制剂的研发情况。我们在此描述构效关系的扩展，以纳入一系列吲哚-3-乙二酰胺衍生物。制备了在吲哚环的4位或5位带有酸性取代基的功能化吲哚-3-乙二酰胺，并将其作为hnps-PLA2抑制剂进行测试。结果发现，带有4-氧代乙酸取代基的吲哚-3-乙二酰胺具有最佳抑制活性。这些抑制剂在效力上比最好的吲哚-3-乙酰胺有所提高，并且LY315920（6m）被选为hnps-PLA2抑制剂进行临床评估。
