Li C S, Black W C, Chan C C, Ford-Hutchinson A W, Gauthier J Y, Gordon R, Guay D, Kargman S, Lau C K, Mancini J
Merck Frosst Centre for Therapeutic Research, Merck Frosst Canada Inc., Pointe-Claire-Dorval, Quebec.
J Med Chem. 1995 Dec 8;38(25):4897-905. doi: 10.1021/jm00025a007.
The recent discovery of an alternative form cyclooxygenase (cyclooxygenase-2, COX-2), which has been proposed to play a significant role in inflammatory conditions, may provide an opportunity to develop anti-inflammatory drugs with fewer side effects than existing non-steroidal anti-inflammatory drugs (NSAIDs). We have now identified 6-[(2,4-difluorophenyl)-thio]-5-methanesulfonamido-1-indanone++ + (20) (L-745,337) as a potent, selective, and orally active COX-2 inhibitor. The structure-activity relationships in this series have been extensively studied. Ortho- and para-substituted 6-phenyl substitutents are optimal for in vitro potency. Replacement of this phenyl ring by a variety of heterocycles gave compounds that were less active. The methanesulfonamido group seems to be the optimal group at the 5-position of the indanone system. Compound 20 has an efficacy profile that is superior or comparable to that of the nonselective COX inhibitor indomethacin in animal models of inflammation, pain, and fever and appears to be nonulcerogenic within the dosage ranges required for functional efficacy. Although 20 and its oxygen linkage analog 2 (flosulide) are equipotent in the in vitro assays, compound 20 is more potent in the rat paw edema assay, has a longer t1/2 in squirrel monkeys, and seems less ulcergenic than 2 in rats.
最近发现的环氧化酶的一种替代形式（环氧化酶-2，COX-2），有人提出它在炎症状态中起重要作用，这可能为开发比现有非甾体抗炎药（NSAIDs）副作用更少的抗炎药提供机会。我们现已鉴定出6-[(2,4-二氟苯基)-硫代]-5-甲磺酰胺基-1-茚满酮++ +（20）（L-745,337）为一种强效、选择性且口服有效的COX-2抑制剂。已对该系列中的构效关系进行了广泛研究。邻位和对位取代的6-苯基取代基对体外活性最为理想。用各种杂环取代该苯环得到的化合物活性较低。甲磺酰胺基似乎是茚满酮系统5位的最佳基团。在炎症、疼痛和发热的动物模型中，化合物20的疗效优于或与非选择性COX抑制剂吲哚美辛相当，并且在功能疗效所需的剂量范围内似乎不会引起溃疡。尽管20及其氧连接类似物2（氟舒林）在体外试验中效力相当，但化合物20在大鼠足爪水肿试验中效力更强，在松鼠猴中的t1/2更长，并且在大鼠中似乎比2引起溃疡的可能性更小。
