Puig C, Crespo M I, Godessart N, Feixas J, Ibarzo J, Jiménez J M, Soca L, Cardelús I, Heredia A, Miralpeix M, Puig J, Beleta J, Huerta J M, López M, Segarra V, Ryder H, Palacios J M
Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024 Barcelona, Spain.
J Med Chem. 2000 Jan 27;43(2):214-23. doi: 10.1021/jm991106b.
A series of 3,4-diaryloxazolones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. The replacement of the methyl sulfone group on the 4-phenyl ring by a sulfonamide moiety resulted in compounds with superior in vivo antiinflammatory properties. In the sulfonamide series, the introduction of a methyl group at the 5-position of the oxazolone ring gave rise to very COX-2-selective compounds but with decreased in vivo activity. Selected 3,4-diaryloxazolones exhibited excellent activities in experimental models of arthritis and hyperalgesia. The in vivo activity of these compounds was confirmed with the evaluation of their antipyretic effectiveness and their ability to inhibit migration of proinflammatory cells. As expected from their COX-2 selectivity, most of the active compounds lacked gastrointestinal toxicity in vivo in rats after a 4-day treatment of 100 mg/kg/day. Within this novel series, sulfonamides 9-11 have been selected for further preclinical evaluation.
制备了一系列3,4-二芳基恶唑酮，并评估了它们抑制环氧合酶-2（COX-2）的能力。在该系列化合物中开展了广泛的构效关系研究，确定了一些强效且选择性的COX-2抑制剂。用磺酰胺部分取代4-苯环上的甲砜基，得到了体内抗炎特性更优的化合物。在磺酰胺系列中，在恶唑酮环的5位引入甲基，得到了非常COX-2选择性的化合物，但体内活性降低。选定的3,4-二芳基恶唑酮在关节炎和痛觉过敏的实验模型中表现出优异的活性。通过评估这些化合物的解热效果及其抑制促炎细胞迁移的能力，证实了它们的体内活性。正如从它们的COX-2选择性所预期的那样，在以100 mg/kg/天的剂量进行4天治疗后，大多数活性化合物在大鼠体内缺乏胃肠道毒性。在这个新系列中，已选择磺酰胺9-11进行进一步的临床前评估。
