Caturla Francisco, Jiménez Juan-Miguel, Godessart Núria, Amat Mercè, Cárdenas Alvaro, Soca Lídia, Beleta Jordi, Ryder Hamish, Crespo María I
Almirall Prodesfarma S.A., Research Center, Cardener 68-74, 08024 Barcelona, Spain.
J Med Chem. 2004 Jul 15;47(15):3874-86. doi: 10.1021/jm049882t.
A series of 2-phenylpyran-4-ones 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. Compounds having a p-methylsulfone group at the 2-phenyl ring showed the best COX-2 inhibitory activity. The introduction of a substituted phenoxy ring at position 3 enhanced both the in vitro and in vivo activity within the series. A selected group of 3-phenoxypyran-4-ones exhibited excellent activity in an experimental model of pyresis. The in vivo antiinflammatory activity of these compounds was confirmed with the evaluation of their antiarthritic and analgesic effectiveness. Moreover, their pharmacokinetic profile in rats is compatible with a once a day administration by oral route in humans. Within this novel series, compounds 21, 31, 34, and 35 have been selected for further preclinical and clinical evaluation.
制备了一系列2-苯基吡喃-4-酮，并对其抑制环氧合酶-2（COX-2）的能力进行了评估。在该系列化合物中开展了广泛的构效关系研究工作，鉴定出了多种强效且具有选择性的COX-2抑制剂。在2-苯基环上具有对甲基砜基团的化合物表现出最佳的COX-2抑制活性。在3位引入取代苯氧基环增强了该系列化合物的体外和体内活性。一组选定的3-苯氧基吡喃-4-酮在发热实验模型中表现出优异的活性。通过评估这些化合物的抗关节炎和镇痛效果，证实了它们的体内抗炎活性。此外，它们在大鼠体内的药代动力学特征与人类每日口服一次的给药方式相符。在这个新系列化合物中，已选择化合物21、31、34和35进行进一步的临床前和临床评估。
