Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta, Canada.
Bioorg Med Chem Lett. 2010 Feb 1;20(3):896-902. doi: 10.1016/j.bmcl.2009.12.073. Epub 2009 Dec 23.
A novel class of phenylacetic acid regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore attached to its C-2, C-3 or C-4 position was designed for evaluation as anti-inflammatory (AI) agents. A number of compounds exhibited a combination of potent in vitro cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) inhibitory activities. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-4-yl)phenylacetic acid (9a) exerted the most potent AI activity among this group of compounds. Molecular modeling studies showed that the N-difluoromethyl-1,2-dihydropyridin-2-one moiety present in 9a inserts into the secondary pocket present in COX-2 to confer COX-2 selectivity, and that the N-difluoromethyl-1,2-dihydropyrid-2-one group (9a) binds close to the region of the 15-LOX enzyme containing catalytic iron (His361, His366). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties that make it an attractive pharmacophore suitable for the design of dual COX-2/5-LOX inhibitory AI drugs.
我们设计了一类新型的苯乙酸区域异构体，其 C-2、C-3 或 C-4 位连接有 N-二氟甲基-1,2-二氢吡啶-2-酮药效团，用作抗炎（AI）药物进行评估。许多化合物表现出体外环氧化酶-2（COX-2）和 5-脂氧合酶（5-LOX）抑制活性的组合。在这组化合物中，2-（1-二氟甲基-2-氧代-1,2-二氢吡啶-4-基）苯乙酸（9a）表现出最强的 AI 活性。分子建模研究表明，9a 中存在的 N-二氟甲基-1,2-二氢吡啶-2-酮部分插入 COX-2 中的次要口袋，赋予 COX-2 选择性，并且 N-二氟甲基-1,2-二氢吡啶-2-酮部分（9a）与包含催化铁（His361、His366）的 15-LOX 酶的区域结合紧密。因此，N-二氟甲基-1,2-二氢吡啶-2-酮部分具有使其成为适合设计双重 COX-2/5-LOX 抑制 AI 药物的有吸引力的药效团的特性。
