文献类型： 外文期刊

作者： Yu, Gang ¹ ; Chowdhury, Morshed A. ¹ ; Abdellatif, Khaled R. A. ¹ ; Dong, Ying ¹ ; Rao, P. N. Praveen ³ ; Das, Dipa ¹ ;

作者机构： 1.Univ Alberta, Fac Pharm & Pharmaceut Sci, Edmonton, AB T6G 2N8, Canada

2.Jiangsu Acad Agr Sci, Nanjing 210014, Jiangsu, Peoples R China

3.Univ Waterloo, Sch Pharm, Waterloo, ON N2L 3G1, Canada

关键词： NSAIDs;Phenylacetic acids;N-Difluoromethyl-1,2-dihydropyrid-2-one pharmacophore;Cyclooxygenase isozyme and 5-lipoxygenase inhibition;Molecular modeling;Anti-inflammatory activity

期刊名称：BIOORGANIC & MEDICINAL CHEMISTRY LETTERS （ 影响因子：2.823； 五年影响因子：2.677 ）

ISSN： 0960-894X

年卷期： 2010 年 20 卷 3 期

页码：

收录情况： SCI

摘要： 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-4yl) 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. (C) 2009 Elsevier Ltd. All rights reserved.