Phenylacetic acid regioisomers possessing a N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore: Evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity

文献类型： 外文期刊

第一作者： Yu, Gang

作者： Yu, Gang;Chowdhury, Morshed A.;Abdellatif, Khaled R. A.;Dong, Ying;Das, Dipankar;Velazquez, Carlos A.;Suresh, Mavanur R.;Knaus, Edward E.;Yu, Gang;Rao, P. N. Praveen

作者机构：

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.

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