文献类型： 外文期刊

作者： Yu, Gang ¹ ; Rao, P. N. Praveen ³ ; Chowdhury, Morshed A. ¹ ; Abdellatif, Khaled R. A. ¹ ; Dong, Ying ¹ ; 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;Acetic acids;Regioisomers;N-Difluoromethyl-1,2-dihydropyrid-2-one pharmacophore;Cyclooxygenase isozyme and 5-lipoxygenase inhibition;Molecular modeling

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 7 期

页码：

收录情况： SCI

摘要： A new group of acetic acid (7a-c, R(1) = H), and propionic acid (7d-f, R(1) = Me), regioisomers wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety is attached via its C-3, C-4, and C-5 position was synthesized. This group of compounds exhibited a more potent inhibition, and hence selectivity, for the cyclooxygenase-2 (COX-2) relative to the COX-1 isozyme. Attachment of the N-difluoromethyl-1, 2-dihydropyrid-2-one ring system to an acetic acid, or propionic acid, moiety confers potent 5-LOX inhibitory activity, that is, absent in traditional arylacetic acid NSAIDs. 2-(1-Difluoromethyl-2-oxo-1,2-dihydropyridin-5-yl) acetic acid (7c) exhibited the best combination of dual COX-2 and 5-LOX inhibitory activities. Molecular modeling (docking) studies showed that the highly electronegative CHF2 substituent present in 7c, that showed a modest selectivity for the COX-2 isozyme, is oriented within the secondary pocket (Val523) present in COX-2 similar to the sulfonamide (SO(2)NH(2)) COX-2 pharmacophore present in celecoxib, and that the N-difluoromethyl-1,2-dihydropyrid-2-one pharmacophore is oriented close to the region containing the LOX enzyme catalytic iron (His361, His366, and His545). Accordingly, the N-difluoromethyl-1,2-dihyrdopyrid-2-one moiety possesses properties suitable for the design of dual COX-2/5LOX inhibitory drugs. (C) 2010 Elsevier Ltd. All rights reserved.