期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 20, 期 3, 页码 896-902出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2009.12.073
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
资金
- Canadian Institutes of Health Research (CIHR) [MOP-14712]
- Jiangsu Government Abroad Study Scholarship, China
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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