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.
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.
Yu
Gang
G
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta, Canada.
Chowdhury
Morshed A
MA
Abdellatif
Khaled R A
KR
Dong
Ying
Y
Praveen Rao
P N
PN
Das
Dipankar
D
Velázquez
Carlos A
CA
Suresh
Mavanur R
MR
Knaus
Edward E
EE
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry* / Q000494:pharmacology; D001094:Arachidonate 5-Lipoxygenase / Q000378:metabolism; D001665:Binding Sites / Q000502:physiology; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D016859:Lipoxygenase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D010648:Phenylacetates / Q000737:chemistry* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D012756:Sheep; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D010648:Phenylacetates; D001094:Arachidonate 5-Lipoxygenase; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; C025136:phenylacetic acid