Synthesis and biological evaluation of N-difluoromethyl-1,2-dihydropyrid-2-one acetic acid regioisomers: dual inhibitors of cyclooxygenases and 5-lipoxygenase.
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 CHF(2) 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-2/5-LOX inhibitory drugs.
Yu
Gang
G
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada T6G 2N8.
Praveen Rao
P N
PN
Chowdhury
Morshed A
MA
Abdellatif
Khaled R A
KR
Dong
Ying
Y
Das
Dipankar
D
Velázquez
Carlos A
CA
Suresh
Mavanur R
MR
Knaus
Edward E
EE
D000085:Acetates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D007536:Isomerism; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D008958:Models, Molecular; D011451:Prostaglandin-Endoperoxide Synthases / Q000737:chemistry / Q000378:metabolism*; D011728:Pyridones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
C539871:2-(N-difluoromethyl-1,2-dihydropyridin-2-one); D000085:Acetates; D016861:Cyclooxygenase Inhibitors; D016859:Lipoxygenase Inhibitors; D011728:Pyridones; D001094:Arachidonate 5-Lipoxygenase; D011451:Prostaglandin-Endoperoxide Synthases