Synthesis of 1-(methanesulfonyl- and aminosulfonylphenyl)acetylenes that possess a 2-(N-difluoromethyl-1,2-dihydropyridin-2-one) pharmacophore: evaluation as dual inhibitors of cyclooxygenases and 5-lipoxygenase with anti-inflammatory activity.
A hitherto unknown class of linear acetylene regioisomers were designed such that a SO(2)Me or SO(2)NH(2) group was located at the ortho-, meta- or para-position of the acetylene C-1 phenyl ring, and a N-difluoromethyl-1,2-dihydropyridin-2-one moiety was attached via its C-5 position to the C-2 position on an acetylene template (scaffold). All three SO(2)Me regioisomers, and the 4-SO(2)NH(2) analog, were potent inhibitors of 5-lipoxygenase (5-LOX IC(50)=3.2-3.5 microM range) relative to the reference drug caffeic acid (IC(50)=4.0 microM). The SO(2)Me regioisomers exhibited weak cyclooxygenease-1 (COX-1) and -2 (COX-2) inhibitory activity with a modest COX-2 selectivity index. The most potent 3-SO(2)Me, 4-SO(2)Me and 4-SO(2)NH(2) compounds, with respective ED(50) values of 66.1, 68.5 and 86.5 mg/kg po, exhibited comparable oral anti-inflammatory (AI) activity to that of the reference drug ibuprofen (ED(50)=67.4 mg/kg po). The N-difluoromethyl-1,2-dihydropyridin-2-one moiety provides a novel pharmacophore for the design of cyclic hydroxamic mimetics capable of inhibiting 5-LOX for exploitation in the development of 5-LOX inhibitory AI drugs.
Chowdhury
Morshed Alam
MA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta., Canada T6G 2N8.
Abdellatif
Khaled R A
KR
Dong
Ying
Y
Rahman
Moshfiqur
M
Das
Dipankar
D
Suresh
Mavanur R
MR
Knaus
Edward E
EE
D000114:Acetylene / Q000031:analogs & derivatives* / Q000138:chemical synthesis*; D000480:Alkynes / Q000138:chemical synthesis / Q000737:chemistry*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D051545:Cyclooxygenase 1 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015195:Drug Design; D007052:Ibuprofen / Q000737:chemistry / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy*; D020128:Inhibitory Concentration 50; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008956:Models, Chemical; D011728:Pyridones / Q000138:chemical synthesis*; D051381:Rats
C539871:2-(N-difluoromethyl-1,2-dihydropyridin-2-one); D000480:Alkynes; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D011728:Pyridones; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D000114:Acetylene; D007052:Ibuprofen