Synthesis and biological evaluation of indomethacin analogs possessing a N-difluoromethyl-1,2-dihydropyrid-2-one ring system: a search for novel cyclooxygenase and lipoxygenase inhibitors.
A novel class of indomethacin analogs were synthesized wherein a N-difluoromethyl-1,2-dihydropyrid-2-one moiety (5-LOX pharmacophore) was attached at its C-4 or C-5 position via either a CO (14a-b) or CH(2) (19a-b) linker to the indole N(1)-position. In this regard, replacement of the 4-chlorobenzoyl group present in indomethacin by N-difluoromethyl-1,2-dihydropyrid-2-one-4-(or 5-)carbonyl and N-difluoromethyl-1,2-dihydropyrid-2-one-4-yl(or 5-yl)methylene moieties furnished compounds showing no inhibitory activities against the COX-2/5-LOX enzymes (except for the weak but selective COX-2 inhibitor 19a, COX-2 IC(50)=31 μM), and moderate in vivo anti-inflammatory activities (except for the methylene compound 19a that was inactive). These structure-activity data indicate replacement of the 4-chlorobenzoyl group present in indomethacin by a N-difluoromethyl-1,2-dihydropyrid-2-one ring system connected by a CO or CH(2) linker is not a suitable approach for the design of dual COX-2/5-LOX inhibitory analogs of indomethacin.
Chowdhury
Morshed A
MA
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alta, Canada.
Huang
Zhangjian
Z
Abdellatif
Khaled R A
KR
Dong
Ying
Y
Yu
Gang
G
Velázquez
Carlos A
CA
Knaus
Edward E
EE
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D001094:Arachidonate 5-Lipoxygenase / Q000737:chemistry* / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000737:chemistry* / Q000378:metabolism; D052246:Cyclooxygenase 2 Inhibitors / Q000138:chemical synthesis / Q000627:therapeutic use; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D007213:Indomethacin / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry* / Q000627:therapeutic use; D051381:Rats; D013329:Structure-Activity Relationship
D000893:Anti-Inflammatory Agents; D052246:Cyclooxygenase 2 Inhibitors; D007211:Indoles; D016859:Lipoxygenase Inhibitors; D011728:Pyridones; C030374:indole; D001094:Arachidonate 5-Lipoxygenase; D051546:Cyclooxygenase 2; D007213:Indomethacin