Abstract |
A group of 4-(4-methanesulfonylphenyl)-3-phenyl-2(5H)furanones possessing an acetyl, 3-oxobut-1-ynyl, [ hydroxyl(or alkoxy)imino]alkyl, [ hydroxyl(or alkoxy)imino]alkynyl, and N- alkoxy(or N-phenoxy)carbonyl-N-hydroxy-N-ethylamino substituents at the para-position of the C-3 phenyl ring of rofecoxib were synthesized. This group of compounds was designed for evaluation as dual inhibitors of cyclooxygenases (COXs) and lipoxygenases (LOXs) that exhibit in vivo anti-inflammatory and analgesic activities. In vitro COX-1/COX-2, and 5-LOX/15-LOX, isozyme inhibition structure-activity relationships identified 3-[4-(1-hydroxyimino)ethylphenyl]-4-(4-methanesulfonylphenyl)-2(5H)furanone (17a) having an optimal combination of COX-2 (COX-2 IC50 = 1.4 microM; COX-2 SI > 71), and 5-LOX and 15 LOX (5-LOX IC50 = 0.28 microM; 15-LOX IC50 = 0.32 microM), inhibitory effects. It was also discovered that 3-[4-(3-hydroxyiminobut-1-ynyl)phenyl]-4-(4-methanesulfonylphenyl)-2(5H)furanone (18a) possesses dual COX-2 (IC50 = 2.7 microM) and 5-LOX (IC50 = 0.30 microM) inhibitor actions. Further in vivo studies employing a rat carrageenan-induced paw edema model showed that the oxime compounds (17a, 18a) were more potent anti-inflammatory agents than the 5-LOX inhibitor caffeic acid, and 15-LOX inhibitor nordihydroguaiaretic acid (NDGA), but less potent than the selective COX-2 inhibitor celecoxib. The results of this investigation showed that incorporation of a para- oxime moiety on the C-3 phenyl ring of rofecoxib provides a suitable template for the design of dual inhibitors of the COX and LOX enzymes.
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Authors | Qiao-Hong Chen, P N Praveen Rao, Edward E Knaus |
Journal | Bioorganic & medicinal chemistry
(Bioorg Med Chem)
Vol. 14
Issue 23
Pg. 7898-909
(Dec 01 2006)
ISSN: 0968-0896 [Print] England |
PMID | 16904331
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
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Chemical References |
- Analgesics
- Anti-Inflammatory Agents
- Cyclooxygenase 2 Inhibitors
- Cyclooxygenase Inhibitors
- Lactones
- Lipoxygenase Inhibitors
- Sulfones
- rofecoxib
- Cyclooxygenase 1
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Topics |
- Analgesics
(chemical synthesis, pharmacology)
- Animals
- Anti-Inflammatory Agents
(chemical synthesis, pharmacology)
- Cyclooxygenase 1
- Cyclooxygenase 2 Inhibitors
- Cyclooxygenase Inhibitors
(chemical synthesis, pharmacology)
- Drug Evaluation, Preclinical
- Humans
- Inhibitory Concentration 50
- Lactones
(chemical synthesis, pharmacology, therapeutic use)
- Lipoxygenase Inhibitors
(chemical synthesis, pharmacology)
- Rats
- Structure-Activity Relationship
- Sulfones
(chemical synthesis, pharmacology, therapeutic use)
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