Synthesis of the butanamide derivative S 19812, a new dual inhibitor of cyclooxygenase and lipoxygenase pathways.
The general synthetic pathway and the interactions with arachidonic acid metabolism of the new compound S 19812 (N-hydroxy-N-methyl 4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl)butanamide, CAS 181308-68-9) were investigated. S 19812 was selected for its well balanced dual inhibition of cyclooxygenase and 5-lipoxygenase pathways in vitro in rat polymorphonuclear neutrophils (PMNs) (IC50 PGE2: 0.10 mumol/l, LTB4: 0.07 mumol/l) and ex vivo in mice blood (ED50 PGE2: 13.1 mg/kg, LTB4: 20.8 mg/kg). These properties make this drug a promising therapeutic agent for pain and inflammation associated with osteoarthritis.
Tordjman
Charles
C
Division of Rheumatology, Institut de Recherches Servier, Suresnes, France.
Sauveur
Frédéric
F
Droual
Monique
M
Briss
Sylvie
S
Andre
Nathalie
N
Bellot
Isabelle
I
Deschamps
Christine
C
Wierzbicki
Michel
M
D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D000001:Calcimycin / Q000494:pharmacology; D051545:Cyclooxygenase 1; D016861:Cyclooxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015232:Dinoprostone / Q000096:biosynthesis; D007202:Indicators and Reagents; D007527:Isoenzymes / Q000378:metabolism; D007975:Leukotriene B4 / Q000096:biosynthesis; D016859:Lipoxygenase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000201:enzymology; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism; D051381:Rats; D013876:Thiophenes / Q000138:chemical synthesis* / Q000494:pharmacology*
D000577:Amides; D000894:Anti-Inflammatory Agents, Non-Steroidal; D016861:Cyclooxygenase Inhibitors; D007202:Indicators and Reagents; D007527:Isoenzymes; D016859:Lipoxygenase Inhibitors; D008565:Membrane Proteins; D013876:Thiophenes; C480199:N-hydroxy-N-methyl 4-(2,3-bis-(4-methoxyphenyl)-thiophen-5-yl)butanamide; D007975:Leukotriene B4; D000001:Calcimycin; D051545:Cyclooxygenase 1; D011451:Prostaglandin-Endoperoxide Synthases; C496512:Ptgs1 protein, mouse; C496513:Ptgs1 protein, rat; D015232:Dinoprostone