Pharmacological characterization of a selective COX-2 inhibitor MF-tricyclic, [3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2-(5H)-furanone], in multiple preclinical species.
Selective type 2 cyclooxygenase (COX-2) inhibitors are often used in preclinical studies without potency and selectivity data in the experimental species. To address this issue, we assessed a selective COX-2 inhibitor MF-tricyclic in four commonly used species, namely mice, rats, guinea pigs and rabbits, in the present study. In both the guinea pig and rabbit whole blood assay, the compound inhibited lipopolysaccharide (LPS)-induced PGE(2) production with an IC(50) (COX-2) of 0.6 and 2.8 microM, respectively. By comparison, the compound displayed a much weaker activity on clot-induced formation of thromboxane with an IC(50) (COX-1) of >10 microM (guinea pigs) and 23 microM (rabbits). In keeping with the in vitro potency data, the compound significantly inhibited interleukin-1 beta (IL-1beta) -induced PGE(2) formation in the rabbit synovium at plasma concentrations near the whole blood assay IC(50) for COX-2 but much lower than that for COX-1. MF-tricyclic was also potent and selective toward COX-2 in mice, inhibiting carrageenan-induced PGE(2) accumulation in the air pouch dose-dependently (ED(50)=0.5 mg/kg) without affecting stomach PGE(2) levels. In rats, MF-tricyclic was found to be effective in three standard in vivo assays utilized for assessing COX-2 inhibitors, namely, LPS-induced pyresis, carrageenan-induced paw edema and adjuvant-induced arthritis at the doses that did not inhibit stomach PGE(2) levels. Similar to that in rats, the compound displayed pharmacological efficacy in mice, guinea pigs and rabbits when tested in the LPS pyresis model. Our data reveal that MF-tricyclic has the desired biochemical and pharmacological properties for selective COX-2 inhibition in all four test species.
Rowland
Steven E
SE
Department of Pharmacology, Molecular Biology and Biochemistry and Chemistry, Merck Frosst Center for Therapeutic Research, Merck Frosst, 16711 Trans-Canada Highway, Kirkland, Quebec, Canada.
Clark
Patsy
P
Gordon
Robert
R
Mullen
Anne K
AK
Guay
Jocelyne
J
Dufresne
Lynn
L
Brideau
Christine
C
Cote
Bernard
B
Ducharme
Yves
Y
Mancini
Joseph
J
Chan
Chi-chung
CC
Audoly
Laurent
L
Xu
Daigen
D
D018712:Analgesics, Non-Narcotic / Q000494:pharmacology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005663:Furans / Q000097:blood / Q000494:pharmacology*; D005753:Gastric Mucosa / Q000378:metabolism; D006168:Guinea Pigs; D053583:Interleukin-1beta / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013270:Stomach / Q000187:drug effects
D018712:Analgesics, Non-Narcotic; D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D005663:Furans; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; C102563:3-(3,4-difluorophenyl)-4-(4-(methylsulfonyl)phenyl)-2(5H)-furanone; D015232:Dinoprostone