Anti-inflammatory and analgesic effects of a novel pyrazole derivative, FR140423.
The pharmacological profile of a novel and newly discovered non-steroidal anti-inflammatory and analgesic compound, 3-(difluoromethyl)-1-(4-methoxyphenyl)-5-[4-(methylsulfinyl)phenyl]pyraz ole (FR140423), was investigated. In recombinant human cyclooxygenase enzyme assays, the inhibition of prostaglandin E2 formation by FR140423 was 150 times more selective for cyclooxygenase-2 than cyclooxygenase-1. Oral administration of FR140423 dose dependently reduced carrageenin-induced paw edema and adjuvant arthritis. These effects were two- to three-fold more potent than those of indomethacin. Unlike indomethacin, FR140423 did not induce mucosal lesions in the stomach. FR140423 showed dose-dependent anti-hyperalgesic effects in the yeast-induced hyperalgesic model. This effect was five-fold more potent than that of indomethacin. Furthermore, FR140423 increased the pain threshold in non-inflamed paws and, unlike indomethacin, it produced an analgesic effect in the tail-flick test. These analgesic effects were blocked by the mu-opioid antagonist naloxone. These results suggest that FR140423, a selective cyclooxygenase-2 inhibitor, is a potent non-steroidal anti-inflammatory drug (NSAID) without gastrointestinal side effects and is a unique compound having morphine-like analgesic effects.
Ochi
T
T
Department of Immunology and Inflammation, Fujisawa Pharmaceutical, Osaka, Japan.
Jobo-Magari
K
K
Yonezawa
A
A
Matsumori
K
K
Fujii
T
T
D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D002351:Carrageenan / Q000633:toxicity; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D005658:Fungi / Q000502:physiology; D007213:Indomethacin / Q000009:adverse effects / Q000494:pharmacology; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D008565:Membrane Proteins; D015394:Molecular Structure; D009270:Naloxone / Q000494:pharmacology; D010147:Pain Measurement; D010437:Peptic Ulcer / Q000139:chemically induced; D010544:Peroxidases / Q000378:metabolism*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011720:Pyrazoles / Q000009:adverse effects / Q000494:pharmacology*; D047069:Pyrazolones; D051381:Rats; D011917:Rats, Inbred Lew; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins; D013454:Sulfoxides