Pharmacology of a selective cyclooxygenase-2 inhibitor, L-745,337: a novel nonsteroidal anti-inflammatory agent with an ulcerogenic sparing effect in rat and nonhuman primate stomach.
Recent studies have shown that there are two isoforms of cyclooxygenases. The constitutive form, cyclooxygenase 1 (COX-1), is believed to be involved in the maintenance of physiological functions. A second isoform, cyclooxygenase 2 (COX-2), has been shown to be induced in inflammation. In the present study, the pharmacology of a selective inhibitor of COX-2, L-745,337 (5-methanesulfonamido-6-(2,4-difluorothiophenyl)-1-indano ne), is described. L-745,337 has IC50 values of 23 +/- 8 nM and > 10 microM for the inhibition of prostaglandin E2 production in whole-cell assays for COX-2 and COX-1, respectively. This compound inhibited carrageenan-induced rat paw edema and rat paw hyperalgesia with ID50 values of 2.00 and 0.37 mg/kg, respectively. In an endotoxin-induced pyresis assay in the rat, L-745,337 significantly reversed the pyretic responses (ID50 = 3.75 mg/kg). L-745,337 did not cause visible gastric lesions in rats at up to 30 mg/kg (4 hr after dosing). In a fecal 51chromium (51Cr) excretion assay to detect gastrointestinal integrity in rats and primates, L-745,337 had no effect at doses up to 100 mg/kg (rat) or after chronic dosing at 20 mg/kg per day for 5 days (primates). In contrast, oral administration of indomethacin, diclofenac or flurbiprofen resulted in substantial increase in fecal 51Cr excretion and/or frank gastric ulceration (rats). L-745,337 significantly inhibited the prostaglandin E2 levels in the inflammatory exudates from the rat pleural cavity after injection with carrageenan but did not inhibit prostaglandin E2 levels in the stomach.(ABSTRACT TRUNCATED AT 250 WORDS)
Chan
C C
CC
Department of Pharmacology, Merck Frosst Center for Therapeutic Research, Kirkland, Quebec, Canada.
Boyce
S
S
Brideau
C
C
Ford-Hutchinson
A W
AW
Gordon
R
R
Guay
D
D
Hill
R G
RG
Li
C S
CS
Mancini
J
J
Penneton
M
M
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D000897:Anti-Ulcer Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002351:Carrageenan / Q000633:toxicity; D002860:Chromium Radioisotopes / Q000032:analysis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D004487:Edema / Q000139:chemically induced / Q000188:drug therapy; D003576:Electron Transport Complex IV / Q000037:antagonists & inhibitors / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005334:Fever / Q000139:chemically induced / Q000188:drug therapy; D006801:Humans; D006930:Hyperalgesia / Q000139:chemically induced / Q000188:drug therapy; D007189:Indans / Q000494:pharmacology* / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008297:Male; D010998:Pleurisy / Q000139:chemically induced / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012453:Saimiri; D013276:Stomach Ulcer / Q000139:chemically induced / Q000517:prevention & control*; D014407:Tumor Cells, Cultured
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000897:Anti-Ulcer Agents; D002860:Chromium Radioisotopes; D016861:Cyclooxygenase Inhibitors; D007189:Indans; D007527:Isoenzymes; C093700:L 745337; D002351:Carrageenan; D003576:Electron Transport Complex IV