The effects of a newly developed nonsteroidal anti-inflammatory drug (M-5011) on arachidonic acid metabolism in rheumatoid synovial fibroblasts.

Abstract

M-5011 (d-2-[4-(3-methyl-2-thienyl)phenyl]propionic acid) is a newly developed nonsteroidal anti-inflammatory drug (NSAID) that displays potent anti-inflammatory and analgesic properties with low ulcerogenic activities in animal models. In this study, the effects of M-5011 on arachidonic acid (AA) metabolism in synovial fibroblasts from patients with rheumatoid arthritis were evaluated and compared with those of other NSAIDs in vitro. Either M-5011 or ketoprofen potently inhibited prostaglandin (PG) E2 production by cyclooxygenase (COX)-2 from exogenous AA in interleukin-1beta (IL-1beta)-stimulated cells. The IC50 values of M-5011 and ketoprofen were 4.4 x 10(-7) and 5.9 x 10(-7) M, respectively. However, diclofenac and indomethacin were one order less potent. Although the latter two drugs exhibited time-dependent and irreversible inhibition on COX-2 in IL-1beta-stimulated cells, the inhibitory effects of M-5011 and ketoprofen were reversible. PGE2 production by COX-1 from exogenous AA in non-stimulated cells was also inhibited by M-5011 with a potency less than that of ketoprofen. In addition, M-5011 inhibited [14C]AA release from prelabeled synovial cells stimulated with bradykinin. However, ketoprofen hardly affected the [14C]AA release. It is likely that the effects of M-5011 on AA metabolism are, in part, responsible for its in vivo efficacy and safety profile.

• Authors: K Tobetto, Y Yamamoto, M Kataoka, T Ando, K Sugimoto, M Himeno
• Journal: Japanese journal of pharmacology (Jpn J Pharmacol) Vol. 75 Issue 4 Pg. 371-9 (Dec 1997) ISSN: 0021-5198 [Print] Japan
• PMID: 9469643 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Carbon Radioisotopes
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors
• Interleukin-1
• Isoenzymes
• Membrane Proteins
• Phenylpropionates
• Arachidonic Acid
• 2-(4-(3-methyl-2-thienyl)phenyl)propionic acid
• Ketoprofen
• Cyclooxygenase 1
• Cyclooxygenase 2
• PTGS1 protein, human
• PTGS2 protein, human
• Prostaglandin-Endoperoxide Synthases
• Dinoprostone
• Bradykinin
• Indomethacin

Topics

• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Arachidonic Acid (metabolism)
• Arthritis, Rheumatoid (drug therapy, metabolism)
• Bradykinin
• Carbon Radioisotopes
• Cells, Cultured
• Cyclooxygenase 1
• Cyclooxygenase 2
• Cyclooxygenase 2 Inhibitors
• Cyclooxygenase Inhibitors (pharmacology)
• Dinoprostone (biosynthesis)
• Dose-Response Relationship, Drug
• Female
• Fibroblasts (drug effects, metabolism)
• Humans
• Indomethacin (pharmacology)
• Interleukin-1 (pharmacology)
• Isoenzymes (metabolism)
• Ketoprofen (pharmacology)
• Membrane Proteins
• Middle Aged
• Phenylpropionates (pharmacology)
• Prostaglandin-Endoperoxide Synthases (metabolism)
• Synovial Membrane (drug effects, metabolism)