The Effects of & Newly Developed Nonsteroidal Anti-inflammatory Drug (M-5011) on Arachidonic Acid Metabolism in Rheumatoid Synovial Fibroblasts

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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.