Tebufelone is a novel nonsteroidal anti-inflammatory
drug (
NSAID), of the di-tert-butylphenol (
DTBP) class, which displays potent anti-inflammatory,
analgesic and anti-pyretic properties in a variety of animal models. In this report, the effects of
Tebufelone on
arachidonic acid (AA) metabolism are reviewed.
Tebufelone potently inhibits the formation of
prostaglandins (
PGE2) a key mediator of
pain and
inflammation, in isolated
enzyme preparations (IC50 = 1.5 microM, KI = 0.35 microM), two in vitro cellular systems: rat peritoneal macrophages (IC50 = 0.02 microM) and human whole blood (IC50 = 0.08 microM), and ex vivo in man. In addition to
PGE2 inhibition, which is common to all
NSAIDs, higher concentrations of
Tebufelone block the in vitro formation of products of the
lipoxygenase pathway [
leukotrienes (
LTB4)] in rat macrophages (IC50 = 20 microM) and human whole blood (IC50 = 22 microM). Substrate incorporation studies (14C-AA) indicate that
Tebufelone reversibly inhibits
cyclooxygenase (CO) and
5-lipoxygenase (5-LO)
enzymes rather than regulating the release of AA.
Tebufelone was shown to be a more potent CO inhibitor than
indomethacin and a less potent 5-LO inhibitor than
RG-5901. Comparisons to structurally related compounds under development (
E-5110, Esai;
KME-4, Kanagafuchi), found
Tebufelone to be the most potent CO inhibitor in vitro. All three
DTBP compounds were equipotent 5-LO inhibitors. It is likely that
Tebufelone's inhibitory effects on AA metabolism are, in part, responsible for its in vivo efficacy and enhanced safety profile.