The p38
mitogen-activated
protein (MAP)
kinase has been implicated in the proinflammatory
cytokine signal pathway, and its inhibitors are potentially useful for the treatment of chronic inflammatory diseases such as
rheumatoid arthritis (RA) and
inflammatory bowel disease. To develop a new drug for RA, we synthesized a novel series of 4-phenyl-5-pyridyl-1,3-thiazoles and evaluated their inhibition of
p38 MAP kinase,
lipopolysaccharide (LPS)-stimulated release of
tumor necrosis factor-alpha (
TNF-alpha) from human monocytic THP-1 cells in vitro, and LPS-induced
TNF-alpha production in vivo in mice. During the course of the study, we found that these compounds risk the inhibition of
cytochrome P450 (CYP)
isoforms by coordination of the 4-pyridyl
nitrogen with
heme iron. We therefore investigated the effects of substitution at the 2-position of the pyridyl ring on the inhibitory activity of
p38 MAP kinase and CYPs in more detail. As a result, N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]
benzamide (8h, TAK-715) exhibited potent inhibitory activity in these assays (inhibition of p38alpha, IC50 = 7.1 nM; LPS-stimulated release of
TNF-alpha from THP-1, IC50 = 48 nM; LPS-induced
TNF-alpha production in mice, 87.6% inhibition
at 10 mg/kg, po) and no inhibitory activity for major CYPs, including
CYP3A4. This compound also showed good bioavailability in mice and rats and significant efficacy in a rat adjuvant-induced
arthritis model. Compound 8h was selected as a clinical candidate and is now under clinical investigation for the treatment of RA.