| Reference | 1. Acta Crystallogr D Biol Crystallogr. 2012 Aug;68(Pt 8):1041-50. doi:
10.1107/S090744491201997X. Epub 2012 Jul 17.
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X-ray structure of p38α bound to TAK-715: comparison with three classic
inhibitors.
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Azevedo R(1), van Zeeland M, Raaijmakers H, Kazemier B, de Vlieg J, Oubrie A.
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Author information: <br>
(1)Merck Research Laboratories, MSD, PO Box 20, 5340 BH Oss, The Netherlands.
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The p38α mitogen-activated protein kinase regulates the synthesis of
pro-inflammatory cytokines in response to stimulation by a diverse set of stress
signals. Various different chemotypes and clinical candidates that inhibit p38α
function have been reported over the years. In this publication, the novel
structure of p38α cocrystallized with the clinical candidate TAK-715 is reported.
Owing to the impact of crystallization conditions on the conformation of protein
kinases (and in particular p38α), the structures of complexes of p38α with
SB-203580, SCIO-469 and VX-745 have also been determined to enable in-depth
comparison of ligand-induced protein conformations. The impact of experimental
conditions on p38α-inhibitor complex structures, most importantly soaking versus
cocrystallization, is discussed. Analysis of the structures and quantification of
the protein-ligand interactions couples ligand-induced protein conformations to
the number of interactions and to inhibitor selectivity against the human kinome.
This shows that for the design of novel kinase inhibitors, selectivity is best
obtained through maximization of the number of interactions throughout the ATP
pocket and the exploitation of specific features in the active site.
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2. J Med Chem. 2005 Sep 22;48(19):5966-79.
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Novel inhibitor of p38 MAP kinase as an anti-TNF-alpha drug: discovery of
N-[4-[2-ethyl-4-(3-methylphenyl)-1,3-thiazol-5-yl]-2-pyridyl]benzamide (TAK-715)
as a potent and orally active anti-rheumatoid arthritis agent.
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Miwatashi S(1), Arikawa Y, Kotani E, Miyamoto M, Naruo K, Kimura H, Tanaka T,
Asahi S, Ohkawa S.
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Author information: <br>
(1)Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., 17-85
Jusohonmachi 2-chome, Yodogawa-ku, Osaka, 532-8686, Japan.
[email protected]
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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.
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