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PDBsum entry 4l8m
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Transferase/transferase inhibitor
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PDB id
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4l8m
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References listed in PDB file
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Key reference
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Title
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Metabolically stable dibenzo[b,E]oxepin-11(6h)-Ones as highly selective p38 map kinase inhibitors: optimizing anti-Cytokine activity in human whole blood.
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Authors
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B.Baur,
K.Storch,
K.E.Martz,
M.I.Goettert,
A.Richters,
D.Rauh,
S.A.Laufer.
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Ref.
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J Med Chem, 2013,
56,
8561-8578.
[DOI no: ]
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PubMed id
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Abstract
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Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H)-ones
were synthesized and tested in a p38α enzyme assay for their inhibition of
tumor necrosis factor-α (TNF-α) release in human whole blood. Compared to the
monosubstituted dibenzo[b,e]oxepin-11(6H)-one derivatives, it has been shown
that the additional introduction of hydrophilic residues at position 9 leads to
a substantial improvement of the inhibitory potency and metabolic stability.
Using protein X-ray crystallography, the binding mode of the disubstituted
dibenzoxepinones and the induction of a glyince flip in the hinge region were
confirmed. The most potent compound of this series, 32e, shows an outstanding
biological activity on isolated p38α, with an IC50 value of 1.6 nM,
extraordinary selectivity (by a factor >1000, Kinase WholePanelProfiler), and
low ATP competitiveness. The ability to inhibit the release of TNF-α from human
whole blood was optimized down to an IC50 value of 125 nM. With the promising
dibenzoxepinone inhibitor 3i, a pharmacokinetic study in mice was conducted.
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