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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
journal contribution
posted on 2013-11-14, 00:00 authored by Benjamin Baur, Kirsten Storch, Kathrin E. Martz, Marcia
I. Goettert, André Richters, Daniel Rauh, Stefan A. LauferFive
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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stabilityMetabolicallyfactorderivativeinhibitionmetabolicallycompoundWholePanelProfilerreleaseselectivityStablecrystallography1.6 nMresidueATP competitivenessinductionabilitybinding moderegiontumorHumanSelective p 38 MAP Kinase Inhibitorsmonosubstituteddisubstituted dibenzoxepinonesintroductionglyince32 epharmacokinetic studyp 38α enzyme assayposition 9BloodFive seriesDibenzoproteinOptimizingdibenzoxepinone inhibitor 3 ioptimizedTNFpotencyIC 50 valuenecrosis125 nM
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