Metabolically Stable Dibenzo[<i>b</i>,<i>e</i>]oxepin-11(6<i>H</i>)‑ones as Highly Selective p38 MAP Kinase Inhibitors: Optimizing Anti-Cytokine Activity in Human Whole Blood

Five series of metabolically stable disubstituted dibenzo­[<i>b</i>,<i>e</i>]­oxepin-11­(6<i>H</i>)-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[<i>b</i>,<i>e</i>]­oxepin-11­(6<i>H</i>)-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, <b>32e</b>, 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 <b>3i</b>, a pharmacokinetic study in mice was conducted

Targeting the Hinge Glycine Flip and the Activation Loop: Novel Approach to Potent p38α Inhibitors

The p38 MAP kinase is a key player in signaling pathways regulating the biosynthesis of inflammatory cytokines. Small molecule p38 inhibitors suppress the production of these cytokines. Therefore p38 is a promising drug target for novel anti-inflammatory drugs. In this study, we report novel dibenzepinones, dibenzoxepines, and benzosuberones as p38α MAP kinase inhibitors. Previously reported dibenzepinones and dibenzoxepines were chemically modified by introduction of functional groups or removal of a phenyl ring. This should result in targeting of the hydrophobic region I, the “deep pocket”, and the hinge glycine flip of the kinase. Potent inhibitors with IC₅₀ values in the single digit nanomolar range (up to 3 nM) were identified. Instead of targeting the “deep pocket” in the DFG-out conformation, interactions with the DFG-motif in the in-conformation could be observed by protein X-ray crystallography