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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• 作者：Benjamin Baur ; Kirsten Storch ; Kathrin E. Martz ; Marcia I. Goettert ; Andr茅 Richters ; Daniel Rauh ; Stefan A. Laufer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：November 14, 2013
• 年：2013
• 卷：56
• 期：21
• 页码：8561-8578
• 全文大小：875K
• 年卷期：v.56,no.21(November 14, 2013)
• ISSN：1520-4804

文摘

Five series of metabolically stable disubstituted dibenzo[b,e]oxepin-11(6H)-ones were synthesized and tested in a p38伪 enzyme assay for their inhibition of tumor necrosis factor-伪 (TNF-伪) 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 p38伪, 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-伪 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.