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Design, Synthesis, and Biological Evaluation of Novel Type I1/2 p38α MAP Kinase Inhibitors with Excellent Selectivity, High Potency, and Prolonged Target Residence Time by Interfering with the R-Spine

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Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard-Karls-Universitaet Tuebingen, Auf der Morgenstelle 8, 72076 Tuebingen, Germany
Faculty of Chemistry and Chemical Biology, Technische Universitaet Dortmund, Otto-Hahn-Strasse 4a, 44227 Dortmund, Germany
§ Netherlands Translational Research Center B.V. (NTRC), Pivot Park, RE1210, Molenstraat 110, 5342 CC Oss, The Netherlands
*Phone: +49 7071 2972459. E-mail: [email protected]
Cite this: J. Med. Chem. 2017, 60, 19, 8027–8054
Publication Date (Web):August 23, 2017
Copyright © 2017 American Chemical Society

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    Abstract Image

    We recently reported 1a (skepinone-L) as a type I p38α MAP kinase inhibitor with high potency and excellent selectivity in vitro and in vivo. However, as a type I inhibitor, it is entirely ATP-competitive and shows just a moderate residence time. Thus, the scope was to develop a new class of advanced compounds maintaining the structural binding features of skepinone-L scaffold like inducing a glycine flip at the hinge region and occupying both hydrophobic regions I and II. Extending this scaffold with suitable residues resulted in an interference with the kinase’s R-Spine. By synthesizing 69 compounds, we could significantly prolong the target residence time with one example to 3663 s, along with an excellent selectivity score of 0.006 and an outstanding potency of 1.0 nM. This new binding mode was validated by cocrystallization, showing all binding interactions typifying type I1/2 binding. Moreover, microsomal studies showed convenient metabolic stability of the most potent, herein reported representatives.

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    The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.7b00745.

    • SMILES and some data (CSV)

    • Experimental and analytical data, including HPLC purity, (HR)MS, and NMR data of compounds 260; additional characterization of binding kinetics; all general methods; experimental section for materials and intermediates; X-ray crystallography; metabolic stability determination in vitro (PDF)

    Accession Codes

    Cocrystal structures of the human p38α MAP kinase in complex with 6j and 8m, respectively, are deposited under the accession codes 5MTY and 5MTX in the Protein Data Bank. Authors will release the atomic coordinates and experimental data upon article publication.

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