2. Academic Validation
  3. Bioisosteric Replacement of Arylamide-Linked Spine Residues with N-Acylhydrazones and Selenophenes as a Design Strategy to Novel Dibenzosuberone Derivatives as Type I 1/2 p38α MAP Kinase Inhibitors

Bioisosteric Replacement of Arylamide-Linked Spine Residues with N-Acylhydrazones and Selenophenes as a Design Strategy to Novel Dibenzosuberone Derivatives as Type I 1/2 p38α MAP Kinase Inhibitors

  • J Med Chem. 2020 Jul 9;63(13):7347-7354. doi: 10.1021/acs.jmedchem.0c00508.
Júlia G B Pedreira 1 2,  Philipp Nahidino 3,  Mark Kudolo 3,  Tatu Pantsar 3 4,  Benedict-Tilman Berger 5 6,  Michael Forster 3,  Stefan Knapp 5 6,  Stefan Laufer 3 7 8,  Eliezer J Barreiro 1 2
Affiliations

Affiliations

  • 1 Laboratory of Evaluation and Synthesis of Bioactive Substances (LASSBio), Federal University of Rio de Janeiro (UFRJ), 21944-971 Rio de Janeiro, Brazil.
  • 2 Graduate Program of Chemistry (PGQu), Chemistry Institute, UFRJ, 21941-909 Rio de Janeiro, Brazil.
  • 3 Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical Sciences, Eberhard Karls Universität, Auf der Morgenstelle 8, 72076 Tübingen, Germany.
  • 4 School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, 70210 Kuopio, Finland.
  • 5 Institute for Pharmaceutical Chemistry, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 9, D-60438 Frankfurt am Main, Germany.
  • 6 Structural Genomics Consortium (SGC), Buchman Institute for Life Sciences, Johann Wolfgang Goethe-University, Max-von-Laue-Str. 15, D-60438 Frankfurt am Main, Germany.
  • 7 Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies", University of Tübingen, 72076 Tübingen, Germany.
  • 8 Tübingen Center for Academic Drug Discovery & Development (TüCAD2), 72076 Tübingen, Germany.
PMID: 32462866 DOI: 10.1021/acs.jmedchem.0c00508
Abstract

The recent disclosure of type I 1/2 inhibitors for p38α MAPK demonstrated how the stabilization of the R-spine can be used as a strategy to greatly increase the target residence time (TRT) of inhibitors. Herein, for the first time, we describe N-acylhydrazone and selenophene residues as spine motifs, yielding metabolically stable inhibitors with high potency on enzymatic, NanoBRET, and whole blood assays, improved metabolic stability, and prolonged TRT.

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