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

Júlia G B Pedreira; Philipp Nahidino; Mark Kudolo; Tatu Pantsar; Benedict-Tilman Berger; Michael Forster; Stefan Knapp; Stefan Laufer; Eliezer J Barreiro

doi:10.1021/acs.jmedchem.0c00508

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. Epub 2020 Jun 11.

Authors

Júlia G B Pedreira^{1

2}, Philipp Nahidino³, Mark Kudolo³, Tatu Pantsar^{3

4}, Benedict-Tilman Berger^{5

6}, Michael Forster³, Stefan Knapp^{5

6}, Stefan Laufer^{3

7

8}, Eliezer J Barreiro^{1

2}

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amides / chemistry
Dibenzocycloheptenes / chemistry*
Drug Design
Drug Stability
Humans
Hydrazones / chemistry
Microsomes, Liver / drug effects
Mitogen-Activated Protein Kinase 14 / antagonists & inhibitors*
Mitogen-Activated Protein Kinase 14 / chemistry
Mitogen-Activated Protein Kinase 14 / metabolism
Organoselenium Compounds / chemistry
Protein Kinase Inhibitors / chemistry*
Protein Kinase Inhibitors / pharmacokinetics
Protein Kinase Inhibitors / pharmacology*
Structure-Activity Relationship*
Time Factors

Substances

Amides
Dibenzocycloheptenes
Hydrazones
Organoselenium Compounds
Protein Kinase Inhibitors
dibenzsuberone
Mitogen-Activated Protein Kinase 14

Grants and funding

WT_/Wellcome Trust/United Kingdom