2. Academic Validation
  3. Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold

Synthesis and biological evaluation of chemokine receptor ligands with 2-benzazepine scaffold

  • Eur J Med Chem. 2017 Jul 28:135:401-413. doi: 10.1016/j.ejmech.2017.04.046.
Simone Thum 1,  Artur K Kokornaczyk 1,  Tomoaki Seki 2,  Monica De Maria 3,  Natalia V Ortiz Zacarias 4,  Henk de Vries 4,  Christina Weiss 5,  Michael Koch 5,  Dirk Schepmann 1,  Masato Kitamura 2,  Nuska Tschammer 6,  Laura H Heitman 4,  Anna Junker 7,  Bernhard Wünsch 8
Affiliations

Affiliations

  • 1 Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
  • 2 Graduate School of Pharmaceutical Sciences, Nagoya University Chikusa, Nagoya 464-8602, Japan.
  • 3 Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University, Schuhstraße 19, 91052 Erlangen, Germany; Department of Developmental Biology, Friedrich Alexander University, Staudtstraße 5, 91058 Erlangen, Germany.
  • 4 Division of Medicinal Chemistry, Leiden Academic Centre for Drug Research (LACDR), Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands.
  • 5 Bayer AG, Pharmaceuticals, Drug Discovery - Lead Discovery Wuppertal, Aprather Weg 18a, Gebäude 456, D-42096 Wuppertal, Germany.
  • 6 NanoTemper Technologies GmbH, Floessergasse 4, 81369 München, Germany.
  • 7 Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität Münster, Germany.
  • 8 Institut für Pharmazeutische und Medizinische Chemie der Westfälischen Wilhelms-Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), Westfälische Wilhelms-Universität Münster, Germany. Electronic address: wuensch@uni-muenster.de.
PMID: 28463783 DOI: 10.1016/j.ejmech.2017.04.046
Abstract

Targeting CCR2 and CCR5 receptors is considered as promising concept for the development of novel antiinflammatory drugs. Herein, we present the development of the first probe-dependent positive allosteric modulator (PAM) of CCR5 receptors with a 2-benzazepine scaffold. Compound 14 (2-isobutyl-N-({[N-methyl-N-(tetrahydro-2H-pyran-4-yl)amino]methyl}phenyl)-1-oxo-2,3-dihydro-1H-2-benzazepine-4-carboxamide) activates the CCR5 receptor in a CCL4-dependent manner, but does not compete with [3H]TAK-779 binding at the CCR5. Furthermore, introduction of a p-tolyl moiety at 7-position of the 2-benzazepine scaffold turns the CCR5 PAM 14 into the selective CCR2 receptor antagonist 26b. The structure affinity and activity relationships presented here offer new insights into ligand recognition by CCR2 and CCR5 receptors.

Keywords

2-Benzazepines; CCR2; CCR5; Chemokine receptors; Positive allosteric modulator; Structure activity relationships; Structure-affinity relationships; TAK-652; TAK-779.

Figures