Synthesis, binding affinity and structure-activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists

Anna Junker, Artur K. Kokornaczyk, Annelien J M Zweemer, Bastian Frehland, Dirk Schepmann, Junichiro Yamaguchi, Kenichiro Itami, Andreas Faust, Sven Hermann, Stefan Wagner, Michael Schäfers, Michael Koch, Christina Weiss, Laura H. Heitman, Klaus Kopka, Bernhard Wünsch

Research output: Contribution to journalArticle

8 Citations (Scopus)

Abstract

CCR2 and CCR5 receptors play a key role in the development and progression of several inflammatory, cardiovascular and autoimmune diseases. Therefore, dual targeting of both receptors appeals as a promising strategy for the treatment of such complex, multifactorial disorders. Herein we report on the design, synthesis and biological evaluation of benzo[7]annulene- and [7]annulenothiophene-based selective and dual CCR2 and CCR5 receptor antagonists. Intermediates were designed in such a way that diversification could be introduced at the end of the synthesis. Starting from the lead compound TAK-779 (1), the quaternary ammonium moiety was exchanged by different non-charged moieties, the 4-methylphenyl moiety was extensively modified and the benzo[7]annulene core was replaced bioisosterically by the [7]annulenothiophene system. The naphthyl derivative 9h represents the most promising dual antagonist (Ki (CCR2) = 25 nM, IC50 (CCR5) = 17 nM), whereas the 6-isopropoxy-3-pyridyl and 4-methoxycarbonylphenyl derivatives 9k and 9r show more than 20-fold selectivity for the CCR2 (Ki = 19 nM) over the CCR5 receptor. This journal is

Original languageEnglish
Pages (from-to)2407-2422
Number of pages16
JournalOrganic and Biomolecular Chemistry
Volume13
Issue number8
DOIs
Publication statusPublished - 2015
Externally publishedYes

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CCR2 Receptors
CCR5 Receptors
Structure-Activity Relationship
affinity
Lead compounds
Derivatives
synthesis
Ammonium Compounds
Autoimmune Diseases
Inhibitory Concentration 50
Cardiovascular Diseases
lead compounds
progressions
selectivity
disorders
CCR5 Receptor Antagonists
(7)annulenothiophene
evaluation

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Biochemistry
  • Medicine(all)

Cite this

Synthesis, binding affinity and structure-activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists. / Junker, Anna; Kokornaczyk, Artur K.; Zweemer, Annelien J M; Frehland, Bastian; Schepmann, Dirk; Yamaguchi, Junichiro; Itami, Kenichiro; Faust, Andreas; Hermann, Sven; Wagner, Stefan; Schäfers, Michael; Koch, Michael; Weiss, Christina; Heitman, Laura H.; Kopka, Klaus; Wünsch, Bernhard.

In: Organic and Biomolecular Chemistry, Vol. 13, No. 8, 2015, p. 2407-2422.

Research output: Contribution to journalArticle

Junker, A, Kokornaczyk, AK, Zweemer, AJM, Frehland, B, Schepmann, D, Yamaguchi, J, Itami, K, Faust, A, Hermann, S, Wagner, S, Schäfers, M, Koch, M, Weiss, C, Heitman, LH, Kopka, K & Wünsch, B 2015, 'Synthesis, binding affinity and structure-activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists', Organic and Biomolecular Chemistry, vol. 13, no. 8, pp. 2407-2422. https://doi.org/10.1039/c4ob02397h
Junker, Anna ; Kokornaczyk, Artur K. ; Zweemer, Annelien J M ; Frehland, Bastian ; Schepmann, Dirk ; Yamaguchi, Junichiro ; Itami, Kenichiro ; Faust, Andreas ; Hermann, Sven ; Wagner, Stefan ; Schäfers, Michael ; Koch, Michael ; Weiss, Christina ; Heitman, Laura H. ; Kopka, Klaus ; Wünsch, Bernhard. / Synthesis, binding affinity and structure-activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists. In: Organic and Biomolecular Chemistry. 2015 ; Vol. 13, No. 8. pp. 2407-2422.
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