Jump to main content
Jump to site search

Issue 8, 2015
Previous Article Next Article

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

Author affiliations

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.

Graphical abstract: Synthesis, binding affinity and structure–activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonists

Back to tab navigation

Supplementary files

Publication details

The article was received on 13 Nov 2014, accepted on 16 Dec 2014 and first published on 16 Dec 2014


Article type: Paper
DOI: 10.1039/C4OB02397H
Author version available: Download Author version (PDF)
Citation: Org. Biomol. Chem., 2015,13, 2407-2422
  •   Request permissions

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

    A. Junker, A. K. Kokornaczyk, A. J. M. Zweemer, B. Frehland, D. Schepmann, J. Yamaguchi, K. Itami, A. Faust, S. Hermann, S. Wagner, M. Schäfers, M. Koch, C. Weiss, L. H. Heitman, K. Kopka and B. Wünsch, Org. Biomol. Chem., 2015, 13, 2407
    DOI: 10.1039/C4OB02397H

Search articles by author

Spotlight

Advertisements