Synthesis, binding affinity and structure-activity relationships of novel, selective and dual targeting CCR2 and CCR5 receptor antagonistsElectronic supplementary information (ESI) available: Purity data, general chemistry aspects, synthetic procedures, materials and experimental details for the assays, 1H, 13C and gHSQC NMR spectra, HPLC analysis, and MS spectra of all compounds. See DOI: 10.1039/c4ob02397h
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...
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Sprache: | eng |
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Zusammenfassung: | 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 (
K
i
(CCR2) = 25 nM, IC
50
(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 (
K
i
= 19 nM) over the CCR5 receptor.
Late-stage diversification led to selective chemokine CCR2 receptor antagonists and dual-targeting CCR2/CCR5 receptor antagonists. |
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ISSN: | 1477-0520 1477-0539 |
DOI: | 10.1039/c4ob02397h |