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

Source: Org Biomol Chem, Volume 13, Issue 8, pp. 2407-22 (2015)

Junker, A.; Kokornaczyk, A.K.; Zweemer, A.J.; Frehland, B.; Schepmann, D.; Yamaguchi, J.; Itami, K.; Faust, A.; Hermann, S.; Wagner, S.; Schäfers, M.; Koch, M.; Weiss, C.; Heitman, L.H.; Kopka, K.; Wünsch, B.
16 December 2014
Online publication

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.

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