2. Academic Validation
  3. Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (chemokine CC receptor subtype 2)

Synthesis and biological evaluation of spirocyclic antagonists of CCR2 (chemokine CC receptor subtype 2)

  • Bioorg Med Chem. 2015 Jul 15;23(14):4034-49. doi: 10.1016/j.bmc.2015.02.019.
Ann Kathrin Strunz 1,  Annelien J M Zweemer 2,  Christina Weiss 3,  Dirk Schepmann 1,  Anna Junker 1,  Laura H Heitman 2,  Michael Koch 3,  Bernhard Wünsch 4
Affiliations

Affiliations

  • 1 Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, 48149 Münster, Germany.
  • 2 Leiden Academic Centre for Drug Research (LACDR), Leiden University, Division of Medicinal Chemistry, Einsteinweg 55, 2333 CC Leiden, The Netherlands.
  • 3 Bayer Pharma AG, Global Drug Discovery-Lead Discovery Wuppertal, Aprather Weg 18a, Gebäude 456, D-42096 Wuppertal, Germany.
  • 4 Institut für Pharmazeutische und Medizinische Chemie, Westfälische Wilhelms-Universität Münster, Corrensstraße 48, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, Germany. Electronic address: wuensch@uni-muenster.de.
PMID: 25766632 DOI: 10.1016/j.bmc.2015.02.019
Abstract

Activation of chemokine CC receptors subtype 2 (CCR2) plays an important role in chronic inflammatory processes such as atherosclerosis, multiple sclerosis and rheumatoid arthritis. A diverse set of spirocyclic butanamides 4 (N-benzyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)butanamides) was prepared by different combination of spirocyclic piperidines 8 (3,4-dihydrospiro[[2]benzopyran-1,4'-piperidines]) and γ-halobutanamides 11. A key step in the synthesis of spirocyclic piperidines 8 was an Oxa-Pictet-Spengler reaction of β-phenylethanols 5 with piperidone acetal 6. The substituted γ-hydroxybutanamides 11c-e were prepared by hydroxyethylation of methyl acetates 13 with ethylene sulfate giving the γ-lactones 14c and 14e. Aminolysis of the γ-lactones 14c and 14e with benzylamines provided the γ-hydroxybutanamides 15c-e, which were converted into the bromides 11c-e by an Appel reaction using polymer-bound PPh3. In radioligand binding assays the spirocyclic butanamides 4 did not displace the iodinated radioligand (125)I-CCL2 from the human CCR2. However, in the CA(2+)-flux assay using human CCR2 strong antagonistic activity of butanamides 4 was detected. Analysis of the IC50-values led to clear relationships between the structure and the inhibition of the CA(2+)-flux. 4g (4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)-N-[3,5-bis(trifluoromethylbenzyl)]-2-(4-fluorophenyl)butanamide) and 4o (N-[3,5-bis(trifluoromethyl)benzyl]-2-cyclopropyl-4-(3,4-dihydrospiro[[2]benzopyran-1,4'-piperidin]-1'-yl)butanamide) represent the most potent CCR2 antagonists with IC50-values of 89 and 17nM, respectively. Micromolar activities were found in the β-arrestin recruitment assay with murine CCR2, but the structure-activity-relationships detected in the CA(2+)-flux assay were confirmed.

Keywords

Appel reaction; Ca(2+) flux; Chemokine CC receptor subtype 2 (CCR2) antagonists; Ethylene sulfate; Oxa-Pictet–Spengler reaction; Polymer-bound triphenylphosphine; Receptor binding studies; Spirocyclic piperidines; Structure–activity-relationships; β-Arrestin recruitment.

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