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
  • 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: [email protected].
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.