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

Add time:07/18/2019    Source:sciencedirect.com

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 125I-CCL2 from the human CCR2. However, in the Ca2+-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 Ca2+-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 17 nM, respectively. Micromolar activities were found in the β-arrestin recruitment assay with murine CCR2, but the structure–activity-relationships detected in the Ca2+-flux assay were confirmed.

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