Structure–Activity
Relationships and Identification
of Optmized CC-Chemokine Receptor
CCR1, 5, and 8 Metal-Ion Chelators
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Abstract
Chemokine
receptors are involved in trafficking of leukocytes and
represent targets for autoimmune conditions, inflammatory diseases,
viral infections, and cancer. We recently published CCR1, CCR8, and
CCR5 agonists and positive modulators based on a three metal-ion chelator
series: 2,2′-bipyridine, 1,10-phenanthroline, and 2,2′;6′,2″-terpyridine.
Here, we have performed an in-depth structure–activity relationship
study and tested eight new optimized analogs. Using density functional
theory calculations we demonstrate that the chelator zinc affinities
depend on how electron-donating and -withdrawing substituents modulate
the partial charges of chelating nitrogens. The zinc affinity was
found to constitute the major factor for receptor potency, although
the activity of some chelators deviate suggesting favorable or unfavorable
interactions. Hydrophobic and halogen substituents are generally better
accommodated in the receptors than polar groups. The new analog brominated
terpyridine (<b>29</b>) resulted in the highest chelator potencies
observed so far CCR1 (EC<sub>50</sub>: 0.49 μM) and CCR8 (EC<sub>50</sub>: 0.28 μM). Furthermore, we identified the first selective
CCR5 agonist chelator, meta dithiomethylated bipyridine (<b>23</b>). The structure–activity relationships contribute to small-molecule
drug development, and the novel chelators constitute valuable tools
for studies of structural mechanisms for chemokine receptor activation