Structure–Activity Relationships and Identification of Optmized CC-Chemokine Receptor CCR1, 5, and 8 Metal-Ion Chelators

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 (EC₅₀: 0.49 μM) and CCR8 (EC₅₀: 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

Modulation in Selectivity and Allosteric Properties of Small-Molecule Ligands for CC-Chemokine Receptors

Among 18 human chemokine receptors, CCR1, CCR4, CCR5, and CCR8 were activated by metal ion Zn­(II) or Cu­(II) in complex with 2,2′-bipyridine or 1,10-phenanthroline with similar potencies (EC₅₀ from 3.9 to 172 μM). Besides being agonists, they acted as selective allosteric enhancers of CCL3. These actions were dependent on a conserved glutamic acid at TM-7 (VII:06/7.39). A screening of 20 chelator analogues in complex with Zn­(II) identified compounds with increased potencies, with <b>7</b> reaching highest potency at CCR1 (EC₅₀ of 0.85 μM), <b>20</b> at CCR8 (0.39 μM), and <b>8</b> at CCR5 (1.0 μM). Altered selectivity for CCR1 and CCR8 over CCR5 (<b>11</b>, <b>12</b>) and a receptor-dependent separation of allosteric from intrinsic properties were achieved (<b>20</b>). The pocket similarities of CCR1 and CCR8, contrary to CCR5 as proposed by the ligand screen, were elaborated by computational modeling. These studies facilitate exploration of chemokine receptors as possible targets for therapeutic intervention