Discovery of 1-(3-phenoxybenzyl)-4-(1-phenyl-1H-1,2,3-triazol-4-yl)piperidine analogues as potent and selective agonists of the human CC chemokine receptor 8

The human Chemokine Receptor 8 (CCR8) plays a role in various autoimmune disorders, such as multiple sclerosis and inflammatory bowel disease, spurring the interest in CC8 agonism as a potential therapeutic strategy. Triazolyl substituted phenoxybenzylpiperidine analogues have been previously synthesized and were shown to act as CCR8 agonists although with moderate potency. In this study, their structure-activity relationship was expanded by the synthesis of a series of 1,4-disubstituted 1,2,3-triazole analogues with structural modifications of the phenoxybenzylpiperidinyl and phenyl moieties. Evaluation in cell-based assays revealed potent and selective CCR8 agonistic activity of several derivatives. Molecular docking was applied to shed a light on their binding mode. Despite its suboptimal pharmacokinetic behaviour, a representative CCR8 Agonist from this series, showed activity in a humanized model mimicking xenogeneic graft-versus-host disease.