Eur J Med Chem. 2026 Jun 13. pii: S0223-5234(26)00509-X. [Epub ahead of print]316
119064
Qifei Li,
Wout Van Eynde,
Tom Van Loy,
Sandra Claes,
Adam Skarka,
Rudolf Andrys,
Kamil Musilek,
Emilie Pollenus,
Susan M Schlenner,
Dominique Schols,
Arnout Voet,
Wim Dehaen,
Steven De Jonghe.
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.
Keywords: 1,2,3-Triazole; Agonist; CCR8; Phenoxybenzylpiperidine