Synthesis and Evaluation of Phenoxybenzylpiperidinyl Analogues as Agonists of the Chemokine Receptor CCR8

The human chemokine receptor 8 (CCR8) received attention as target for the treatment of various autoimmune disorders. Phenoxybenzylpiperidine analogues are known to act as CCR8 agonists, although their structure-activity relationship (SAR) has been studied to a limited extent. In this study, the SAR of phenoxybenzylpiperidinyl analogues was explored in a systematic way by fusion or insertion of various heterocyclic groups on the piperidinyl ring, yielding a set of 21 novel phenoxybenzylpiperidinyl derivatives. Evaluation of potential CCR8 agonism in a cell-based assay revealed that the newly synthesized compounds were clearly less potent than the reference compounds, with the most potent analogues displaying an EC₅₀ value of 4 µM. Despite the fact that CCR8 agonism tolerated quite some structural variety on the piperidinyl moiety, this study demonstrated that the substitution pattern has some structural constraints for CCR8 agonism.