4-Piperidin-4-ylidenemethyl-benzamides as δ-opioid receptor agonists for CNS indications: Identifying clinical candidates

A series of 4-piperidin-4-ylidenemethyl-benzamide δ-opioid receptor agonists is described with an emphasis on balancing the potency, subtype selectivity and in vitro ADME and safety properties. The three sites impacting SAR are substitutions on the aryl group (R1), the piperidine nitrogen (R2), and the amide (R3). Each region contributes to the balance of properties for δ opioid activity and a desirable CNS profile, and two clinical candidates (20 and 24) were advanced.