Optimization of benzimidazole series as opioid receptor-like 1 (ORL1) antagonists: SAR study directed toward improvement of selectivity over hERG activity

A structure–activity relationship (SAR) study on the benzimidazole series of opioid receptor-like 1 (ORL1) antagonists related to 1 is described. Optimization of 1 by introduction of a hydrophilic substituent into the thioether part resulted in identification of potent ORL1 antagonists with high selectivity over binding affinity for hERG and other opioid receptors.

Optimization of benzimidazole series as ORL1 antagonists is reported. Compound 7h exhibited potent ORL1 activity with high selectivity over binding affinity for hERG.Figure optionsDownload as PowerPoint slide