Design, synthesis, and structure–activity relationship study of a novel class of ORL1 receptor antagonists based on N-biarylmethyl spiropiperidine

Based on reported structures, a focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37, 1′-{[1-(3-chloropyridin-2-yl)-1H-pyrazol-4-yl]methyl}-3H-spiro[2-benzofuran-1,4′-piperidine], which exhibits excellent selectivity to μ, κ, and human ether-a-go-go related gene potassium channel.

Graphical abstractA focused library of biarylmethyl bound to the nitrogen atom of spiropiperidine was designed. Systematic modifications allowed the discovery of a synthetically feasible and highly potent ORL1 antagonist 37.Figure optionsDownload full-size imageDownload as PowerPoint slide