Synthesis and biological evaluation of imidazole derivatives as novel NOP/ORL1 receptor antagonists: Exploration and optimization of alternative pyrazole structure

Nonpeptidic small-molecule NOP/ORL1 receptor antagonists with an imidazole scaffold were designed and synthesized to investigate alternatives to the pyrazole analog. Systematic modification of the original pyrazole lead [Kobayashi et al., Bioorg. Med. Chem. Lett.2009, 19, 3627; Kobayashi et al., Bioorg. Med. Chem. Lett., in press] to change the heterocyclic core, substituted side chain, and pendant functional group demonstrated that examining the structure–activity relationship for novel templates allowed the identification of potent, fully substituted 4-aminomethyl-1H-imidazole and 2-aminomethyl-1H-imidazole. These compounds exhibited excellent potency for ORL1 receptor with minimal P-gp efflux and/or reduced hERG affinity.

Graphical abstractA novel series of 4-aminomethyl- and 2-aminomethyl-1H-imidazolederivatives as nociceptin/orphanin FQ (N/OFQ) receptor antagonists was discovered.Figure optionsDownload full-size imageDownload as PowerPoint slide