Identification of a Novel Spiropiperidine Opioid Receptor-like 1 Antagonist Class by a Focused Library Approach Featuring 3D-Pharmacophore Similarity

Abstract

A focused library approach identifying novel leads to develop a potent ORL1 antagonist is described. Beginning from a compound identified by random screening, an exploratory library that exhibited a diverse display of pharmacophores was designed. After evaluating ORL1 antagonistic activity, a highly focused library was designed based on 3D-pharmacophore similarity to known actives. A novel D-proline amide class was identified in this library and was found to possess potent ORL1 antagonistic activity.