Imidazole-derived agonists for the neurotensin 1 receptor.

Abstract A scaffold-hop program seeking full agonists of the neurotensin-1 (NTR1) receptor identified the probe molecule ML301 ( 1 ) and associated analogs, including its naphthyl analog ( 14 ) which exhibited similar properties. Compound 1 showed full agonist behavior (79–93%) with an EC 50 of 2.0–4.1 μM against NTR1. Compound 1 also showed good activity in a Ca mobilization FLIPR assay (93% efficacy at 298 nM), consistent with it functioning via the G q coupled pathway, and good selectivity relative to NTR2 and GPR35. In further profiling, 1 showed low potential for promiscuity and good overall pharmacological data. This report describes the discovery, synthesis, and SAR of 1 and associated analogs. Initial in vitro pharmacologic characterization is also presented.