Imidazole-derived agonists for the neurotensin 1 receptor

  • Bioorg Med Chem Lett. 2014 Jan 1;24(1):262-7. doi: 10.1016/j.bmcl.2013.11.026.
Paul M Hershberger  1 ,  Michael P Hedrick  2 ,  Satyamaheshwar Peddibhotla  3 ,  Arianna Mangravita-Novo  3 ,  Palak Gosalia  2 ,  Yujie Li  2 ,  Wilson Gray  2 ,  Michael Vicchiarelli  3 ,  Layton H Smith  3 ,  Thomas D Y Chung  2 ,  James B Thomas  4 ,  Marc G Caron  5 ,  Anthony B Pinkerton  2 ,  Lawrence S Barak  5 ,  Gregory P Roth  3
Affiliations
  • 1. Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA. Electronic address: [email protected].
  • 2. Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
  • 3. Conrad Prebys Center for Chemical Genomics at Sanford-Burnham Medical Research Institute, Orlando, FL 32827, USA.
  • 4. RTI International, 3040 E Cornwallis Road, Durham, NC 27709, USA.
  • 5. Duke University Medical Center, Durham, NC 27710, USA.
PMID: 24332089 DOI: 10.1016/j.bmcl.2013.11.026
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 EC50 of 2.0-4.1μM against NTR1. Compound 1 also showed good activity in a CA mobilization FLIPR assay (93% efficacy at 298nM), consistent with it functioning via the Gq 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.

Keywords
Agonist; Imidazole; Methamphetamine; Neurotensin 1.