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: phershberger@sanfordburnham.org.
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.

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