| Article ID | Journal | Published Year | Pages | File Type |
|---|---|---|---|---|
| 10592822 | Bioorganic & Medicinal Chemistry Letters | 2014 | 14 Pages |
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 2.0-4.1 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 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.
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Physical Sciences and Engineering
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Organic Chemistry
Authors
Paul M. Hershberger, Michael P. Hedrick, Satyamaheshwar Peddibhotla, Arianna Mangravita-Novo, Palak Gosalia, Yujie Li, Wilson Gray, Michael Vicchiarelli, Layton H. Smith, Thomas D.Y. Chung, James B. Thomas, Marc G. Caron, Anthony B. Pinkerton,