Discovery of β-Arrestin Biased, Orally Bioavailable, and CNS Penetrant Neurotensin Receptor 1 (NTR1) Allosteric Modulators

  • J Med Chem. 2019 Sep 12;62(17):8357-8363. doi: 10.1021/acs.jmedchem.9b00340.
Anthony B Pinkerton  1 ,  Satyamaheshwar Peddibhotla  1 ,  Fusayo Yamamoto  1 ,  Lauren M Slosky  2 ,  Yushi Bai  2 ,  Patrick Maloney  1 ,  Paul Hershberger  1 ,  Michael P Hedrick  1 ,  Bekhi Falter  1 ,  Robert J Ardecky  1 ,  Layton H Smith  1 ,  Thomas D Y Chung  1 ,  Michael R Jackson  1 ,  Marc G Caron  2 ,  Lawrence S Barak  2
Affiliations
  • 1. Conrad Prebys Center for Chemical Genomics , Sanford Burnham Prebys Medical Discovery Institute , La Jolla , California 92037 , United States.
  • 2. Duke University Medical Center , Durham , North Carolina 27709 , United States.
PMID: 31390201 DOI: 10.1021/acs.jmedchem.9b00340
Abstract

Neurotensin Receptor 1 (NTR1) is a G protein coupled receptor that is widely expressed throughout the central nervous system where it acts as a neuromodulator. Neurotensin receptors have been implicated in a wide variety of CNS disorders, but despite extensive efforts to develop small molecule ligands there are few reports of such compounds. Herein we describe the optimization of a quinazoline based lead to give 18 (SBI-553), a potent and brain penetrant NTR1 allosteric modulator.

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