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Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5.

Authors
  • Yang, Fukang1
  • Snyder, Lawrence B1
  • Balakrishnan, Anand1
  • Brown, Jeffrey M1
  • Sivarao, Digavalli V1
  • Easton, Amy1
  • Fernandes, Alda1
  • Gulianello, Michael1
  • Hanumegowda, Umesh M1
  • Huang, Hong1
  • Huang, Yanling1
  • Jones, Kelli M1
  • Li, Yu-Wen1
  • Matchett, Michele1
  • Mattson, Gail1
  • Miller, Regina1
  • Santone, Kenneth S1
  • Senapati, Arun1
  • Shields, Eric E1
  • Simutis, Frank J1
  • And 5 more
  • 1 Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States. , (United States)
Type
Published Article
Journal
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society
Publication Date
Mar 10, 2016
Volume
7
Issue
3
Pages
289–293
Identifiers
DOI: 10.1021/acsmedchemlett.5b00450
PMID: 26985317
Source
Medline
Keywords
License
Unknown

Abstract

Positive allosteric modulators (PAMs) of the metabotropic glutamate receptor subtype 5 (mGluR5) are of interest due to their potential therapeutic utility in schizophrenia and other cognitive disorders. Herein we describe the discovery and optimization of a novel oxazolidinone-based chemotype to identify BMS-955829 (4), a compound with high functional PAM potency, excellent mGluR5 binding affinity, low glutamate fold shift, and high selectivity for the mGluR5 subtype. The low fold shift and absence of agonist activity proved critical in the identification of a molecule with an acceptable preclinical safety profile. Despite its low fold shift, 4 retained efficacy in set shifting and novel object recognition models in rodents.

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