Dataset Information

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

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.

SUBMITTER: Yang F

PROVIDER: S-EPMC4789665 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature

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

Yang Fukang F Snyder Lawrence B LB Balakrishnan Anand A Brown Jeffrey M JM Sivarao Digavalli V DV Easton Amy A Fernandes Alda A Gulianello Michael M Hanumegowda Umesh M UM Huang Hong H Huang Yanling Y Jones Kelli M KM Li Yu-Wen YW Matchett Michele M Mattson Gail G Miller Regina R Santone Kenneth S KS Senapati Arun A Shields Eric E EE Simutis Frank J FJ Westphal Ryan R Whiterock Valerie J VJ Bronson Joanne J JJ Macor John E JE Degnan Andrew P AP

ACS medicinal chemistry letters 20160104 3

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 abse ...[more]

PMID: 26985317

Dataset Information

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

Publications

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

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