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ACS Med Chem Lett. 2016 Jan 4;7(3):289-93. doi: 10.1021/acsmedchemlett.5b00450. eCollection 2016 Mar 10.

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

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1
Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.

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.

KEYWORDS:

cognition; mGluR5; neurotoxicity; positive allosteric modulator; schizophrenia

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