Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5.
Basic Information
ID: ALA3804767
Journal: ACS Med Chem Lett
Title: Discovery and Preclinical Evaluation of BMS-955829, a Potent Positive Allosteric Modulator of mGluR5.
Authors: Yang F, Snyder LB, Balakrishnan A, Brown JM, Sivarao DV, Easton A, Fernandes A, Gulianello M, Hanumegowda UM, Huang H, Huang Y, Jones KM, Li YW, Matchett M, Mattson G, Miller R, Santone KS, Senapati A, Shields EE, Simutis FJ, Westphal R, Whiterock VJ, Bronson JJ, Macor JE, Degnan AP.
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.
CiteXplore: 26985317
DOI: 10.1021/acsmedchemlett.5b00450
Patent ID: ┄