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

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• 作者：Fukang Yang ; Lawrence B. Snyder ; Anand Balakrishnan ; Jeffrey M. Brown ; Digavalli V. Sivarao ; Amy Easton ; Alda Fernandes ; Michael Gulianello ; Umesh M. Hanumegowda ; Hong Huang ; Yanling Huang ; Kelli M. Jones ; Yu-Wen Li ; Michele Matchett ; Gail Mattson ; Regina Miller ; Kenneth S. Santone ; Arun Senapati ; Eric E. Shields ; Frank J. Simutis ; Ryan Westphal ; Valerie J. Whiterock ; Joanne J. Bronson ; John E. Macor ; Andrew P. Degnan
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：March 10, 2016
• 年：2016
• 卷：7
• 期：3
• 页码：289-293
• 全文大小：303K
• ISSN：1948-5875

文摘

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.