title: 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.
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Fukang
authors.initials: F
authors.lastname: Yang
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Lawrence B
authors.initials: LB
authors.lastname: Snyder
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Anand
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Digavalli V
authors.initials: DV
authors.lastname: Sivarao
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Alda
authors.initials: A
authors.lastname: Fernandes
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Gulianello
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Umesh M
authors.initials: UM
authors.lastname: Hanumegowda
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Hong
authors.initials: H
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Yanling
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Kelli M
authors.initials: KM
authors.lastname: Jones
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Yu-Wen
authors.initials: YW
authors.lastname: Li
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Matchett
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Gail
authors.initials: G
authors.lastname: Mattson
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Regina
authors.initials: R
authors.lastname: Miller
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Santone
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Arun
authors.initials: A
authors.lastname: Senapati
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Shields
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Simutis
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Westphal
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Whiterock
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Bristol-Myers Squibb Research & Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
keywords: cognition; mGluR5; neurotoxicity; positive allosteric modulator; schizophrenia