title: Oxazolidinone-based allosteric modulators of mGluR5: Defining molecular switches to create a pharmacological tool box.
abstract: Herein we describe the structure activity relationships uncovered in the pursuit of an mGluR5 positive allosteric modulator (PAM) for the treatment of schizophrenia. It was discovered that certain modifications of an oxazolidinone-based chemotype afforded predictable changes in the pharmacological profile to give analogs with a wide range of functional activities. The discovery of potent silent allosteric modulators (SAMs) allowed interrogation of the mechanism-based liabilities associated with mGluR5 activation and drove our medicinal chemistry effort toward the discovery of low efficacy (fold shift) PAMs devoid of agonist activity. This work resulted in the identification of dipyridyl 22 (BMS-952048), a compound with a favorable free fraction, efficacy in a rodent-based cognition model, and low potential for convulsions in mouse.
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Hong
authors: H
authors: Huang
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Andrew P
authors: AP
authors: Degnan
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Anand
authors: A
authors: Balakrishnan
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Amy
authors: A
authors: Easton
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Michael
authors: M
authors: Gulianello
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Yanling
authors: Y
authors: Huang
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Michele
authors: M
authors: Matchett
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Gail
authors: G
authors: Mattson
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Regina
authors: R
authors: Miller
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Kenneth S
authors: KS
authors: Santone
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Arun
authors: A
authors: Senapati
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Eric E
authors: EE
authors: Shields
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Digavalli V
authors: DV
authors: Sivarao
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Lawrence B
authors: LB
authors: Snyder
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Ryan
authors: R
authors: Westphal
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Valerie J
authors: VJ
authors: Whiterock
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Fukang
authors: F
authors: Yang
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: Joanne J
authors: JJ
authors: Bronson
authors: Bristol-Myers Squibb Research & Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors: John E
authors: JE
authors: Macor
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D003292:Convulsants / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D023303:Oxazolidinones / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D003292:Convulsants; D023303:Oxazolidinones; D064529:Receptor, Metabotropic Glutamate 5
keywords: Cognition; Positive allosteric modulator; Schizophrenia; Silent allosteric modulator; mGlu5; mGluR5