title: Difluorocyclobutylacetylenes as positive allosteric modulators of mGluR5 with reduced bioactivation potential.
abstract: Schizophrenia is a serious illness that affects millions of patients and has been associated with N-methyl-d-aspartate receptor (NMDAR) hypofunction. It has been demonstrated that activation of metabotropic glutamate receptor 5 (mGluR5) enhances NMDA receptor function, suggesting the potential utility of mGluR5 positive allosteric modulators (PAMs) in the treatment of schizophrenia. Herein we describe the optimization of an mGluR5 PAM by replacement of a phenyl with aliphatic heterocycles and carbocycles as a strategy to reduce bioactivation in a biaryl acetylene chemotype. Replacement with a difluorocyclobutane followed by further optimization culminated in the identification of compound 32, a low fold shift PAM with reduced bioactivation potential. Compound 32 demonstrated favorable brain uptake and robust efficacy in mouse novel object recognition (NOR) at low doses.
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States. Electronic address: andrew.degnan@bms.com.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Darrell
authors.initials: D
authors.lastname: Maxwell
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Anand
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Gulianello
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Umesh
authors.initials: U
authors.lastname: Hanumegowda
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hill-Drzewi
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Regina
authors.initials: R
authors.lastname: Miller
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Santone
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Arun
authors.initials: A
authors.lastname: Senapati
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Eric E
authors.initials: EE
authors.lastname: Shields
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Digavalli V
authors.initials: DV
authors.lastname: Sivarao
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Westphal
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Whiterock
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zhuo
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Bristol-Myers Squibb Co., Research and Development, 5 Research Parkway, Wallingford, CT 06492, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D006801:Humans; D051379:Mice; D015394:Molecular Structure; D023303:Oxazolidinones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5 / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: C000620858:5-(2,3-dichlorophenyl)-4-(5-((3,3-difluorocyclobutyl)ethynyl)pyridin-3-yl)oxazolidin-2-one; D023303:Oxazolidinones; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5
keywords: Bioactivation; Cognition; PAMs; Schizophrenia; mGluR5