title: Development of 1H-Pyrazolo[3,4-b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators.
abstract: The metabotropic glutamate receptor 5 (mGluR5) is an attractive target for the treatment of schizophrenia due to its role in regulating glutamatergic signaling in association with theN-methyl-d-aspartate receptor (NMDAR). We describe the synthesis of 1H-pyrazolo[3,4-b]pyridines and their utility as mGluR5 positive allosteric modulators (PAMs) without inherent agonist activity. A facile and convergent synthetic route provided access to a structurally diverse set of analogues that contain neither the aryl-acetylene-aryl nor aryl-methyleneoxy-aryl elements, the predominant structural motifs described in the literature. Binding studies suggest that members of our new chemotype do not engage the receptor at the MPEP and CPPHA mGluR5 allosteric sites. SAR studies culminated in the first non-MPEP site PAM, 1H-pyrazolo[3,4-b]pyridine31(BMT-145027), to improve cognition in a preclinical rodent model of learning and memory.
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Hill
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Haiquan
authors.initials: H
authors.lastname: Fang
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Brown
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Thaddeus
authors.initials: T
authors.lastname: Molski
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Amy
authors.initials: A
authors.lastname: Easton
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Xiaojun
authors.initials: X
authors.lastname: Han
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Regina
authors.initials: R
authors.lastname: Miller
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Melissa
authors.initials: M
authors.lastname: Hill-Drzewi
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Lizbeth
authors.initials: L
authors.lastname: Gallagher
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Michele
authors.initials: M
authors.lastname: Matchett
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Michael
authors.initials: M
authors.lastname: Gulianello
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Anand
authors.initials: A
authors.lastname: Balakrishnan
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Bertekap
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Santone
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Whiterock
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Xiaoliang
authors.initials: X
authors.lastname: Zhuo
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Joanne J
authors.initials: JJ
authors.lastname: Bronson
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: John E
authors.initials: JE
authors.lastname: Macor
authors.affiliation: Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
authors.forename: Andrew P
authors.initials: AP
authors.lastname: Degnan
keywords: glutamate; mGluR5; novel object recognition; positive allosteric modulator; schizophrenia