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Development of 1H-Pyrazolo[3,4-b]pyridines as Metabotropic Glutamate Receptor 5 Positive Allosteric Modulators.

Authors
  • Hill, Matthew D1
  • Fang, Haiquan1
  • Brown, Jeffrey M1
  • Molski, Thaddeus1
  • Easton, Amy1
  • Han, Xiaojun1
  • Miller, Regina1
  • Hill-Drzewi, Melissa1
  • Gallagher, Lizbeth1
  • Matchett, Michele1
  • Gulianello, Michael1
  • Balakrishnan, Anand1
  • Bertekap, Robert L1
  • Santone, Kenneth S1
  • Whiterock, Valerie J1
  • Zhuo, Xiaoliang1
  • Bronson, Joanne J1
  • Macor, John E1
  • Degnan, Andrew P1
  • 1 Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States. , (United States)
Type
Published Article
Journal
ACS Medicinal Chemistry Letters
Publisher
American Chemical Society
Publication Date
Dec 08, 2016
Volume
7
Issue
12
Pages
1082–1086
Identifiers
PMID: 27994742
Source
Medline
Keywords
Language
English
License
Unknown

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 the N-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]pyridine 31 (BMT-145027), to improve cognition in a preclinical rodent model of learning and memory.

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