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

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

  • ACS Med Chem Lett. 2016 Oct 3;7(12):1082-1086. doi: 10.1021/acsmedchemlett.6b00292.
Matthew D Hill 1,  Haiquan Fang 1,  Jeffrey M Brown 1,  Thaddeus Molski 1,  Amy Easton 1,  Xiaojun Han 1,  Regina Miller 1,  Melissa Hill-Drzewi 1,  Lizbeth Gallagher 1,  Michele Matchett 1,  Michael Gulianello 1,  Anand Balakrishnan 1,  Robert L Bertekap 1,  Kenneth S Santone 1,  Valerie J Whiterock 1,  Xiaoliang Zhuo 1,  Joanne J Bronson 1,  John E Macor 1,  Andrew P Degnan 1
Affiliations

Affiliation

  • 1 Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.
PMID: 27994742 DOI: 10.1021/acsmedchemlett.6b00292
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.

Keywords

glutamate; mGluR5; novel object recognition; positive allosteric modulator; schizophrenia.

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