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

Matthew D Hill; Haiquan Fang; Jeffrey M Brown; Thaddeus Molski; Amy Easton; Xiaojun Han; Regina Miller; Melissa Hill-Drzewi; Lizbeth Gallagher; Michele Matchett; Michael Gulianello; Anand Balakrishnan; Robert L Bertekap; Kenneth S Santone; Valerie J Whiterock; Xiaoliang Zhuo; Joanne J Bronson; John E Macor; Andrew P Degnan

doi:10.1021/acsmedchemlett.6b00292

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. eCollection 2016 Dec 8.

Authors

Matthew D Hill¹, Haiquan Fang¹, Jeffrey M Brown¹, Thaddeus Molski¹, Amy Easton¹, Xiaojun Han¹, Regina Miller¹, Melissa Hill-Drzewi¹, Lizbeth Gallagher¹, Michele Matchett¹, Michael Gulianello¹, Anand Balakrishnan¹, Robert L Bertekap¹, Kenneth S Santone¹, Valerie J Whiterock¹, Xiaoliang Zhuo¹, Joanne J Bronson¹, John E Macor¹, Andrew P Degnan¹

Affiliation

¹ Research and Development, Bristol-Myers Squibb , 5 Research Parkway, Wallingford, Connecticut 06492-7660, United States.

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.