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1,3,5‐Trisubstituted Pyrazoles as Potent Negative Allosteric Modulators of the mGlu 2/3 Receptors
Author(s) -
Van Gool Michiel,
Alonso De Diego Sergio A.,
Delgado Oscar,
Trabanco Andrés A.,
Jourdan Fabrice,
Macdonald Gregor J.,
Somers Marijke,
Ver Donck Luc
Publication year - 2017
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700101
Subject(s) - potency , allosteric regulation , allosteric modulator , metabotropic glutamate receptor , metabotropic receptor , glutamate receptor , metabotropic glutamate receptor 2 , in vitro , pharmacology , in vivo , receptor , chemistry , biochemistry , biology , microbiology and biotechnology
The metabotropic glutamate subtype 2 (mGlu 2 ) receptor is a presynaptic membrane receptor distributed widely in brain that provides feedback inhibitory control of glutamate release. Inhibition of the mGlu 2 receptor function with a negative allosteric modulator (NAM) enhances activity‐dependent glutamate release, which may be of therapeutic benefit for the treatment of neurological and psychiatric disorders. An attractive pyrazole hit was identified after a high‐throughput screening (HTS) campaign. The evolution of this hit is described by structure–activity relationship (SAR) studies on specific parts of the molecule. From near micromolar potency we could obtain compounds with single‐digit nanomolar activity in the mGlu 2 NAM GTPγS assay. In addition to SAR on in vitro potency, a more detailed overview is given with a specific set of compounds on the excellent agreement between in vitro potency, free brain concentration, and ex vivo mGlu 2 receptor occupancy. Finally, to obtain improved drug‐like compounds, plans for future research are suggested toward increasing free brain concentration while maintaining high in vitro potency.