Abstract
The design, synthesis and SAR studies of novel 4,5,6,7-tetrahydropyrazolopyrazines as metabotropic glutamate receptor 5 (mGluR5) negative allosteric modulators (NAMs) are presented in this letter. Starting from a HTS hit compound (1, IC50=477nM), optimization of various groups led to the synthesis of a potent mGluR5 NAM (32, IC50=75nM) with excellent rat PK profile and good brain penetration. This compound produced oral antidepressant-like effect in a mouse tale suspension model (MED: 30mg/kg).
Keywords:
CNS drug discovery; Hit to lead studies; Negative allosteric modulator; mGluR5.
Copyright © 2016 Elsevier Ltd. All rights reserved.
MeSH terms
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Allosteric Regulation
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Animals
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Antidepressive Agents / chemical synthesis*
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Antidepressive Agents / metabolism
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Antidepressive Agents / therapeutic use
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Brain / metabolism
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Depression / drug therapy
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Disease Models, Animal
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Half-Life
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Humans
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Mice
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Microsomes, Liver / metabolism
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Protein Binding
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Pyrazines / chemical synthesis*
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Pyrazines / chemistry
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Pyrazines / pharmacokinetics
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Pyrazoles / chemical synthesis*
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Pyrazoles / chemistry
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Pyrazoles / pharmacokinetics
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Pyridines / chemical synthesis
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Pyridines / chemistry*
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Pyridines / pharmacokinetics
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Rats
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Receptor, Metabotropic Glutamate 5 / chemistry
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Receptor, Metabotropic Glutamate 5 / metabolism*
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Structure-Activity Relationship
Substances
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4,5,6,7-tetrahydropyrazolopyrazine
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Antidepressive Agents
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Pyrazines
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Pyrazoles
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Pyridines
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Receptor, Metabotropic Glutamate 5