Abstract
High throughput screening led to the identification of nicotinamide derivative 2 as a structurally novel mGluR5 antagonist. Optimization of the modular scaffold led to the discovery of 16m, a compound with high affinity for mGluR5 and excellent selectivity over other glutamate receptors. Compound 16m exhibits a favorable PK profile in rats, robust anxiolytic-like effects in three different animal models of fear and anxiety, as well as a good PK/PD correlation.
Copyright 2009 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Amides / chemical synthesis
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Amides / chemistry*
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Amides / pharmacokinetics
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Aminopyridines / chemical synthesis
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Aminopyridines / chemistry*
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Aminopyridines / pharmacokinetics
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Animals
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Anti-Anxiety Agents / chemical synthesis
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Anti-Anxiety Agents / chemistry*
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Anti-Anxiety Agents / pharmacokinetics
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Humans
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Microsomes, Liver / metabolism
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Peptides / chemistry*
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Rats
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Rats, Sprague-Dawley
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate / antagonists & inhibitors*
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Receptors, Metabotropic Glutamate / metabolism
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Structure-Activity Relationship
Substances
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Amides
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Aminopyridines
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Anti-Anxiety Agents
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GRM5 protein, human
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Grm5 protein, rat
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Peptides
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate