Abstract
Structure-activity relationship studies on the phenyl ring of 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile 2 led to the discovery that small, non-hydrogen bond donor substituents at the 3-position led to a substantial increase in in vitro potency. In particular, 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (7) is a highly potent and selective mGlu5 receptor antagonist with good rat pharmacokinetics, brain penetration, and in vivo receptor occupancy.
MeSH terms
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Animals
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Brain / drug effects
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Brain / metabolism
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Excitatory Amino Acid Antagonists / chemical synthesis*
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Excitatory Amino Acid Antagonists / chemistry
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Excitatory Amino Acid Antagonists / pharmacology*
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Kinetics
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Mice
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Molecular Structure
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Nitriles / chemistry*
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Nitriles / pharmacology*
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Pyridines / chemistry*
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Rats
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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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Sensitivity and Specificity
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Structure-Activity Relationship
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Substrate Specificity
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Tetrazoles / chemistry*
Substances
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Excitatory Amino Acid Antagonists
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Nitriles
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Pyridines
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Receptor, Metabotropic Glutamate 5
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Receptors, Metabotropic Glutamate
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Tetrazoles
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benzonitrile