Abstract
In a search for GABAA alpha5 ligands that combine high subtype binding selectivity with a marked inverse agonism imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepines were identified as a promising class. A short tandem reaction allowed rapid access to this chemical series, thereby facilitating rapid SAR generation which guided the optimization process. Two compounds (10e and 11f) were found to be active in an in vivo paradigm for cognitive improvement.
MeSH terms
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Adjuvants, Anesthesia / pharmacology
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Animals
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Anticonvulsants / chemical synthesis
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Anticonvulsants / chemistry*
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Anticonvulsants / pharmacokinetics
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Benzodiazepines / chemical synthesis
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Benzodiazepines / chemistry*
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Benzodiazepines / pharmacokinetics
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Benzodiazepines / pharmacology
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Cell Line
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Cognition Disorders / drug therapy*
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Drug Inverse Agonism
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GABA-A Receptor Agonists
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Humans
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Memory, Short-Term / drug effects
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Microsomes, Liver / metabolism
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Rats
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Receptors, GABA-A / metabolism*
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Scopolamine / pharmacology
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Structure-Activity Relationship
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Triazoles / chemical synthesis
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Triazoles / chemistry*
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Triazoles / pharmacology
Substances
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Adjuvants, Anesthesia
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Anticonvulsants
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GABA-A Receptor Agonists
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Receptors, GABA-A
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Triazoles
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Benzodiazepines
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Scopolamine