Abstract
A range of heterocycle fused azepines were synthesized in order to find a CNS penetrant, selective 5-HT(2C) agonist for the treatment of incontinence. The pyridazo-azepines such as compound 11 were shown to be potent 5-HT(2C) agonists and have potential for CNS penetration and good in vitro ADME properties but lacked selectivity against 5-HT(2B). Fusing a further heterocycle gave the selective triazolopyrimido-azepines. An example of this series, compound 36, was shown to be potent, selective, metabolically stable in vitro and efficacious in an in vivo model of stress urinary incontinence.
MeSH terms
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Animals
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Azepines / chemical synthesis
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Azepines / chemistry*
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Azepines / pharmacology
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CHO Cells
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Cell Line
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Cricetinae
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Cricetulus
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Dogs
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Drug Discovery
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Humans
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Pyrimidines / chemical synthesis
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Pyrimidines / chemistry*
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Pyrimidines / pharmacology
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Receptor, Serotonin, 5-HT2B / metabolism
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Receptor, Serotonin, 5-HT2C / metabolism
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Recombinant Proteins / agonists
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Recombinant Proteins / metabolism
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Serotonin 5-HT2 Receptor Agonists*
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Serotonin Receptor Agonists / chemical synthesis
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Serotonin Receptor Agonists / chemistry*
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Serotonin Receptor Agonists / pharmacology
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Transfection
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Urinary Incontinence / drug therapy*
Substances
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Azepines
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Pyrimidines
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Receptor, Serotonin, 5-HT2B
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Receptor, Serotonin, 5-HT2C
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Recombinant Proteins
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Serotonin 5-HT2 Receptor Agonists
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Serotonin Receptor Agonists