Abstract
The discovery of a novel class of peripheral tryptophan hydroxylase (TPH) inhibitors is described. This class of TPH inhibitors exhibits excellent potency in in vitro biochemical and cell-based assays, and it selectively reduces serotonin levels in the murine intestine after oral administration without affecting levels in the brain. These TPH1 inhibitors may provide novel treatments for gastrointestinal disorders associated with dysregulation of the serotonergic system, such as chemotherapy-induced emesis and irritable bowel syndrome.
MeSH terms
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Animals
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Cell Line
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Cross-Linking Reagents / chemistry
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Crystallography, X-Ray
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Enzyme Inhibitors / chemical synthesis
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Enzyme Inhibitors / chemistry*
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Enzyme Inhibitors / pharmacology
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Enzyme Inhibitors / therapeutic use*
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Gastrointestinal Diseases / drug therapy*
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Gastrointestinal Diseases / enzymology*
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Humans
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Inhibitory Concentration 50
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Mice
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Models, Molecular
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Molecular Structure
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Rats
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Serotonin / metabolism*
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Structure-Activity Relationship
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Tryptophan Hydroxylase / antagonists & inhibitors*
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Tryptophan Hydroxylase / chemistry
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Tryptophan Hydroxylase / metabolism
Substances
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Cross-Linking Reagents
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Enzyme Inhibitors
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Serotonin
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Tryptophan Hydroxylase