Abstract
The incorporation of constrained tertiary amines into an existing class of N-benzyl-4-aminopiperidinyl chromone-based MCHr1 antagonists led to the identification of a series of chiral racemic compounds that displayed good to excellent functional potency, binding affinity, and selectivity over the hERG channel. Further separation of two distinct chiral racemic compounds into their corresponding pairs of enantiomers revealed a considerable selectivity for MCHr1 for one configuration, in addition to a striking difference in oral exposure between one pair of enantiomers in diet-induced obese mice. Oral administration of the most potent compound in this class in the same animal model led to significant reduction of fat mass in a semi-chronic model for weight loss.
MeSH terms
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Animals
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Anti-Obesity Agents / chemical synthesis
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Anti-Obesity Agents / pharmacology
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Appetite Depressants / pharmacology
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Body Weight / drug effects
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Brain / metabolism
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Cell Line
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Chromones / chemical synthesis*
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Chromones / pharmacology*
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Diet
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Dietary Fats
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Ether-A-Go-Go Potassium Channels / drug effects
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Fenfluramine / pharmacology
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Indicators and Reagents
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Mice
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Molecular Conformation
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Piperidines / chemical synthesis*
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Piperidines / pharmacology*
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Potassium Channel Blockers / chemical synthesis
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Potassium Channel Blockers / pharmacology
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Receptors, Somatostatin / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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7-fluorocarboxychromone-4-aminopiperidine
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Anti-Obesity Agents
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Appetite Depressants
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Chromones
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Dietary Fats
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Ether-A-Go-Go Potassium Channels
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Indicators and Reagents
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Mchr1 protein, mouse
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Piperidines
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Potassium Channel Blockers
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Receptors, Somatostatin
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Fenfluramine