Abstract
Optimization of HTS hit 1 for NPY Y5 receptor binding affinity, CYP450 inhibition, solubility and metabolic stability led to the identification of some orally available oxygen-linker derivatives for in vivo study. Among them, derivative 4i inhibited food intake induced by the NPY Y5 selective agonist, and chronic oral administration of 4i in DIO mice caused a dose-dependent reduction of body weight gain.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Administration, Oral
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Animals
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Anti-Obesity Agents / chemistry*
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Anti-Obesity Agents / pharmacokinetics
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Anti-Obesity Agents / therapeutic use
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Benzimidazoles / chemistry*
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Benzimidazoles / pharmacokinetics
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Benzimidazoles / pharmacology
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Benzimidazoles / therapeutic use
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Cytochrome P-450 Enzyme Inhibitors
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Cytochrome P-450 Enzyme System / metabolism
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Half-Life
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Mice
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Obesity / drug therapy
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Rats
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Receptors, Neuropeptide Y / agonists*
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Receptors, Neuropeptide Y / metabolism
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Structure-Activity Relationship
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Sulfones / chemistry*
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Sulfones / pharmacology
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Sulfones / therapeutic use
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Weight Gain / drug effects
Substances
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Anti-Obesity Agents
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Benzimidazoles
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Cytochrome P-450 Enzyme Inhibitors
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Receptors, Neuropeptide Y
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Sulfones
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neuropeptide Y5 receptor
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Cytochrome P-450 Enzyme System
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benzimidazole