Abstract
Optimization of the lead 2a led to the identification of a novel diarylketoxime class of melanin-concentrating hormone 1 receptor (MCH-1R) antagonists. Our focus was directed toward improvement of hERG activity and metabolic stability. The representative derivative 4b showed potent and dose-dependent body weight reduction in diet-induced obese (DIO) C57BL/6J mice after oral administration. The synthesis and structure-activity relationships of the novel diarylketoxime MCH-1R antagonists are described.
MeSH terms
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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 / pharmacology
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Anti-Obesity Agents / therapeutic use*
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Body Weight / drug effects
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Ether-A-Go-Go Potassium Channels / metabolism*
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Humans
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Mice
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Mice, Inbred C57BL
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Obesity / drug therapy*
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Oximes / chemistry*
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Oximes / pharmacokinetics
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Oximes / pharmacology
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Oximes / therapeutic use*
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Protein Binding
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Receptors, Somatostatin / antagonists & inhibitors*
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Receptors, Somatostatin / metabolism
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Structure-Activity Relationship
Substances
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Anti-Obesity Agents
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Ether-A-Go-Go Potassium Channels
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MCHR1 protein, human
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Mchr1 protein, mouse
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Oximes
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Receptors, Somatostatin