Abstract
4-(1-Benzo[1,3]dioxol-5-ylmethylpiperidine-4-ylmethyl)-6-chlorochromen-2-one (7) is a potent, orally bioavailable melanin concentrating hormone receptor 1 (MCHr1) antagonist that causes dose-dependent weight loss in diet-induced obese mice. Further evaluation of 7 in an anesthetized dog model of cardiovascular safety revealed adverse hemodynamic effects at a plasma concentration comparable to the minimally effective therapeutic concentration. These results highlight the need for scrutiny of the cardiovascular safety profile of MCHr1 antagonists.
MeSH terms
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Administration, Oral
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Animals
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Anti-Obesity Agents / adverse effects
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Anti-Obesity Agents / chemical synthesis
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Anti-Obesity Agents / pharmacology
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Biological Availability
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Blood Pressure / drug effects
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Brain / metabolism
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Cell Line, Tumor
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Coumarins / adverse effects
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Coumarins / chemical synthesis*
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Coumarins / pharmacology
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Dogs
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Eating / drug effects
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Energy Metabolism
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Humans
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Male
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Mice
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Mice, Obese
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Myocardial Contraction / drug effects
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Piperidines / adverse effects
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Piperidines / chemical synthesis*
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Piperidines / pharmacology
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Radioligand Assay
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Receptors, Pituitary Hormone / antagonists & inhibitors*
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Receptors, Somatostatin / antagonists & inhibitors*
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Structure-Activity Relationship
Substances
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Anti-Obesity Agents
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Coumarins
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Mchr1 protein, mouse
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Piperidines
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Receptors, Pituitary Hormone
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Receptors, Somatostatin
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melanin-concentrating hormone receptor