Abstract
Optimization of a high-throughput screening hit against melanin-concentrating hormone receptor 1 (MCHr1) led to the discovery of 2-(4-benzyloxy-phenyl)-N-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-6-yl]acetamide (7a). This compound was found to be a high-affinity ligand for MCHr1 and a potent inhibitor of MCH-mediated Ca(2+) release, showed good plasma and CNS exposure upon oral dosing in diet-induced obese mice, and is the first reported MCHr1 antagonist that is efficacious upon oral dosing in a chronic model of weight loss.
MeSH terms
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Acetamides / chemical synthesis*
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Acetamides / pharmacokinetics
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Acetamides / pharmacology
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Administration, Oral
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Animals
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Anti-Obesity Agents / chemical synthesis*
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Anti-Obesity Agents / pharmacokinetics
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Anti-Obesity Agents / pharmacology
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Binding, Competitive
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Brain / metabolism
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Calcium / metabolism
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Chronic Disease
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Indazoles / chemical synthesis*
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Indazoles / pharmacokinetics
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Indazoles / pharmacology
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Mice
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Obesity / drug therapy*
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology
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Radioligand Assay
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Receptors, Somatostatin / antagonists & inhibitors*
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Structure-Activity Relationship
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Tissue Distribution
Substances
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2-(4-benzyloxyphenyl)-N-(1-(2-pyrrolidin-1-ylethyl)-1H-indazol-6-yl)acetamide
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Acetamides
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Anti-Obesity Agents
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Indazoles
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Mchr1 protein, mouse
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Pyrrolidines
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Receptors, Somatostatin
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Calcium