Abstract
We report a series of potent and selective MC4R agonists based on spiroindane amide privileged structures for potential treatments of obesity. Among the synthetic methods used, Method C allows rapid synthesis of the analogs. The series of compounds can afford high potency on MC4R as well as good rodent pharmacokinetic profiles. Compound 1r (MK-0489) demonstrates MC4R mediated reduction of food intake and body weight in mouse models. Compound 1r is efficacious in 14-day diet-induced obese (DIO) rat models.
Copyright 2010 Elsevier Ltd. All rights reserved.
MeSH terms
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Amides / chemistry*
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Amides / pharmacokinetics
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Amides / therapeutic use
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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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Body Weight / drug effects
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Humans
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Mice
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Mice, Knockout
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Obesity / drug therapy*
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Pyrrolidines / chemistry*
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / therapeutic use
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Rats
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Rats, Sprague-Dawley
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Receptor, Melanocortin, Type 4 / agonists*
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Receptor, Melanocortin, Type 4 / metabolism
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Spiro Compounds / chemistry*
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Spiro Compounds / pharmacokinetics
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Spiro Compounds / therapeutic use
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Structure-Activity Relationship
Substances
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Amides
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Anti-Obesity Agents
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MC4R protein, human
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MK-0489
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Pyrrolidines
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Receptor, Melanocortin, Type 4
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Spiro Compounds