Abstract
Obesity is a global epidemic associated with multiple severe diseases. Several pharmacotherapies have been investigated including the melanin concentrating hormone (MCH) and its receptor 1. The development of MCHR1 antagonists are described with a specific perspective on different chemotypes investigated in efforts to overcome hERG liabilities while having orally active, potent and selective compounds with sufficient brain penetration. A chemometric comparison of ∼2000 diverse MCHR1 and ∼1000 diverse hERG ligands underline the structural similarities. A binding pocket analysis of a MCHR1 model and recent X-ray structures of GPCRs invoked in selectivity issues indicate a way to support future drug design.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Anti-Obesity Agents / chemistry
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Anti-Obesity Agents / pharmacology*
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Anti-Obesity Agents / therapeutic use
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Biphenyl Compounds / chemistry
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Biphenyl Compounds / pharmacology*
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Biphenyl Compounds / therapeutic use
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Crystallography, X-Ray
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Drug Design
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors
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Humans
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Models, Molecular
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Molecular Structure
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Naphthalenes / chemistry
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Naphthalenes / pharmacology*
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Naphthalenes / therapeutic use
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Obesity / drug therapy*
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Piperidines / chemistry
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Piperidines / pharmacology*
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Piperidines / therapeutic use
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Pyrimidines / chemistry
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Pyrimidines / pharmacology*
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Pyrimidines / therapeutic use
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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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Biphenyl Compounds
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Ether-A-Go-Go Potassium Channels
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MCHR1 protein, human
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Naphthalenes
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Piperidines
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Pyrimidines
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Receptors, Somatostatin
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SNAP7941
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T-226296