Abstract
An initial SAR study resulted in the identification of the novel, potent MCHR1 antagonist 2. After further profiling, compound 2 was discovered to be a potent inhibitor of the hERG potassium channel, which prevented its further development. Additional optimization of this structure resulted in the discovery of the potent MCHR1 antagonist 11 with a dramatically reduced hERG liability. The decrease in hERG activity was confirmed by several in vivo preclinical cardiovascular studies examining QT prolongation. This compound demonstrated good selectivity for MCHR1 and possessed good pharmacokinetic properties across preclinical species. Compound 11 was also efficacious in reducing body weight in two in vivo mouse models. This compound was selected for clinical evaluation and was given the code AMG 076.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Body Weight / drug effects
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Brain / drug effects
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Brain / metabolism
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Carbazoles / chemical synthesis
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Carbazoles / chemistry*
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Carbazoles / pharmacokinetics
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Cyclohexanecarboxylic Acids / chemical synthesis
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Cyclohexanecarboxylic Acids / chemistry*
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Cyclohexanecarboxylic Acids / pharmacokinetics
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Diet, High-Fat
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Dogs
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Drug Evaluation, Preclinical
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels / antagonists & inhibitors*
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Ether-A-Go-Go Potassium Channels / metabolism
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Female
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Rats
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Receptors, Pituitary Hormone / antagonists & inhibitors*
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Receptors, Pituitary Hormone / genetics
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Receptors, Pituitary Hormone / metabolism
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Structure-Activity Relationship
Substances
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Carbazoles
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Cyclohexanecarboxylic Acids
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ERG1 Potassium Channel
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Ether-A-Go-Go Potassium Channels
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Receptors, Pituitary Hormone
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melanin-concentrating hormone receptor