Abstract
The discovery and optimization of novel pyrrolo[3,4-b]pyridin-7(6H)-one MCH-R1 antagonists are described. A systematic SAR study probing the effects of aryl-, benzyl- and arylthio-substituents at the 2-position of the pyrrolo[3,4-b]pyridin-7(6H)-ones led to identification of the 2-[(4-fluorophenyl)thio] derivative 7b as a highly potent MCH-R1 antagonist. This compound also has favorable pharmacokinetic properties along with a high metabolic stability and a minimal impact on CYP isoforms and hERG.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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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 / therapeutic use
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Half-Life
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Humans
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Obesity / drug therapy
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Protein Binding
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Pyridines / chemical synthesis*
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Pyridines / chemistry
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Pyridines / pharmacokinetics
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Pyrimidines / chemistry*
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Pyrimidines / metabolism
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Pyrimidines / pharmacokinetics
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Pyrroles / chemistry*
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Pyrroles / metabolism
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Pyrroles / pharmacokinetics
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Pyrrolidinones / chemical synthesis*
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Pyrrolidinones / chemistry
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Pyrrolidinones / pharmacokinetics
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Rats
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Receptors, Pituitary Hormone / antagonists & inhibitors*
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Receptors, Pituitary Hormone / metabolism
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Structure-Activity Relationship
Substances
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Anti-Obesity Agents
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Pyridines
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Pyrimidines
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Pyrroles
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Pyrrolidinones
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Receptors, Pituitary Hormone
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melanin-concentrating hormone receptor
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pyrrolopyrimidine