Abstract
A ligand-based approach to identify potential starting points for a dual MCH-1R antagonist/DPPIV inhibitor medicinal chemistry program was undertaken. Potential ligand pairs were identified by analysis of MCH-1R and DPPIV in vitro data. A highly targeted synthetic effort lead to the discovery of pyridone 11, a dual MCH-1R antagonist/DPPIV inhibitor with selectivity over DPP8 and DPP9.
Copyright © 2012 Elsevier Ltd. All rights reserved.
MeSH terms
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Animals
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Anti-Obesity Agents / chemical synthesis*
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Anti-Obesity Agents / pharmacology
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CHO Cells
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Cricetinae
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Dipeptidases / antagonists & inhibitors
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Dipeptidases / metabolism
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Dipeptidyl Peptidase 4 / metabolism
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Dipeptidyl-Peptidase IV Inhibitors / chemical synthesis*
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Dipeptidyl-Peptidase IV Inhibitors / pharmacology
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / metabolism
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Drug Design
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacology
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Ligands
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Pyridones / chemical synthesis*
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Pyridones / pharmacology
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Receptors, Somatostatin / antagonists & inhibitors*
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Receptors, Somatostatin / metabolism
Substances
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Anti-Obesity Agents
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Dipeptidyl-Peptidase IV Inhibitors
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Hypoglycemic Agents
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Ligands
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MCHR1 protein, human
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Pyridones
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Receptors, Somatostatin
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Dipeptidases
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DPP9 protein, human
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
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DPP4 protein, human
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DPP8 protein, human
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Dipeptidyl Peptidase 4