Abstract
Modifications of DPP-4 inhibitor 5, that was discovered by structure based design, are described and structure-activity relationships discussed. With analogue 7k one of the most potent non-covalent inhibitors of DPP-4 reported to date (IC(50)=0.38nM) was discovered. X-ray structure of inhibitor 7k bound to DPP-4 revealed a hydrogen bonding interaction with Q553. First successful efforts in balancing overall properties, as demonstrated by improved metabolic stability, highlight the potential of this series.
MeSH terms
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Amides / chemical synthesis*
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Amides / pharmacology
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Aminobutyrates / chemistry*
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Animals
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Chemistry, Pharmaceutical / methods
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Crystallography, X-Ray / methods
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Dipeptidyl-Peptidase IV Inhibitors* / chemical synthesis*
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Dipeptidyl-Peptidase IV Inhibitors* / pharmacology
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Drug Design
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Glucagon-Like Peptide 1 / antagonists & inhibitors
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Hydrogen Bonding
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Inhibitory Concentration 50
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Microsomes, Liver / drug effects*
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Microsomes, Liver / metabolism
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Rats
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Structure-Activity Relationship
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Sulfonamides / chemical synthesis*
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Sulfonamides / pharmacology
Substances
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Amides
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Aminobutyrates
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Dipeptidyl-Peptidase IV Inhibitors
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Sulfonamides
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2-amino-4-phenylbutyric acid
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Glucagon-Like Peptide 1