Abstract
A series of (4-substituted prolyl)prolinenitriles were synthesized and evaluated as inhibitors of dipeptidylpeptidase IV (DPP-IV). Among those tested, the 4beta-[4-(hydroxyphenyl)prolyl]prolinenitriles showed a potent inhibitory activity with a long duration of action. Metabolic formation of the corresponding phenol glucuronates was found to contribute to their long duration of action. The activity profiles of the synthesized compounds are reported and structure-activity relationships are also presented.
MeSH terms
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Animals
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Area Under Curve
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Biological Availability
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Chromatography, Thin Layer
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Dipeptidyl-Peptidase IV Inhibitors*
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Drug Design
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Drug Stability
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Glucuronidase / chemistry
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Humans
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In Vitro Techniques
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Indicators and Reagents
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Male
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Microsomes, Liver / drug effects
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Microsomes, Liver / enzymology
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacokinetics
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Protease Inhibitors / pharmacology*
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Rats
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Rats, Sprague-Dawley
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Solutions
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Spectrometry, Mass, Fast Atom Bombardment
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Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
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Spectroscopy, Fourier Transform Infrared
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Structure-Activity Relationship
Substances
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Dipeptidyl-Peptidase IV Inhibitors
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Indicators and Reagents
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Protease Inhibitors
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Solutions
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Glucuronidase