Potent inhibitors of dipeptidyl peptidase IV and their mechanisms of inhibition

Dipeptidyl peptidase IV (DP IV) is a proline specific serine protease which cleaves Xaa-Pro-dipeptides from the N-terminus of longer peptides. A series of product analogous amino acid amides containing different structure modifications like substitution of a ring atom, variation of the ring size and...

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Bibliographic Details
Published inAdvances in experimental medicine and biology Vol. 477; p. 117
Main Authors Stöckel-Maschek, A, Stiebitz, B, Born, I, Faust, J, Mögelin, W, Neubert, K
Format Journal Article
LanguageEnglish
Published United States 2000
Subjects
Animals
Binding, Competitive
Dipeptides - metabolism
Dipeptidyl Peptidase 4 - chemistry
Dipeptidyl Peptidase 4 - drug effects
Dipeptidyl Peptidase 4 - metabolism
Kinetics
Molecular Structure
Protein Binding
Pyrrolidines - chemistry
Pyrrolidines - pharmacology
Serine Proteinase Inhibitors - chemistry
Serine Proteinase Inhibitors - pharmacology
Structure-Activity Relationship
Swine
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Summary:Dipeptidyl peptidase IV (DP IV) is a proline specific serine protease which cleaves Xaa-Pro-dipeptides from the N-terminus of longer peptides. A series of product analogous amino acid amides containing different structure modifications like substitution of a ring atom, variation of the ring size and/or the introduction of a thioxo amide bond, phosphono amide bond or reduced amide bond were done to characterize these compounds as inhibitors of DP IV. These compounds are mostly classical reversible inhibitors of DP IV. In contrast amino acyl-2-cyanopyrrolidides inhibit DP IV according to a slow-binding mechanism with inhibition constants in the nanomolare range. On the other hand, diaryl dipeptide phosphonates inhibit irreversibly. In conclusion, this work shows, that the mechanism of inhibition of DP IV depends on the structure of the investigated compounds.
ISSN:0065-2598