Abstract
To find potent and selective inhibitors of dipeptidyl peptidase IV (DPP-IV), we synthesized a series of 2-cyanopyrrolidine with P2-site 4-substituted glutamic acid derivatives and tested their activities against DPP-IV, DPP8, and DPP-II. Analogues that incorporated a bulky substituent at the first carbon position of benzylamine or isoquinoline showed over 30-fold selectivity for DPP-IV over both DPP8 and DPP-II. From structure-activity relationship studies, we speculate that the S2 site of DPP8 might be similar to that of DPP-IV, while DPP-IV inhibitor with N-substituted glycine in the P2 site and/or with a moiety involving in hydrophobic interaction with the side chain of Phe357 might provide a better selectivity for DPP-IV over DPP8.
MeSH terms
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Adenosine Deaminase Inhibitors
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Binding Sites
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Dipeptidases / antagonists & inhibitors
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Dipeptidyl Peptidase 4
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / antagonists & inhibitors*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / pharmacology
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Glutamic Acid / analogs & derivatives*
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Glutamic Acid / chemical synthesis
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Glutamic Acid / pharmacology
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Glycoproteins / antagonists & inhibitors
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Humans
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Hydrophobic and Hydrophilic Interactions
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Inhibitory Concentration 50
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Models, Molecular
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Protein Binding
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Pyrrolidines / chemical synthesis
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Pyrrolidines / pharmacology
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Structure-Activity Relationship
Substances
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Adenosine Deaminase Inhibitors
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Enzyme Inhibitors
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Glycoproteins
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Pyrrolidines
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Glutamic Acid
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Dipeptidases
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Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
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dipeptidyl peptidase II
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DPP4 protein, human
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DPP8 protein, human
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Dipeptidyl Peptidase 4