Abstract
Based on the structures of NVP-DPP728 (1) and NVP-LAF237 (Vildagliptin, 2), three series of DPP-IV inhibitors were synthesized by linking substituted anilines, benzylamines, and phenylethylamines to (2S)-cyanopyrrolidine through a linker. More than 20 compounds were evaluated for their in vitro DPP-IV inhibition and selectivity profile over DPP-II, DPP8, and FAP enzymes. Selected compounds 5f and 7i showed in vivo plasma DPP-IV inhibition and inhibited glucose excursion in OGTT after oral administration in Wistar rats. Compound 5f (DPP-IV IC50 = 116 nM) has the potential for development as antidiabetic agent.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adamantane / analogs & derivatives
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Adenosine Deaminase Inhibitors*
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Amides / chemical synthesis
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Amides / pharmacology*
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Aniline Compounds
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Animals
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Benzylamines
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Diabetes Mellitus, Type 2 / drug therapy*
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Dipeptidyl Peptidase 4
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Dipeptidyl-Peptidase IV Inhibitors*
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Glycoproteins / antagonists & inhibitors*
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Inhibitory Concentration 50
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Nitriles
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Phenethylamines
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Pyrrolidines
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Rats
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Rats, Wistar
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Structure-Activity Relationship
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Vildagliptin
Substances
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1-(((2-((5-cyanopyridin-2-yl)amino)ethyl)amino)acetyl)-2-cyano-(S)-pyrrolidine
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Adenosine Deaminase Inhibitors
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Amides
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Aniline Compounds
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Benzylamines
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Dipeptidyl-Peptidase IV Inhibitors
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Glycoproteins
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Nitriles
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Phenethylamines
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Pyrrolidines
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butyramide
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DPP4 protein, human
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Dipeptidyl Peptidase 4
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Vildagliptin
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Adamantane