Abstract
Dipeptidyl peptidase IV (DPP-IV) inhibitors are promising antidiabetic drugs, and several drugs are in the developmental stage. We previously reported that the introduction of fluorine to the 4-position of 2-cyanopyrrolidine enhanced the DPP-IV inhibitory effect. In the present report, we examined the structure-activity relationship (SAR) of 2-cyano-4-fluoropyrrolidine with N-substituted glycine at the 1-position. We report the identification of a potent and stable DPP-IV inhibitor (TS-021) with a long-term persistent plasma drug concentration and a potent antihyperglycemic activity.
MeSH terms
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Animals
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Blood Glucose / metabolism
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Cyanides / chemistry*
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Dipeptidyl Peptidase 4 / metabolism*
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Dipeptidyl-Peptidase IV Inhibitors*
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Fluorine Compounds / blood
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Fluorine Compounds / chemical synthesis
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Fluorine Compounds / chemistry
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Fluorine Compounds / pharmacology
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Insulin / blood
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Male
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Models, Molecular
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Molecular Structure
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Protease Inhibitors / blood
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / chemistry
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Protease Inhibitors / pharmacology*
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Pyrrolidines / blood
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology*
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Rats
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Structure-Activity Relationship
Substances
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Blood Glucose
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Cyanides
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Dipeptidyl-Peptidase IV Inhibitors
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Fluorine Compounds
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Insulin
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Protease Inhibitors
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Pyrrolidines
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Dipeptidyl Peptidase 4