Abstract
A series of (2S)-cyanopyrrolidines with glutamic acid derivatives at the P2 site have been prepared and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV). The structure-activity relationships (SAR) led to the discovery of potent 3-substituted glutamic acid analogues, providing enhanced chemical stability and excellent selectivity over the closely related enzymes, DPP8, DPP-II and FAP. Compound 13f exhibited the ability to both significantly decrease the glucose excursion and inhibit plasma DPP-IV activity.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Administration, Oral
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Animals
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Dipeptidyl Peptidase 4 / blood
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Dipeptidyl Peptidase 4 / metabolism
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Dipeptidyl-Peptidase IV Inhibitors* / chemical synthesis*
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Dipeptidyl-Peptidase IV Inhibitors* / chemistry
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Dipeptidyl-Peptidase IV Inhibitors* / pharmacology
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Drug Design
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Glucose / metabolism
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Glutamic Acid / chemistry*
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Mice
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Mice, Inbred C57BL
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Structure-Activity Relationship
Substances
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Dipeptidyl-Peptidase IV Inhibitors
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Pyrrolidines
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Glutamic Acid
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Dipeptidyl Peptidase 4
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Glucose