Abstract
Dipeptidyl peptidase IV (DPP-IV) inhibition has the potential to become a valuable therapy for type 2 diabetes. The synthesis and structure-activity relationship of a new DPP-IV inhibitor class, N-substituted-glycyl-2-cyanopyrrolidines, are described as well as the path that led from clinical development compound 1-[2-[5-cyanopyridin-2-yl)amino]ethylamino]acetyl-2-cyano-(S)-pyrrolidine (NVP-DPP728, 8c) to its follow-up, 1-[[(3-hydroxy-1-adamantyl) amino]acetyl]-2-cyano-(S)-pyrrolidine (NVP-LAF237, 12j). The pharmacological profile of 12j in obese Zucker fa/fa rats along with pharmacokinetic profile comparison of 8c and 12j in normal cynomolgus monkeys is discussed. The results suggest that 12j is a potent, stable, selective DPP-IV inhibitor possessing excellent oral bioavailability and potent antihyperglycemic activity with potential for once-a-day administration.
MeSH terms
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Adamantane / analogs & derivatives
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Adamantane / chemical synthesis*
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Adamantane / chemistry
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Adamantane / pharmacology
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Administration, Oral
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Animals
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Biological Availability
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Blood Glucose / analysis
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Caco-2 Cells
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Crystallography, X-Ray
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Diabetes Mellitus, Type 2 / blood
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Diabetes Mellitus, Type 2 / drug therapy
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Dipeptidyl Peptidase 4 / metabolism*
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Enzyme Inhibitors / chemical synthesis*
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacology
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology
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Macaca fascicularis
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Male
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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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Rats, Zucker
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Structure-Activity Relationship
Substances
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1-(((3-hydroxy-1-adamantyl)amino)acetyl)-2-cyanopyrrolidine
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Blood Glucose
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Enzyme Inhibitors
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Hypoglycemic Agents
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Pyrrolidines
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Dipeptidyl Peptidase 4
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Adamantane