Abstract
Dipeptidyl peptidase-IV (DPP-IV) inhibitors are poised to be the next major drug class for the treatment of type 2 diabetes. Structure-activity studies of substitutions at the C5 position of the 2-cyanopyrrolidide warhead led to the discovery of potent inhibitors of DPP-IV that lack activity against DPP8 and DPP9. Further modification led to an extremely potent (Ki(DPP)(-)(IV) = 1.0 nM) and selective (Ki(DPP8) > 30 microM; Ki(DPP9) > 30 microM) clinical candidate, ABT-279, that is orally available, efficacious, and remarkably safe in preclinical safety studies.
MeSH terms
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Adenosine Deaminase / chemistry
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Adenosine Deaminase Inhibitors*
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Administration, Oral
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Animals
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Binding Sites
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Caco-2 Cells
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Crystallography, X-Ray
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Diabetes Mellitus, Type 2 / drug therapy
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Dipeptidyl Peptidase 4 / chemistry
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Dipeptidyl-Peptidase IV Inhibitors*
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Dogs
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Female
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Glucose Intolerance / drug therapy
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Glycoproteins / antagonists & inhibitors*
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Glycoproteins / chemistry
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology
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Macaca fascicularis
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Models, Molecular
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Molecular Structure
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Pyridines / chemical synthesis*
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Pyridines / pharmacokinetics
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Pyridines / pharmacology
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / pharmacokinetics
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Pyrrolidines / pharmacology
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Rats
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Rats, Sprague-Dawley
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Rats, Zucker
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Stereoisomerism
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Structure-Activity Relationship
Substances
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2-(4-((2-(2-cyano-5-ethynyl-1-pyrrolidinyl)-2-oxoethyl)amino)-4-methyl-1-piperidinyl)-4-pyridinecarboxylic acid
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Adenosine Deaminase Inhibitors
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Dipeptidyl-Peptidase IV Inhibitors
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Glycoproteins
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Hypoglycemic Agents
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Pyridines
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Pyrrolidines
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DPP4 protein, human
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Dipeptidyl Peptidase 4
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Adenosine Deaminase