Abstract
A novel series of beta-amino amides incorporating fused heterocycles, i.e., triazolopiperazines, were synthesized and evaluated as inhibitors of dipeptidyl peptidase IV (DPP-IV) for the treatment of type 2 diabetes. (2R)-4-Oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)butan-2-amine (1) is a potent, orally active DPP-IV inhibitor (IC(50) = 18 nM) with excellent selectivity over other proline-selective peptidases, oral bioavailability in preclinical species, and in vivo efficacy in animal models. MK-0431, the phosphate salt of compound 1, was selected for development as a potential new treatment for type 2 diabetes.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Administration, Oral
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Animals
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Binding Sites
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Biochemistry / methods
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Blood Glucose / analysis
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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 4 / drug effects*
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Dipeptidyl Peptidase 4 / metabolism
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Dogs
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Dose-Response Relationship, Drug
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Drug Evaluation, Preclinical / methods
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / pharmacokinetics
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Enzyme Inhibitors / pharmacology*
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Glucagon / blood
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Glucagon / drug effects
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Glucagon-Like Peptide 1
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Glucose Tolerance Test
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacokinetics
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Hypoglycemic Agents / pharmacology*
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Mice
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Mice, Inbred C57BL
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Models, Molecular
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Peptide Fragments / blood
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Peptide Fragments / drug effects
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Protein Conformation
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Protein Precursors / blood
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Protein Precursors / drug effects
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Pyrazines / chemistry*
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Pyrazines / pharmacokinetics
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Pyrazines / pharmacology*
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Rats
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Sitagliptin Phosphate
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Structure-Activity Relationship
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Triazoles / chemistry*
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Triazoles / pharmacokinetics
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Triazoles / pharmacology*
Substances
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Blood Glucose
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Enzyme Inhibitors
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Hypoglycemic Agents
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Peptide Fragments
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Protein Precursors
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Pyrazines
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Triazoles
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Glucagon-Like Peptide 1
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Glucagon
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Dipeptidyl Peptidase 4
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Sitagliptin Phosphate