Abstract
Dipeptidyl peptidase-4 inhibitors hold great potential for the treatment of type 2 diabetes. A series of 1-(γ-1,2,3-triazol substituted prolyl)-(S)-3,3-difluoropyrrolidines were designed, synthesized, and evaluated as novel dipeptidyl peptidase-4 inhibitors. Most of the compounds exhibited good in vitro potency against dipeptidyl peptidase-4. Among these, compounds 7j, 7q, and 7s displayed good dipeptidyl peptidase-4 activity and excellent selectivity versus other proteases including dipeptidyl peptidase-8, dipeptidyl peptidase-9, and FAP. The possible binding modes of compounds 7j, 7q, and 7s with dipeptidyl peptidase-4 were also explored by molecular docking simulation.
© 2012 John Wiley & Sons A/S.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Binding Sites
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Dipeptidyl Peptidase 4 / chemistry*
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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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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / chemistry
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Hypoglycemic Agents / pharmacology
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Molecular Docking Simulation
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Proline / analogs & derivatives*
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Proline / chemical synthesis
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Proline / chemistry
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Proline / metabolism
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Stereoisomerism
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Structure-Activity Relationship
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Triazoles / chemical synthesis*
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Triazoles / chemistry
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Triazoles / metabolism
Substances
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1-(5-((3,3-difluoropyrrolidin-1-yl)carbonyl)pyrrolidin-3-yl)-4-(4-fluoro-3-methylphenyl)-1H-1,2,3-triazole
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1-(5-((3,3-difluoropyrrolidin-1-yl)carbonyl)pyrrolidin-3-yl)-4-(4-phenylphenyl)-1H-1,2,3-triazole
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Dipeptidyl-Peptidase IV Inhibitors
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Hypoglycemic Agents
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Triazoles
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methyl 1-(5-((3,3-difluoropyrrolidin-1-yl)carbonyl)pyrrolidin-3-yl)-1H-1,2,3-triazole-4-carboxylate
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Proline
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Dipeptidyl Peptidase 4