Abstract
Dipeptidyl peptidase IV (DPP4) inhibitors are emerging as a new class of therapeutic agents for the treatment of type 2 diabetes. They exert their beneficial effects by increasing the levels of active glucagon-like peptide-1 and glucose-dependent insulinotropic peptide, which are two important incretins for glucose homeostasis. Starting from a high-throughput screening hit, we were able to identify a series of piperidinone- and piperidine-constrained phenethylamines as novel DPP4 inhibitors. Optimized compounds are potent, selective, and have good pharmacokinetic profiles.
MeSH terms
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Adenosine Deaminase Inhibitors*
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Animals
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Biological Availability
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Crystallography, X-Ray
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Dipeptidyl Peptidase 4
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Dipeptidyl-Peptidase IV Inhibitors*
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Glycoproteins / antagonists & inhibitors*
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Humans
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Molecular Conformation
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Phenethylamines / chemical synthesis*
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Phenethylamines / pharmacokinetics
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Phenethylamines / pharmacology
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Piperidines / chemical synthesis*
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Piperidines / pharmacokinetics
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Piperidines / pharmacology
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Piperidones / chemical synthesis
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Piperidones / pharmacokinetics
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Piperidones / pharmacology
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Rats
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Adenosine Deaminase Inhibitors
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Dipeptidyl-Peptidase IV Inhibitors
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Glycoproteins
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Phenethylamines
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Piperidines
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Piperidones
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DPP4 protein, human
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Dipeptidyl Peptidase 4