Abstract
A highly ligand efficient lead molecule was rapidly developed into a DPP-IV selective candidate series using focused small library synthesis. A significant hurdle for series advancement was genetic safety since some agents in this series impaired chromosome division that was detected using the in vitro micronucleus assay. A recently developed high-throughput imaging-based in vitro micronucleus assay enabled the identification of chemical space with a low probability of micronucleus activity. Advanced profiling of a subset within this space identified a compound with a clean safety profile, an acceptable human DPP-IV inhibition profile based on the rat PK/PD model and a projected human dose that was suitable for clinical development.
MeSH terms
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Animals
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Diabetes Mellitus, Type 2 / drug therapy
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Diabetes Mellitus, Type 2 / enzymology*
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Dipeptidyl Peptidase 4 / blood
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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* / pharmacology
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Dipeptidyl-Peptidase IV Inhibitors* / therapeutic use*
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Dogs
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Humans
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Hypoglycemic Agents / chemical synthesis
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Hypoglycemic Agents / pharmacology
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Hypoglycemic Agents / therapeutic use
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Phenethylamines / chemistry
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Phenethylamines / pharmacology
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Phenethylamines / therapeutic use
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Piperidines / chemistry
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Piperidines / pharmacology
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Piperidines / therapeutic use
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Rats
Substances
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Dipeptidyl-Peptidase IV Inhibitors
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Hypoglycemic Agents
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Phenethylamines
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Piperidines
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DPP4 protein, human
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Dipeptidyl Peptidase 4