Abstract
Efforts to further elucidate structure-activity relationships (SAR) within our previously disclosed series of beta-quaternary amino acid linked l-cis-4,5-methanoprolinenitrile dipeptidyl peptidase IV (DPP-IV) inhibitors led to the investigation of vinyl substitution at the beta-position of alpha-cycloalkyl-substituted glycines. Despite poor systemic exposure, vinyl-substituted compounds showed extended duration of action in acute rat ex vivo plasma DPP-IV inhibition models. Oxygenated putative metabolites were prepared and were shown to exhibit the potency and extended duration of action of their precursors in efficacy models measuring glucose clearance in Zucker(fa/fa) rats. Extension of this approach to adamantylglycine-derived inhibitors led to the discovery of highly potent inhibitors, including hydroxyadamantyl compound BMS-477118 (saxagliptin), a highly efficacious, stable, and long-acting DPP-IV inhibitor, which is currently undergoing clinical trials for treatment of type 2 diabetes.
MeSH terms
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Adamantane / analogs & derivatives*
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Adamantane / chemical synthesis*
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Adamantane / pharmacology
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Animals
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Biological Availability
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Blood Glucose / analysis
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Diabetes Mellitus, Type 2 / drug therapy*
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Diabetes Mellitus, Type 2 / physiopathology
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Dipeptides / chemical synthesis*
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Dipeptides / pharmacology
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Dipeptidyl Peptidase 4 / metabolism*
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Glucose Tolerance Test
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Glycine / analogs & derivatives*
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Glycine / chemical synthesis*
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Glycine / pharmacology
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Humans
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Hypoglycemic Agents / chemical synthesis*
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Hypoglycemic Agents / pharmacology
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In Vitro Techniques
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Insulin / blood
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Male
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Mice
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Mice, Obese
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Microsomes, Liver / metabolism
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Nitriles / chemical synthesis
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Nitriles / pharmacology
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Proline / analogs & derivatives
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Proline / chemical synthesis
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Proline / pharmacology
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Protease Inhibitors / chemical synthesis*
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Protease Inhibitors / pharmacology
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Rats
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Rats, Zucker
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Stereoisomerism
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Structure-Activity Relationship
Substances
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Blood Glucose
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Dipeptides
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Hypoglycemic Agents
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Insulin
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Nitriles
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Protease Inhibitors
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Proline
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saxagliptin
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Dipeptidyl Peptidase 4
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Adamantane
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Glycine