Discovery and preclinical profile of Saxagliptin (BMS-477118): a highly potent, long-acting, orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes

J Med Chem. 2005 Jul 28;48(15):5025-37. doi: 10.1021/jm050261p.

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

  • Adamantane / analogs & derivatives*
  • Adamantane / chemical synthesis*
  • Adamantane / pharmacology
  • Animals
  • Biological Availability
  • Blood Glucose / analysis
  • Diabetes Mellitus, Type 2 / drug therapy*
  • Diabetes Mellitus, Type 2 / physiopathology
  • Dipeptides / chemical synthesis*
  • Dipeptides / pharmacology
  • Dipeptidyl Peptidase 4 / metabolism*
  • Glucose Tolerance Test
  • Glycine / analogs & derivatives*
  • Glycine / chemical synthesis*
  • Glycine / pharmacology
  • Humans
  • Hypoglycemic Agents / chemical synthesis*
  • Hypoglycemic Agents / pharmacology
  • In Vitro Techniques
  • Insulin / blood
  • Male
  • Mice
  • Mice, Obese
  • Microsomes, Liver / metabolism
  • Nitriles / chemical synthesis
  • Nitriles / pharmacology
  • Proline / analogs & derivatives
  • Proline / chemical synthesis
  • Proline / pharmacology
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Rats
  • Rats, Zucker
  • Stereoisomerism
  • Structure-Activity Relationship

Substances

  • Blood Glucose
  • Dipeptides
  • Hypoglycemic Agents
  • Insulin
  • Nitriles
  • Protease Inhibitors
  • Proline
  • saxagliptin
  • Dipeptidyl Peptidase 4
  • Adamantane
  • Glycine