Saxagliptin

A highly potent, long-acting, orally active DPP4 inhibitor with Ki of 0.6 nM; shows no CYP3A4 inhibition up to 100 uM, and good oral exposure.Diabetes Approved (In Vitro) :Saxagliptin (100 nM; 48 hours; INS-1 832/13 cells) treatment significantly induceS β-cell proliferation.Saxagliptin (100 nM; 48 hours; INS-1 832/13 cells) treatment increases the p-AKT and active β-catenin protein levels, paralleled with the increase of c-myc and cyclin D1 protein expression.Saxagliptin acts by preventing the degradation of glucagon-like peptide-1 and hence increases secretion of insulin and decreases secretion of glucagon. (In Vivo) :Saxagliptin (1 mg/kg; for 12 weeks) treatment in high-fat diet/streptozotocin-induced diabetic rats, significant improvement in pancreas insulin secretion capacity evaluated by hyperglycemia clamp and increased β-cell to α-cell areas ratio are observed.Saxagliptin dose-dependently inhibits plasma DPP-4 activity in Han-Wistar rats, by ~70% at 7 hours postdose with 1 mg/kg and by ~90% at 7 hours postdose with 10 mg/kg. At 24 hours postdose, ~20% and 70% inhibition, respectively, remained.