Sitagliptin phosphate monohydrate

• Catalog No.: S4002
• CAS Number: 654671-77-9
• M. F.: C16H18F6N5O6P
• M. W.: 521.3082002
• Storage: -20°C

SYNONYMS

• IUPAC name: (3R)-3-amino-1-[3-(trifluoromethyl)-5H,6H,7H,8H-[1,2,4]triazolo[4,3-a]pyrazin-7-yl]-4-(2,4,5-trifluorophenyl)butan-1-one phosphoperoxol hydrate hydrogen
• IUPAC Traditional name: phosphoperoxol sitagliptin hydrate hydrogen(.)
• Synonyms: Januvia; MK-0431

DATABASE IDS

• CAS Number: 654671-77-9

PROPERTIES

• Target: DPP-4
• Solubility: DMSO
• Storage Condition: -20°C

DETAILS

Description (English)

Biological Activity

• Description: Sitagliptin phosphate (MK-0431) is a potent inhibitor of DPP-IV with IC50 of 19 nM in Caco-2 cell extracts.
• Targets: DPP-4
• IC50: 19 nM ^[1]
• In Vitro: As an orally active agent, Sitagliptin phosphate exhibits a potent inhibitory effect on DPP-4 with IC50 of 19 nM from Caco-2 cell extracts. ^[1] MK0431 reduces in vitro migration of isolated splenic CD4 T-cells through a pathway involving cAMP/PKA/Rac1 activation. ^[2] A recent study demonstrates that sitagliptin exerts a novel, direct action in order to stimulate GLP-1 secretion by the intestinal L cell through a DPP-4-independent, protein kinase A- and MEK-ERK1/2-dependent pathway. It therefore reduces the effect of autoimmunity on graft survival. ^[3]
• In Vivo: In vivo, the ED50 value of Sitagliptin phosphate for inhibition of plasma DPP-4 activity is calculated to be 2.3 mg/kg 7 hour postdose and 30 mg/kg 24 hour postdose in freely fed Han-Wistar rats. ^[1] The streptozotocin-induced type 1 diabetes mouse model exhibits elevated DPP-4 levels in the plasma that can be substantially inhibited in mice on an Sitagliptin phosphate diet. This is achieved by a positive effect on the regulation of hyperglycemia, potentially through prolongation of islet graft survival. ^[4] The plasma clearance and volume of distribution of Sitagliptin phosphate are higher in rats (40–48 mL/min/kg, 7–9 L/kg) than in dogs (9 mL/min/kg, 3 L/kg); and its half-life is shorter in rats,2 hours compared with 4 hours in dogs. ^[5]
• Clinical Trials: Sitagliptin phosphate is currently under Phase III clinical trials in patients with type 2 diabetes.
• Features: Sitagliptin phosphate is a potent, orally active inhibitor of DPP-4.

Protocol

• Protocol: Cell Assay ^[2]
• Cell Lines: CD4 T-cells
• Concentrations: 100 μM
• Incubation Time: 1 hour
• Methods: CD4T-cells are plated on membrane inserts in serum-free RPMI 1640, and cell migration is assayed using Transwell chambers (Corning), in the presence or absence of purified porcine kidney DPP-4 (32.1 units/mg; 100 mU/mL final concentration) and DPP-4 inhibitor (100 μM). After 1 hour, cells on the upper surface are removed mechanically, and cells that have migrated into the lower compartment are counted. The extent of migration is expressed relative to the control sample.
• Protocol: Animal Study ^[1]
• Animal Models: Freely fed Han-Wistar rats
• Formulation: 0.5% aqueous hyroxyethylcellulose.
• Doses: ≤10 mg/kg
• Administration: Administered via p.o.

References

• References: [1] Thomas L et al. J Pharmacol Exp Ther. 2008; 325(1): 175-182.
• References: [2] Kim SJ et al. Diabetes. 2009; 58(3): 641-651.
• References: [3] Sangle GV et al. Endocrinology. 2012; 153(2): 564-573.
• References: [4] Kim SJ et al. Diabetes. 2008; 57(5); 1331-1339.
• References: [5] Beconi MG et al. Drug Metab Dispos.2007; 35(4): 525-532.

REFERENCES

• Thomas L et al. J Pharmacol Exp Ther. 2008; 325(1): 175-182.
• Kim SJ et al. Diabetes. 2009; 58(3): 641-651.
• Sangle GV et al. Endocrinology. 2012; 153(2): 564-573.
• Kim SJ et al. Diabetes. 2008; 57(5); 1331-1339.
• Beconi MG et al. Drug Metab Dispos.2007; 35(4): 525-532.