Sitagliptin phosphate monohydrate
Catalog No.S4002 Synonyms: MK-0431
Molecular Weight(MW): 523.32
Sitagliptin phosphate monohydrate is a potent inhibitor of DPP-IV with IC50 of 19 nM in Caco-2 cell extracts.
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|Description||Sitagliptin phosphate monohydrate is a potent inhibitor of DPP-IV with IC50 of 19 nM in Caco-2 cell extracts.|
|Features||A potent, orally active inhibitor of DPP-4.|
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.  MK0431 reduces in vitro migration of isolated splenic CD4 T-cells through a pathway involving cAMP/PKA/Rac1 activation.  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. 
|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.  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.  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. |
Plasma DPP-4 Activity :DPP-4 is extracted from confluent Caco-2 cells. After 5 minutes of incubation at room temperature with lysis buffer (10 mM Tris-HCl, 150 mM NaCl, 0.04 U/mL aprotinin, 0.5% Nonidet P40, pH 8.0), cells are centrifuged at 35,000 g at 4 °C for 30 minutes, and the supernatant is stored at -80°C. Assays are performed by mixing 20 μL of appropriate compound dilutions with 50 μL of the substrate for the DPP-4 enzyme, H-Ala-Pro-7-amido-4-trifluoromethylcoumarin (final concentration in the assay, 100 μM) and 30 μL of the Caco-2 cell extract (diluted 1000-fold with 100 mM Tris-HCl, 100 mM NaCl, pH 7.8). Plates are incubated at room temperature for 1 hour, and fluorescence is measured at excitation/emission wavelengths of 405/535 nm using a SpectraMax GeminiXS. Dissociation kinetics of inhibitors from the DPP-4 enzyme is determined after a 1-hour preincubation of Caco-2 cell extracts with high inhibitor concentrations (30 nM for BI 1356, 3 μM for vildagliptin). The enzymatic reaction is started by adding the substrate H-Ala-Pro-7-amido-4-trifluoromethylcoumarin after a 3000-fold dilution of the preincubation mixture with assay buffer. Under these conditions, the difference in DPP-4 activity at a certain time point in the presence or absence of an inhibitor reflects the amount of this inhibitor still bound to the DPP-4 enzyme. Maximal reaction rates (fluorescence units/seconds × 1000) at 10-minute intervals are calculated using the SoftMax software of the SpectraMax and corrected for the rate of an uninhibited reaction [(vcontrol-vinhibitor)/vcontrol].
|In vitro||DMSO||100 mg/mL (191.08 mM)|
|Water||41 mg/mL (78.34 mM)|
|In vivo||Add solvents individually and in order:
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Clinical Trial Information
|NCT Number||Recruitment||Conditions||Sponsor/Collaborators||Start Date||Phases|
|NCT02363335||Completed||Healthy Volunteers||National Institute on Aging (NIA)|National Institutes of Health Clinical Center (CC)||January 26, 2015||Phase 1|
|NCT02689362||Not yet recruiting||Diabetes Mellitus, Type 2||Eurofarma Laboratorios S.A.||March 2017||Phase 2|
|NCT02917031||Recruiting||Type 2 Diabetes Mellitus|Heart Failure||AstraZeneca||January 2017||Phase 4|
|NCT02882477||Not yet recruiting||Diabetes Mellitus|Iron Metabolism Disorders|Gastroduodenal Ulcer|Optic Atrophy|Sensorineural Hearing Loss|Platelet Dysfunction||Hadassah Medical Organization||December 2016||Phase 2|Phase 3|
|NCT02956044||Recruiting||Type2 Diabetes Mellitus||Theracos||November 2016||Phase 1|
|NCT02920918||Recruiting||Heart Failure, Systolic|Diabetes Mellitus, Type 2||Virginia Commonwealth University|Janssen Scientific Affairs, LLC||October 2016||Phase 4|
Answers to questions you may have can be found in the inhibitor handling instructions. Topics include how to prepare stock solutions, how to store inhibitors, and issues that need special attention for cell-based assays and animal experiments.
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