Home Metabolism DPP inhibitor Sitagliptin phosphate monohydrate

Sitagliptin phosphate monohydrate

Catalog No.S4002 Synonyms: MK-0431

For research use only.

Sitagliptin phosphate monohydrate (MK-0431) is a potent inhibitor of DPP-IV with IC50 of 19 nM in Caco-2 cell extracts.

Sitagliptin phosphate monohydrate Chemical Structure

CAS No. 654671-77-9

Selleck's Sitagliptin phosphate monohydrate has been cited by 6 Publications

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Biological Activity

Description Sitagliptin phosphate monohydrate (MK-0431) 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.
Targets
DPP-4 [1]
(Cell-free assay)
19 nM
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]

Protocol (from reference)

Kinase Assay:[1]
  • Plasma DPP-4 Activity[2] :

    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].
Cell Research:[2]
  • Cell lines: CD4 T-cells
  • Concentrations: 100 μM
  • Incubation Time: 1 hour
  • Method: 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.
Animal Research:[1]
  • Animal Models: Freely fed Han-Wistar rats
  • Dosages: ≤10 mg/kg
  • Administration: Administered via p.o.

Solubility (25°C)

In vitro

In vivo

Add solvents to the product individually and in order
(Data is from Selleck tests instead of citations):
Saline
For best results, use promptly after mixing.

 30 mg/mL

Chemical Information

Molecular Weight 523.32
Formula

C16H15F6N5O.H3PO4.H2O
CAS No. 654671-77-9
Storage 3 years -20°C powder
2 years -80°C in solvent
Smiles C1CN2C(=NN=C2C(F)(F)F)CN1C(=O)CC(CC3=CC(=C(C=C3F)F)F)N.O.OP(=O)(O)O

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Method for preparing in vivo formulation: Take μL DMSO master liquid, next addμL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O, mix and clarify.

Method for preparing in vivo formulation: Take μL DMSO master liquid, next add μL Corn oil, mix and clarify.

Note: 1. Please make sure the liquid is clear before adding the next solvent.
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Clinical Trial Information

NCT Number Recruitment Interventions Conditions Sponsor/Collaborators Start Date Phases
NCT05219409 Not yet recruiting Drug: Sitagliptin|Device: Professional CGM Type 1 Diabetes University of Milan December 2022 Phase 2|Phase 3
NCT05403281 Completed Drug: DW6012 Healthy Subjects Dong Wha Pharmaceutical Co. Ltd. November 5 2021 Phase 1
NCT03359590 Completed Drug: Sitagliptin 100 mg|Drug: Placebo Pharmacological Action Profil Institut für Stoffwechselforschung GmbH|Merck Sharp & Dohme LLC March 21 2018 Phase 2
NCT03659461 Completed Drug: Sitagliptin Type 2 Diabetes Mellitus|PreDiabetes National University of Malaysia October 1 2017 Not Applicable
NCT03233178 Completed Other: Non-interventional T2DM (Type 2 Diabetes Mellitus)|Fatty Liver|NAFLD LMC Diabetes & Endocrinology Ltd. January 2017 --

(data from https://clinicaltrials.gov, updated on 2022-08-01)

Tech Support

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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