Vonoprazan Fumarate (TAK-438)

Catalog No.S8016

Vonoprazan Fumarate (TAK-438) is a novel P-CAB (potassium-competitive acid blocker) that reversibly inhibits H+/K+, ATPase with IC50 of 19 nM (pH 6.5), controls gastric acid secretion. Phase 3.

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Vonoprazan Fumarate (TAK-438) Chemical Structure

Vonoprazan Fumarate (TAK-438) Chemical Structure
Molecular Weight: 461.46

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Quality Control & MSDS

Product Information

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Product Description

Biological Activity

Description Vonoprazan Fumarate (TAK-438) is a novel P-CAB (potassium-competitive acid blocker) that reversibly inhibits H+/K+, ATPase with IC50 of 19 nM (pH 6.5), controls gastric acid secretion. Phase 3.
Targets H+/K+-ATPase [1]
IC50 19 nM
In vitro TAK-438 is a pyrrole derivative with a chemical structure that is completely different from the P-CABs developed to date. TAK-438 inhibits gastric H+, K+-ATPase activity in a concentration-dependent manner. Under neutral conditions (pH 7.5), the inhibitory activity of TAK-438 is almost the same as that under weakly acidic conditions (pH 6.5). TAK-438 does not inhibit Na+, K+-ATPase activity even at concentration 500 times higher than their IC50 values against gastric H+,K+-ATPase activity. TAK-438 inhibits gastric H+, K+-ATPase in a K+-competitive manner with Ki of 3 nM. [2]
In vivo TAK-438 inhibits basal gastric acid secretion in a dose-dependent manner, and the ID50 value is 1.26 mg/kg . Intravenous administration of TAK-438 dose-dependently increases the pH of the gastric perfusate, and the increase in pH is sustained for 5 h after administration. At the 1 mg/kg dose, the pH plateaues 90 min after administration, and the highest pH value reached is 5.9. [2] In addition, TAK-438 shows a potent and longer-lasting inhibitory effect on the histamine-stimulated gastric acid secretion in rats and dogs. TAK-438 shows significant antisecretory activity through high accumulation and slow clearance from the gastric tissue. TAK-438 is unaffected by the gastric secretory state, unlike PPIs. [3]
Features Capable of inhibiting H+, K+-ATPase under acidic or neutral conditions.

Protocol(Only for Reference)

Kinase Assay: [1]

Proton Potassium Adenosine Triphosphatase (H+, K+-ATPase) Inhibitory Activity Test A gastric mucosal membrane microsomal fraction is prepared from the stomach of swine. First, the stomach is removed, washed with tap water, and immersed in 3 M brine, and the surface of the mucosal membrane is wiped with a paper towel. The gastric mucosal membrane is detached, chopped, and homogenized in a 0.25 M saccharose solution (pH 6.8) containing 1 mM EDTA and 10 mM tris-hydrochloric acid using polytron. The obtained homogenate is centrifuged at 20000g for 30 min and the supernatant is centrifuged at 100000g for 90 min. The precipitate is suspended in 0.25 M saccharose solution, superimposed on a 0.25 M saccharose solution containing 7.5% Ficoll, and centrifuged at 100000g for 5 h. The fraction containing the interface between the both layers is recovered, and centrifugally washed with 0.25 M saccharose solution. The obtained microsomal fraction is used as a proton, potassium adenosine triphosphatase standard product. To 40 μL of a 50 mM HEPES-Tris buffer (5 mM magnesium chloride, 10 mM potassium chloride, 10 μM valinomycin, pH 6.5) containing 2.5 μg/mL (based on the protein concentration) of the enzyme standard product is added a test compound (5 μL) dissolved in a 10% aqueous dimethyl sulfoxide solution, and the mixture is incubated at 37 °C for 30 min. The enzyme reaction is started by adding 5 μL of a 2 mM adenosine triphosphate Tris salt solution (50 mM HEPES-Tris buffer (5 mM magnesium chloride, pH 6.5)). The enzyme reaction is carried out at 37 °C for 20 min, and 15 μL of a malachite green solution (0.12% malachite green solution in sulfuric acid (2.5 mol/L), 7.5% ammonium molybdate, and 11% Tween 20 are mixed at a ratio of 100:25:2) is added to quench the reaction. After the mixture is allowed to stand at room temperature for 15 min, the resulting reaction product of inorganic phosphorus with malachite green is colorimetrically determined at a wavelength of 610 nm. In addition, the amount of the inorganic phosphoric acid in the reaction solution free of potassium chloride is measured in the same manner, which is subtracted from the inorganic phosphoric acid amount in the presence of potassium chloride to determine the H+, K+-ATPase activity. The inhibitory rate (%) is determined from the activity value of the control and the activity values of various concentrations of the test compound, and the 50% inhibitory concentration (IC50) of the H+, K+-ATPase activity is determined.

Animal Study: [3]

Animal Models Male Sprague-Dawley rats
Formulation 0.5% methylcellulose solution
Dosages 1, 2, and 4 mg/kg
Administration Orally

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

SpeciesMouseRatRabbitGuinea pigHamsterDog
Weight (kg)0.020.151.80.40.0810
Body Surface Area (m2)0.0070.0250.150.050.020.5
Km factor36128520
Animal A (mg/kg) = Animal B (mg/kg) multiplied by  Animal B Km
Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×  mouse Km(3)  = 11.2 mg/kg
rat Km(6)
1

References

[1] Arikawa Y, et al. J Med Chem, 2012, 55(9), 4446-4456.

[2] Hori Y, et al. J Pharmacol Exp Ther, 2010, 335(1), 231-238.

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Clinical Trial Information( data from http://clinicaltrials.gov, updated on 2016-07-30)

NCT Number Recruitment Conditions Sponsor
/Collaborators
Start Date Phases
NCT02037477 Completed Healthy Takeda January 2014 Phase 3
NCT01630746 Completed Erosive Esophagitis Takeda July 2012 Phase 3
NCT01568398 Completed Gastric Ulcer|Duodenal Ulcer Takeda May 2012 Phase 3
NCT01568385 Completed Gastric Ulcer|Duodenal Ulcer Takeda April 2012 Phase 3
NCT01456247 Completed Gastric Ulcers|Duodenal Ulcers Takeda March 2012 Phase 3

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Chemical Information

Download Vonoprazan Fumarate (TAK-438) SDF
Molecular Weight (MW) 461.46
Formula

 

C17H16FN3O2S.C4H4O4
CAS No. 1260141-27-2
Storage 3 years -20℃powder
6 months-80℃in solvent
Synonyms N/A
Solubility (25°C) * In vitro DMSO 62 mg/mL (134.35 mM)
Water <1 mg/mL (<1 mM)
Ethanol <1 mg/mL (<1 mM)
In vivo 0.5% methylcellulose 17 mg/mL
* <1 mg/ml means slightly soluble or insoluble.
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.
Chemical Name 1H-Pyrrole-3-methanamine, 5-(2-fluorophenyl)-N-methyl-1-(3-pyridinylsulfonyl)-, 2-butenedioate (1:1)

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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