H+/K+-ATPase (IC50 = 19 nM)

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. 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. [1]

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Proton pump inhibitors (PPIs) are widely used for the treatment of acid-related diseases. However, several medical needs such as suppression of night-time acid secretion and rapid symptom relief remain unmet. In this study, we investigated the effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker, on acid secretion in rats and dogs under various conditions, in comparison with the PPI lansoprazole [2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridyl] methyl]sulfinyl]-1H-benzimidazole], to characterize the antisecretory action of TAK-438. TAK-438 showed a more potent and longer-lasting inhibitory effect than lansoprazole on the histamine-stimulated gastric acid secretion in rats and dogs. A pharmacokinetic study in rats showed that TAK-438 accumulated and was retained in the gastric tissue for more than 24 h, unlike that in the plasma. TAK-438 showed significant antisecretory activity with or without cimetidine pretreatment, in contrast to lansoprazole, which did not show antisecretory activity after cimetidine pretreatment in rats. TAK-438 increased the pH of the gastric perfusate to 5.7 in an unstimulated condition, and this effect was maintained in the presence of subsequent histamine stimulation. On the other hand, lansoprazole also increased the pH in an unstimulated condition, but this effect diminished after histamine stimulation. These results indicated that TAK-438 exerted a more potent and longer-lasting antisecretory effect than lansoprazole through high accumulation and slow clearance from the gastric tissue. In addition, TAK-438 was unaffected by the gastric secretory state, unlike PPIs. Therefore, TAK-438 can provide a novel mechanism of action to improve the present PPI-based treatment of acid-related diseases [2].

Proton pump inhibitors (PPIs) are widely used in the treatment of acid-related diseases. However, several unmet medical needs, such as suppression of night-time acid secretion and rapid symptom relief, remain. In this study, we investigated the pharmacological effects of 1-[5-(2-fluorophenyl)-1-(pyridin-3-ylsulfonyl)-1H-pyrrol-3-yl]-N-methylmethanamine monofumarate (TAK-438), a novel potassium-competitive acid blocker (P-CAB), on gastric acid secretion in comparison with lansoprazole, a typical PPI, and SCH28080 [3-(cyanomethyl)-2-methyl,8-(phenylmethoxy)imidazo(1,2-a)pyridine], a prototype of P-CAB. TAK-438, SCH28080, and lansoprazole inhibited H(+),K(+)-ATPase activity in porcine gastric microsomes with IC(50) values of 0.019, 0.14, and 7.6 μM, respectively, at pH 6.5. The inhibitory activity of TAK-438 was unaffected by ambient pH, whereas the inhibitory activities of SCH28080 and lansoprazole were weaker at pH 7.5. The inhibition by TAK-438 and SCH28080 was reversible and achieved in a K(+)-competitive manner, quite different from that by lansoprazole. [1]

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Effect of TAK-438, SCH28080, and Lansoprazole on Gastric H+,K+-ATPase Activity.[1]
The inhibitory effect of TAK-438, SCH28080, and lansoprazole on gastric H+,K+-ATPase activity is shown in Fig. 2. Under weakly acidic conditions (pH 6.5), all three compounds inhibited gastric H+,K+-ATPase activity in a concentration-dependent manner. The inhibitory activity of TAK-438 was the most potent. The IC50 values of TAK-438, SCH28080, and lansoprazole were 0.019, 0.14, and 7.6 μM, respectively (Table 1). Under neutral conditions (pH 7.5), the inhibitory activity of TAK-438 was almost...

Inhibiton of Histamine-Stimulated Acid Secretion in Anesthetized Rats (iv) [J Med Chem. 2012 May 10;55(9):4446-56.]
Seven-week-old male Jcl:Sprague Dawley (SD) rats were used. The animals were fasted for 24 h but had free access to water before the experiment. The pylorus was ligated after anesthetization with urethane (1.2 g/kg, ip), and the abdomen was closed. Drugs and the vehicle were given intravenously just after the pylorus ligation. Three minutes later, histamine·2HCl (30 mg/kg per 10 mL) was injected subcutaneously. Three hours after histamine administration, the rats were sacrificed by CO2 asphyxiation and the stomachs were removed. The gastric contents were collected and centrifuged at 3000 rpm for 10 min. The volume of each sample was measured and the acid concentration was determined by automatic titration to pH 7.0 with 0.1 mol/L NaOH, and the total acid output during the 3 h period (μequiv/(3 h)) was calculated.

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Histamine-Stimulated Acid Secretion in Heidenhain Pouch Dogs [J Med Chem. 2012 May 10;55(9):4446-56.]
Drugs and the vehicle were given orally (0.2 mL/kg) to the dogs in a blind manner. Histamine·2HCl (30 μg/kg) was injected subcutaneously 1 day before and 1, 3, 6, 24, and 48 h after drugs and the vehicle administration. The gastric juice from the pouch was collected continuously for three consecutive 30 min periods after each dosing with histamine·2HCl. The volume of gastric juice was measured, and the acid concentration was determined by automatic titration to pH 7.0 with 0.1 mol/L NaOH solution. The total acid output during the 90 min period (μequiv/(90 min)) from each time was calculated and expressed as a percentage of the predosing value measured 1 day before the administration.

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Dissolved in 0.5% methylcellulose solution; 1, 2, and 4 mg/kg; oral administration

Male Sprague-Dawley rats

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the clinical use of vonoprazan during breastfeeding. Because of liver damage that occurred in nursing rodents, the manufacturer recommends that nursing mothers should pump and discard human milk while taking and for 2 days after the last dose. An alternate drug may be preferred.

◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.

◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
In healthy subjects, the plasma protein binding of vonoprazan ranges from 85% to 88%. At plasma concentrations between 0.1 and 10 mcg/mL, the plasma protein binding of vonoprazan is independent of concentration.

[1]. J Pharmacol Exp Ther.2010 Oct;335(1):231-8;
[2]. J Pharmacol Exp Ther.2011 Jun;337(3):797-804.

Vonoprazan Fumarate is the fumarate salt form of vonoprazan, a pyrrole derivative and reversible potassium-competitive acid blocker (P-CAB), with potential antacid activity. Upon administration, vonoprazan specifically and competitively binds to the gastric hydrogen-potassium ATPase (H+/K+ ATPase) proton pump at or, more likely, near its potassium ion (K+) binding site and sterically inhibits K+ binding. This blocks the activation of the H+/K+ ATPase by K+, inhibits the proton pump and prevents gastric acid secretion, thereby lowering gastric acid levels.
See also: Vonoprazan (has active moiety); Amoxicillin; clarithromycin; vonoprazan fumarate (component of); Amoxicillin; vonoprazan fumarate (component of).

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The results of this study showed that TAK-438 had a more potent inhibitory effect on porcine gastric H+,K+-ATPase activity than did lansoprazole, a typical PPI, or SCH28080, a prototype P-CAB. In addition, the inhibitory effect of TAK-438 was unaffected by ambient pH, whereas the inhibitory effect of lansoprazole and SCH28080 was attenuated at pH 7.5. PPIs exert their inhibitory activity after undergoing molecular rearrangement under the acidic condition in parietal cells that allows them to ...[1]

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We reported previously that TAK-438 is a novel P-CAB that inhibits H+, K+-ATPase in a reversible and K+-competitive manner and exerts potent inhibition of gastric acid secretion in rats (Hori et al., 2010). The results of this study showed that in rats and dogs TAK-438 exerts a more potent and longer-lasting inhibitory effect on gastric acid secretion than lansoprazole. It was reported that the duration of the inhibitory effect of CS-526 and SCH28080, the aforementioned P-CABs, on gastric acid...[2]

C17H16FN3O2S.C4H4O4

461.46

461.105

C, 54.66; H, 4.37; F, 4.12; N, 9.11; O, 20.80; S, 6.95

1260141-27-2

881681-00-1;1260141-27-2 (fumarate);1260141-27-2;

45375887

Typically exists as White to off-white solid at room temperature

3.829

3

9

7

32

629

0

FC(C=CC=C1)=C1C2=CC(CNC)=CN2S(=O)(C3=CC=CN=C3)=O.OC(/C=C/C(O)=O)=O

ROGSHYHKHPCCJW-WLHGVMLRSA-N

InChI=1S/C17H16FN3O2S.C4H4O4/c1-19-10-13-9-17(15-6-2-3-7-16(15)18)21(12-13)24(22,23)14-5-4-8-20-11-14;5-3(6)1-2-4(7)8/h2-9,11-12,19H,10H2,1H3;1-2H,(H,5,6)(H,7,8)/b;2-1+

(E)-but-2-enedioic acid;1-[5-(2-fluorophenyl)-1-pyridin-3-ylsulfonylpyrrol-3-yl]-N-methylmethanamine

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)