Vonoprazan Fumarate (formerly TAK-438, TAK 438, trade name Takecab), the fumarate salt of Vonoprazan, is a novel, orally bioactive and potent P-CAB (potassium-competitive acid blocker) that has been approved in Janpan in 2015 for the treatment of gastroduodenal ulcer and reflux esophagitis. It acts by reversibly inhibiting H+/K+, ATPase with an IC50 of 19 nM (pH 6.5), controls gastric acid secretion. In cultured gastric glands, TAK-438 treatment resulted in a longer and stronger acid formation inhibition. The inhibition effect of TAK-438 on acid secretion seemed to be associated with gastric parietal cell physiology.
理化性质和储存条件
| Molecular Weight (MW) | 461.46 |
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| Formula | C17H16FN3O2S.C4H4O4 |
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| CAS No. | 1260141-27-2 (fumarate); |
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| Storage | -20℃ for 3 years in powder form |
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| -80℃ for 2 years in solvent |
| Solubility (In vitro) | DMSO: 62 mg/mL (134.4 mM) |
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| Water:<1 mg/mL |
| Ethanol:<1 mg/mL |
| Solubility (In vivo) | 0.5% methylcellulose: 17 mg/mL |
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| Synonyms | TAK438, Vonoprazan Fumarate, TAK-438, TAK 438, Takecab |
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实验参考方法
| In Vitro | In vitro activity: 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.
Kinase Assay: Vonoprazan (TAK-438 free base) is an orally active potassium-competitive acid blocker which inhibits H+, K+-ATPase activity with an IC50 of 19 nM. |
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| 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. 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. |
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| Animal model | Male Sprague-Dawley rats |
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| Formulation & Dosage | Dissolved in 0.5% methylcellulose solution; 1, 2, and 4 mg/kg; oral administration |
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| References | J Pharmacol Exp Ther. 2010 Oct;335(1):231-8; J Pharmacol Exp Ther. 2011 Jun;337(3):797-804. |
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