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Tenatoprazole (formerly known as TU-199; TU 199; Ulsacare; Protop) is a prodrug of the proton pump inhibitor (PPI) class with the potential for the treatment of gastroesophageal reflux disease. It inhibits proton transport with IC50 of 3.2 μM. Tenatoprazole is a drug candidate that was undergoing clinical testing as a potential treatment for reflux oesophagitis and peptic ulcer. Tenatoprazole has an imidazopyridine ring in place of the benzimidazole moiety found in other proton pump inhibitors, and has a half-life about seven times longer than other PPIs.
Physicochemical Properties
| Molecular Formula | C16H18N4O3S | |
| Molecular Weight | 346.4 | |
| Exact Mass | 346.109 | |
| CAS # | 113712-98-4 | |
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| PubChem CID | 636411 | |
| Appearance | White to pink solid powder | |
| Density | 1.4±0.1 g/cm3 | |
| Boiling Point | 591.5±60.0 °C at 760 mmHg | |
| Melting Point | 178-180°C | |
| Flash Point | 311.5±32.9 °C | |
| Vapour Pressure | 0.0±1.7 mmHg at 25°C | |
| Index of Refraction | 1.674 | |
| LogP | 1.36 | |
| Hydrogen Bond Donor Count | 1 | |
| Hydrogen Bond Acceptor Count | 7 | |
| Rotatable Bond Count | 5 | |
| Heavy Atom Count | 24 | |
| Complexity | 455 | |
| Defined Atom Stereocenter Count | 0 | |
| InChi Key | ZBFDAUIVDSSISP-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C16H18N4O3S/c1-9-7-17-12(10(2)14(9)23-4)8-24(21)16-18-11-5-6-13(22-3)19-15(11)20-16/h5-7H,8H2,1-4H3,(H,18,19,20) | |
| Chemical Name | 5-methoxy-2-[(4-methoxy-3,5-dimethylpyridin-2-yl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine | |
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| HS Tariff Code | 2934.99.9001 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets |
Tenatoprazole (TU-199) primarily targets gastric parietal cell H+/K+-ATPase [2][4] It also targets Tsg101 (a key component of ESCRT machinery) for inhibiting virus release[3] |
| ln Vitro |
In Heidenhain-pouch dogs, tenatoprazole (TU-199) (0.1, 0.2, 0.4 mg/kg; oral; single) dose-dependently suppresses gastric acid secretion induced by histamine infusion [4]. In primary cultured rat gastric glands, Tenatoprazole (0.1-10 μM) dose-dependently inhibited gastric acid secretion: 1 μM reduced H+ release by 40%, 3 μM by 65%, and 10 μM by 90% at 24 hours, via irreversible inhibition of H+/K+-ATPase [2] - In EBV-positive Raji and Akata cells, Tenatoprazole (20-100 μM) inhibited EBV release following phorbol ester-induced reactivation: 50 μM reduced viral particle secretion by 60% at 48 hours, without affecting cell viability (>85% viability at 100 μM); it disrupted Tsg101-mediated viral budding by binding to Tsg101's UEV domain [3] - Western blot analysis showed Tenatoprazole (50 μM) reduced Tsg101-viral glycoprotein B (gB) interaction by 55% in Raji cells, inhibiting viral particle assembly [3] |
| ln Vivo |
Tenatoprazole provides slow activation in vivo, which is predicted by its chemical activation rate in fasting rats. Tenatoprazole inhibits about 20–30% of enzyme activity even though acid secretion in fasting rats. (S)-tenatoprazole sodium salt hydrate provides a higher Cmax of 183 ng/mL, Tmax of 1.3 hours and AUC of 822 ngh/mL in dog. In healthy human volunteers (randomized three-way crossover study), oral Tenatoprazole (30 mg) showed different effects on intragastric pH based on administration time: - Fasting morning administration: Mean intragastric pH >4 for 14.2 hours/24h, pH >3 for 16.8 hours/24h [1] - Fasting evening administration: Mean pH >4 for 12.5 hours/24h, pH >3 for 15.3 hours/24h [1] - Fed bedtime administration: Mean pH >4 for 9.8 hours/24h, pH >3 for 12.1 hours/24h [1] - In Sprague-Dawley rats with indomethacin-induced gastroduodenal ulcers, oral Tenatoprazole (1-10 mg/kg/day for 14 days) dose-dependently promoted ulcer healing: 10 mg/kg group showed 78% ulcer area reduction, compared to 62% for omeprazole 10 mg/kg; gastric acid secretion was inhibited by 85% at 24 hours post-administration [2] - In beagle dogs, oral Tenatoprazole (0.3-3 mg/kg) dose-dependently inhibited pentagastrin-stimulated gastric acid secretion: 1 mg/kg achieved 90% inhibition at 8 hours, with the effect lasting for 24 hours; intragastric pH was maintained above 4 for 18 hours [4] |
| Enzyme Assay |
H+/K+-ATPase activity inhibition assay: Gastric microsomes enriched with H+/K+-ATPase were isolated from rats/dogs. Serial concentrations of Tenatoprazole (0.01-20 μM) were incubated with the enzyme, ATP (2 mM), and reaction buffer at 37°C for 60 minutes. Released inorganic phosphate was detected by colorimetric assay, and inhibitory rates were calculated relative to vehicle controls [2][4] |
| Cell Assay |
Gastric acid secretion assay: Primary rat gastric glands were seeded in collagen-coated plates and treated with Tenatoprazole (0.1-10 μM). Acid secretion was measured by monitoring pH changes in the culture medium using a pH-sensitive fluorescent probe, and inhibition rates were quantified [2] - EBV release inhibition assay: EBV-positive Raji/Akata cells were seeded in 6-well plates, activated with phorbol 12-myristate 13-acetate (PMA) to induce viral reactivation, and treated with Tenatoprazole (20-100 μM) for 48 hours. Culture supernatants were collected, and viral particles were quantified by plaque assay. Tsg101-viral gB interaction was detected by co-immunoprecipitation and Western blot [3] |
| Animal Protocol |
Rats and dogs Rat gastroduodenal ulcer model: Sprague-Dawley rats (200-250 g) were intraperitoneally injected with indomethacin (40 mg/kg) to induce ulcers. Rats were randomized (n=10/group) and treated with: (1) vehicle (0.5% carboxymethylcellulose sodium) oral; (2) Tenatoprazole 1/3/10 mg/kg/day oral; (3) omeprazole 10 mg/kg/day oral. Treatment lasted 14 days, with ulcer area measured by planimetry and gastric acid secretion assessed by pyloric ligation [2] - Dog gastric acid secretion model: Beagle dogs (8-10 kg) were fasted for 18 hours, randomized (n=6/group), and treated with Tenatoprazole 0.3/1/3 mg/kg oral. Two hours post-administration, pentagastrin (1 μg/kg) was intravenously injected to stimulate acid secretion. Gastric juice was collected every 2 hours for 24 hours, with acid output (mmol/h) and pH measured [4] - Human clinical study (crossover design): 12 healthy volunteers (20-30 years old) were randomized to three treatment sequences: (1) fasting morning Tenatoprazole 30 mg; (2) fasting evening Tenatoprazole 30 mg; (3) fed bedtime Tenatoprazole 30 mg. Each treatment period lasted 7 days, with a 7-day washout between periods. Intragastric pH was monitored continuously for 24 hours on day 7 of each period [1] - Tenatoprazole was dissolved in 0.5% carboxymethylcellulose sodium for animal oral administration; human formulations were oral tablets [1][2][4] |
| Toxicity/Toxicokinetics |
In rats treated with Tenatoprazole (10 mg/kg/day for 14 days), no body weight loss (<3%) or histopathological abnormalities were detected in liver, kidney, or gastrointestinal tract; hematological and liver/kidney function indices remained within normal ranges [2] - In healthy volunteers receiving Tenatoprazole (30 mg/day for 7 days), no significant adverse reactions (e.g., nausea, diarrhea, fatigue) were reported; vital signs and laboratory parameters were normal [1] |
| References |
[1]. Comparison of the effects of fasting morning, fasting evening and fed bedtime administration of tenatoprazole on intragastric pH in healthy volunteers: a randomized three-way crossover study. Aliment Pharmacol Ther. 2006;23(8):1179-1187. [2]. Effects of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion and gastroduodenal ulcers in rats. Methods Find Exp Clin Pharmacol. 1999;21(2):115-122. [3]. Prazoles Targeting Tsg101 Inhibit Release of Epstein-Barr Virus following Reactivation from Latency. J Virol. 2021;95(13):e0246620. [4]. The long-lasting effect of TU-199, a novel H+, K(+)-ATPase inhibitor, on gastric acid secretion in dogs. J Pharm Pharmacol. 1999;51(4):457-464. |
| Additional Infomation |
5-methoxy-2-[(4-methoxy-3,5-dimethyl-2-pyridinyl)methylsulfinyl]-1H-imidazo[4,5-b]pyridine is an imidazopyridine. Tenatoprazole (TU-199) is a novel, long-acting proton pump inhibitor (PPI) with improved pharmacodynamic properties compared to traditional PPIs [1][2][4] Its core mechanisms include: irreversible binding to gastric parietal cell H+/K+-ATPase to block H+ secretion and suppress gastric acid production (underpinning its use for acid-related diseases); targeting Tsg101 to disrupt ESCRT-dependent viral budding, inhibiting Epstein-Barr Virus (EBV) release from reactivated cells [2][3][4] Its efficacy is significantly influenced by administration time: fasting morning administration provides the longest duration of intragastric pH control (pH >4 for ~14 hours), superior to fasting evening or fed bedtime administration [1] It exhibits long-lasting gastric acid inhibition in dogs (24 hours) and rats, and promotes gastroduodenal ulcer healing with higher efficacy than omeprazole in rat models [2][4] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (7.22 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (7.22 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (6.00 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.8868 mL | 14.4342 mL | 28.8684 mL | |
| 5 mM | 0.5774 mL | 2.8868 mL | 5.7737 mL | |
| 10 mM | 0.2887 mL | 1.4434 mL | 2.8868 mL |