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Proton pump[1]
Zastaprazan is a potassium-competitive acid blocker (P-CAB) that inhibits the gastric H+/K+-ATPase (proton pump). It binds reversibly and competitively to both active and inactive proton pumps. [1] Zastaprazan specifically targets the gastric H+/K+-ATPase (proton pump) and acts as a reversible K+-competitive inhibitor. It is a potent and selective inhibitor of gastric H+/K+-ATPase with an IC50 of 16.7 nM and exhibits over 400-fold selectivity over Na+/K+-ATPase activity. By binding to the K+-binding site on the pump, it rapidly and reversibly blocks acid secretion, providing a mechanism distinct from traditional proton pump inhibitors (PPIs). |
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| ln Vitro |
The mechanism of action is described: unlike proton pump inhibitors (PPIs), Zastaprazan does not require acidic activation; it can directly inhibit proton pumps regardless of their activation state. Its metabolism is not dependent on CYP2C19, and it is acid-stable, eliminating the need for an enteric coating. [1]
Zastaprazan is a small molecule therapeutic agent. The presence of the International Nonproprietary Name stem "-prazan" in its nomenclature classifies it as a proton pump inhibitor that operates independently of acid-activated conversion. Currently, Zastaprazan is being evaluated in clinical study NCT05814809, a trial designed to assess its safety profile and pharmacokinetic characteristics in healthy adult participants. The compound possesses a monoisotopic molecular mass of 362.21 Daltons. In cell-free enzyme assays, Zastaprazan inhibits porcine gastric H+/K+-ATPase activity with an IC50 of 16.7 nM, showing strong and dose-dependent inhibition. It exhibits >400-fold selectivity over Na+/K+-ATPase. At 2 mg/kg, JP-1366 inhibits basal and histamine-stimulated gastric acid secretion in pylorus-ligated rats. Zastaprazan exhibits a more than 2-fold higher inhibitory effect on esophageal injury than TAK-438 in GERD lesions and has a more potent inhibitory effect in indomethacin- or aspirin-induced gastric ulcer rat models. |
| ln Vivo |
In a phase I study in healthy volunteers (referenced), Zastaprazan demonstrated potent gastric acid suppression, achieving intragastric pH > 4 within 2 hours and sustaining acid suppression for 24 hours in a dose-dependent manner. [1]
In this phase III study in patients with erosive esophagitis (EE), Zastaprazan 20 mg once daily for up to 8 weeks resulted in a cumulative healing rate (full analysis set) of 97.92% (141/144) at week 8 and 95.14% (137/144) at week 4. The week 4 healing rate was significantly higher than that of esomeprazole 40 mg (87.68%, P = 0.026). [1] In patients with baseline LA classification grade B/C/D, the 4-week and 8-week healing rates with Zastaprazan were numerically higher than with esomeprazole (91.84% vs 78.72% at week 4; 95.92% vs 89.36% at week 8). [1] Symptom response, assessed by Reflux Disease Questionnaire (RDQ) and GERD-Health Related Quality of Life (GERD-HRQL) scores, showed significant improvement from baseline with Zastaprazan treatment, comparable to esomeprazole. [1] Serum gastrin levels increased significantly from baseline to the end of treatment in the Zastaprazan group (from 45.3 ± 87.0 pg/mL to 114.9 ± 116.2 pg/mL, P < 0.0001). The increase was slightly higher than in the esomeprazole group (P = 0.047), but levels returned to baseline 2 weeks after treatment completion. [1] In vivo, Zastaprazan (JP-1366, 2 mg/kg) effectively inhibits basal and histamine-stimulated gastric acid secretion in pylorus-ligated rats. It inhibits esophageal mucosal damage in a reflux esophagitis model with an ED50 of 0.53 mg/kg. The compound shows greater efficacy than TAK-438 in GERD models and exerts potent protective effects against NSAID-induced gastric ulcers. In human clinical trials, a 20 mg dose of Zastaprazan achieved a time with gastric pH >4 of 85.19%, while 40 mg achieved 91.84%, comparable to or greater than esomeprazole 40 mg (72.06%). |
| Enzyme Assay |
The in vitro H+/K+-ATPase inhibition assay uses porcine gastric vesicles or purified enzyme preparations. The enzyme (10 ug protein) is incubated in buffer containing 20 mM Pipes (pH 6.5), 140 mM KCl, 2 mM MgCl2, and 1 mM ATP. Zastaprazan is serially diluted (0.001-10 uM) and added to the reaction. After 30 minutes at 37degC, the reaction is terminated with trichloroacetic acid. Inorganic phosphate (Pi) released is quantified using the malachite green assay. The IC50 (16.7 nM) is calculated from the concentration-response curve. Na+/K+-ATPase inhibition is assessed similarly using porcine renal enzyme to confirm selectivity (>400-fold).
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| Cell Assay |
For in vitro cellular assays, isolated rabbit gastric glands are prepared by collagenase digestion and perfused. Glands are pre-incubated with Zastaprazan (0.001-10 uM) for 15 minutes, then stimulated with 100 uM histamine or 1 mM dbcAMP for 60 minutes at 37degC. Acid secretion is measured by the accumulation of [14C]-aminopyrine (AP) into the glands. The ratio of intracellular to extracellular AP is calculated, and EC50 values are derived from dose-response curves. The selectivity over Na+/K+-ATPase is confirmed using porcine renal membrane preparations.
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| Animal Protocol |
Study Design and Methodology: [1]
This phase III, multicenter, randomized, double-blind, noninferiority trial enrolled 300 participants with endoscopically confirmed erosive esophagitis. Subjects were randomly assigned to receive either 20 mg of zastaprazan or 40 mg of esomeprazole once daily for up to eight weeks. The primary endpoint was the cumulative proportion of patients with endoscopically confirmed healing of EE at week 8. Secondary endpoints included the healing rate at week 4, symptomatic response, and quality of life measures. Additionally, safety profiles and changes in serum gastrin levels were evaluated. Key Findings [1] In the full analysis set, the cumulative healing rate at week 8 was 97.92% (141/144) in the zastaprazan group and 94.93% (131/138) in the esomeprazole group (P=0.178). At week 4, the healing rate was significantly higher with zastaprazan compared to esomeprazole (95.14% [137/144] vs. 87.68% [121/138]; P=0.026). No statistically significant differences were observed between the two groups in the per-protocol analysis for healing rates at week 4 or week 8, nor in symptom response, quality of life assessments, or overall safety profiles. Serum gastrin levels increased during treatment in both groups, with a significant between-group difference (P=0.047), but returned to baseline levels after treatment discontinuation. An in vivo reflux esophagitis model is used to evaluate Zastaprazan. Male Sprague-Dawley rats (200-250 g) undergo ligation of the pylorus and forestomach to create a reflux esophagitis model. Zastaprazan is administered orally at doses of 0.1-10 mg/kg (formulated in 0.5% methylcellulose) twice daily for 4 days. On day 4, the esophagus is examined, and the area of esophageal mucosal lesions is measured. The ED50 for inhibition of esophageal mucosal damage is calculated (ED50 = 0.53 mg/kg). In the pylorus-ligated rat model, Zastaprazan (2 mg/kg, i.d.) is given immediately after pylorus ligation, and gastric acid output is measured over 4 hours. |
| ADME/Pharmacokinetics |
Zastaprazan is acid-stable and does not require an enteric coating. Its metabolism is not dependent on CYP2C19. [1]
It can be dosed irrespective of meals. [1] From referenced data, the elimination half-life of Zastaprazan at a 20 mg dose is 8.6 hours. [1] The proportion of time with intragastric pH > 4 over 24 hours after dosing is 83% for the 20 mg dose, which is known to be associated with healing of esophageal erosions. [1] Onset of action is rapid, with gastric pH rising above 4 within 2 hours after oral administration of 20 mg. [1] Zastaprazan has been evaluated in human clinical pharmacokinetic studies. Population PK analysis has been conducted using data from 92 patients with erosive GERD and 68 healthy volunteers. The compound is orally administered and exhibits dose-dependent plasma exposure. A Phase 1 clinical trial has evaluated the effect of food on pharmacokinetics and pharmacodynamics of a single oral dose of JP-1366 tablets. Mass balance and metabolism studies using [14C]-JP-1366 in healthy Chinese adults have been conducted to characterize absorption, distribution, metabolism, and excretion. |
| Toxicity/Toxicokinetics |
In this phase III study, Zastaprazan was well tolerated. The overall incidence of treatment-emergent adverse events (TEAEs) in the Zastaprazan group was 16.22% (24/148), compared with 22.15% (33/149) in the esomeprazole group. [1]
Drug-related adverse events (ADRs) occurred in 4.73% (7/148) of Zastaprazan-treated subjects, compared with 9.40% (14/149) in the esomeprazole group. No serious adverse events or deaths were reported in either group. [1] The most frequently reported TEAEs in the Zastaprazan group were gastrointestinal disorders (7.43%), including hiatus hernia (2.70%), infections (2.70%, all COVID-19), and nervous system disorders (2.03%, including headache). [1] One subject in the Zastaprazan group discontinued treatment due to a TEAE (skin rash from lacquer poisoning), which was not considered drug-related. [1] No significant changes in vital signs, ECG findings, or laboratory tests (including liver function) were observed during the study period. [1] Serum gastrin levels increased during treatment but returned to baseline after treatment cessation. [1] Specific toxicity data for Zastaprazan is not available. As a P-CAB, safety profiles from clinical trials indicate good tolerability. Common adverse events associated with acid-suppressing agents may include headache, diarrhea, nausea, and abdominal pain. Long-term use may be associated with hypergastrinemia, which could theoretically lead to enterochromaffin-like cell hyperplasia. Comprehensive toxicology studies in animals and humans have been conducted as part of its regulatory approval process in South Korea. |
| References | |
| Additional Infomation |
Background: Zastaprazan (JP-1366) is a novel potassium-competitive acid blocker developed by Onconic Therapeutics for the treatment of gastroesophageal reflux disease (GERD), specifically erosive esophagitis. Chemically, it has an imidazopyridine backbone substituted with an azetidine group. [1]
Mechanism of action: As a P-CAB, Zastaprazan reversibly and competitively inhibits gastric H+/K+-ATPase on both active and inactive proton pumps, leading to rapid and sustained acid suppression. Unlike PPIs, it does not require acid activation, and its efficacy is independent of CYP2C19 genotype. [1] Clinical efficacy: In this phase III study, Zastaprazan 20 mg once daily demonstrated noninferior efficacy to esomeprazole 40 mg in healing EE at 8 weeks. The 4-week healing rate was numerically higher with Zastaprazan, suggesting a faster onset of action. [1] Comparison with other P-CABs: The 8-week healing rate of Zastaprazan (97.92%–100%) is comparable to that of other approved P-CABs such as vonoprazan, tegoprazan, fexuprazan, and kevoprazan. The pharmacokinetic profile (half-life 8.6 h, pH > 4 holding time 83%) is favorable. [1] Safety: Zastaprazan was well tolerated with a low incidence of drug-related adverse events, comparable to esomeprazole and other P-CABs. No new safety signals were identified. [1] Zastaprazan (JP-1366) is a pharmaceutical drug approved for clinical use. It was approved in South Korea in 2024 for the treatment of erosive gastroesophageal reflux disease (GERD). An NDA has been submitted to the China NMPA for the treatment of reflux esophagitis. Its molecular formula is C22H26N4O with a molecular weight of 362.48. Zastaprazan is a novel potassium-competitive acid blocker (P-CAB) that mediates strong, selective, and dose-dependent inhibition of H+/K+-ATPase (IC50 = 16.7 nM). |
| Molecular Formula |
C22H26N4O
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|---|---|
| Molecular Weight |
362.468044757843
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| Exact Mass |
362.21
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| Elemental Analysis |
C, 72.90; H, 7.23; N, 15.46; O, 4.41
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| CAS # |
2133852-18-1
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| Related CAS # |
2936619-43-9 (citrate)
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| PubChem CID |
138622158
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| Appearance |
White to off-white solid powder
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| LogP |
4.4
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
27
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| Complexity |
526
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1C=C(C2=NC(C)=C(C)N2C=1)NCC1C(C)=CC=CC=1C)N1CCC1
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| InChi Key |
FEQFUBYYZYQTOJ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C22H26N4O/c1-14-7-5-8-15(2)19(14)12-23-20-11-18(22(27)25-9-6-10-25)13-26-17(4)16(3)24-21(20)26/h5,7-8,11,13,23H,6,9-10,12H2,1-4H3
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| Chemical Name |
azetidin-1-yl-[8-[(2,6-dimethylphenyl)methylamino]-2,3-dimethylimidazo[1,2-a]pyridin-6-yl]methanone
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| Synonyms |
Zastaprazan; 2133852-18-1; Zastaprazan [INN]; W9S9KZX5MD; Zastaprazan (INN);
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO: 33.33 mg/mL (91.95 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.90 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 (6.90 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 25.0 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 | 2.7588 mL | 13.7942 mL | 27.5885 mL | |
| 5 mM | 0.5518 mL | 2.7588 mL | 5.5177 mL | |
| 10 mM | 0.2759 mL | 1.3794 mL | 2.7588 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
Link: https://clinicaltrials.gov/ct2/show/NCT07471867
Conditions:Chronic Coronary SyndromeLink: https://clinicaltrials.gov/ct2/show/NCT07467213
Conditions:Acute Myocardial Infarction (AMI)|Gastrointestinal BleedingLink: https://clinicaltrials.gov/ct2/show/NCT07268820
Conditions:GERD
Title:Phase 1 Study of JLP-2302 and JP-1366: PK and Safety in Healthy Volunteers
Status:Completed
updateDate:2025-09-18
Ctid:NCT07181538
Link: https://clinicaltrials.gov/ct2/show/NCT07181538
Conditions:HealthyLink: https://clinicaltrials.gov/ct2/show/NCT07160790
Conditions:Non-erosive Gastroesophageal Reflux DiseaseLink: https://clinicaltrials.gov/ct2/show/NCT06439563
Conditions:Peptic UlcerLink: https://clinicaltrials.gov/ct2/show/NCT05443984
Conditions:Erosive EsophagitisLink: https://clinicaltrials.gov/ct2/show/NCT05712681
Conditions:HealthyLink: https://clinicaltrials.gov/ct2/show/NCT05448001
Conditions:Gastric UlcerLink: https://clinicaltrials.gov/ct2/show/NCT05814809
Conditions:HealthyLink: https://clinicaltrials.gov/ct2/show/NCT04282954
Conditions:GERDProducts are for research use only; We do not sell to patients
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