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| Targets |
Netazepide targets the cholecystokinin B receptor (CCKBR), also known as the CCK2 receptor or gastrin receptor. CCKBR is a G protein-coupled receptor (GPCR) that is activated by gastrin and cholecystokinin (CCK). It is expressed in the gastrointestinal tract, particularly in gastric parietal cells, where it stimulates gastric acid secretion, and in various tissues including the pancreas and brain. Overactivation of CCKBR by hypergastrinemia is associated with the development of gastric neuroendocrine tumors and other gastrointestinal pathologies. Netazepide acts as a selective antagonist at CCKBR, blocking gastrin- and CCK-mediated signaling. It exhibits selectivity for CCKBR over CCKAR (CCK1 receptor), which reduces the risk of off-target effects related to CCKAR modulation. By inhibiting CCKBR, Netazepide reduces gastric acid secretion and may suppress the growth of gastrin-dependent tumors.
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| ln Vitro |
In vitro, Netazepide inhibits gastrin/CCK-B receptor activity and suppresses the expression of Pappalysin 2 in type 1 gastric neuroendocrine tumor cells. The compound demonstrates high affinity for CCKBR with potent antagonist activity. In cell-based assays, Netazepide blocks gastrin-stimulated signaling pathways, including calcium mobilization and ERK phosphorylation, in CCKBR-expressing cells. The compound's antiproliferative effects have been demonstrated in gastric neuroendocrine tumor cell lines, where it inhibits cell proliferation and induces apoptosis. Netazepide also reduces the secretion of gastrin-regulated hormones and growth factors. These in vitro findings support the compound's potential as a therapeutic agent for gastrin-dependent tumors and hypergastrinemic conditions. The compound's selectivity for CCKBR over CCKAR has been confirmed in receptor binding and functional assays.
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| ln Vivo |
Anesthetized rats' stomach acid secretion induced by pentagastrin is inhibited by sograzepide (Netazepide; YF 476; YM-220) (0.1 μmol/kg; intravenous injection), with an ED50 of 87 nmol/kg[1]. With an ED50 value of 0.0086 μM/kg, sograzepide (Netazepide; YF 476; YM-220) (intravenous injection; 10 μM/kg) reduces pentagastrin-induced acid secretion but has no effect on histamine or bethanechol. acid secretion brought on by bases [2]. With ED50 values of 0.018 and 0.020 μM/kg, sograzepide (Netazepide; YF 476; YM-220) (IV; PO) suppresses pentagastrin-stimulated stomach acid secretion in a dose-dependent manner in Heidenhain pouch dogs [2].
In vivo, Netazepide induces regression of type 1 gastric neuroendocrine tumors in patients and in animal models. In clinical studies, oral administration of Netazepide has been shown to reduce tumor size and number in patients with type 1 gastric neuroendocrine tumors. The compound also reduces gastric acid secretion and serum gastrin levels in vivo. In animal models, Netazepide inhibits gastrin-stimulated acid secretion and prevents the development of gastric hyperplasia and neoplasia associated with hypergastrinemia. The compound's oral bioavailability and favorable pharmacokinetic profile support its use as an investigational therapeutic agent. These in vivo findings demonstrate the potential of Netazepide for the treatment of gastrin-related disorders and gastric neuroendocrine tumors. |
| Enzyme Assay |
In vitro receptor binding assays for Netazepide typically involve competition binding studies using radiolabeled gastrin or CCK. A typical protocol: membrane preparations from CCKBR-expressing cells (e.g., CHO-CCKBR) are incubated with [¹²⁵I]-gastrin or [¹²⁵I]-CCK-8 (20-50 pM) and varying concentrations of Netazepide (0.01 nM to 10 μM) in binding buffer (50 mM Tris-HCl, pH 7.4, 5 mM MgCl₂, 0.1% BSA, 0.1 mM bacitracin) for 60-120 minutes at room temperature. Non-specific binding is determined in the presence of 1 μM unlabeled gastrin or CCK-8. Bound radioactivity is separated by rapid filtration through glass fiber filters and quantified by scintillation counting. IC₅₀ and Kᵢ values are calculated from competition curves. For selectivity assays, binding to CCKAR is assessed using similar protocols with CCKAR-expressing membranes. Functional assays measure inhibition of gastrin-stimulated calcium mobilization or ERK phosphorylation in CCKBR-expressing cells.
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| Cell Assay |
In vitro cell-based assays for Netazepide are performed using CCKBR-expressing cell lines such as CHO-CCKBR, HEK293-CCKBR, or gastric neuroendocrine tumor cell lines. A typical protocol: cells are seeded in 96-well plates at 20,000-50,000 cells/well and cultured overnight. Cells are serum-starved for 2-4 hours, then pre-incubated with Netazepide at concentrations ranging from 0.01 nM to 10 μM for 30 minutes. Cells are stimulated with gastrin or CCK-8 (10-100 nM) for 5-30 minutes. Signaling readouts include calcium flux (measured using Fluo-4 or Fura-2 AM), ERK phosphorylation (measured by phospho-ERK ELISA or Western blot), and cAMP accumulation (measured by ELISA or HTRF). For proliferation assays, cells are treated with Netazepide (0.01-10 μM) for 24-72 hours, and cell viability or proliferation is assessed using MTT, BrdU incorporation, or CellTiter-Glo assays. Apoptosis is assessed by Annexin V/PI staining and flow cytometry. Each condition is tested in triplicate, and experiments are repeated at least three times.
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| Animal Protocol |
In vivo animal studies for Netazepide are conducted in rodent models of hypergastrinemia and gastric neuroendocrine tumors. A typical protocol: male or female rats or mice are administered Netazepide via oral gavage at doses ranging from 1 to 30 mg/kg, daily for 2-8 weeks. In models of hypergastrinemia (e.g., transgenic mice overexpressing gastrin or rats treated with proton pump inhibitors), endpoints include serum gastrin levels (measured by ELISA), gastric acid secretion (measured by gastric pH or acid output), and histopathological examination of gastric mucosa for hyperplasia, neuroendocrine cell proliferation, and tumor formation. For tumor regression studies, animals with established gastric neuroendocrine tumors are treated with Netazepide, and tumor size is monitored by endoscopy or ultrasonography. At study termination, tissues are harvested for biomarker analysis (e.g., CCKBR expression, proliferation markers, apoptosis markers).
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| ADME/Pharmacokinetics |
Pharmacokinetic properties of Netazepide have been characterized in preclinical and clinical studies. The compound is orally active and has demonstrated favorable oral bioavailability. Following oral administration, Netazepide is absorbed and reaches therapeutic concentrations in the systemic circulation. The compound's half-life, volume of distribution, and clearance have been evaluated in animal models and in human subjects. Netazepide is metabolized primarily in the liver, and its metabolites are eliminated via the renal and biliary routes. The compound's pharmacokinetic profile supports once-daily or twice-daily dosing in clinical studies. Specific pharmacokinetic parameters (e.g., Cmax, Tmax, AUC, t₁/₂) have been reported in clinical trial publications. The compound is stable under recommended storage conditions and should be stored as specified by the manufacturer.
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| Toxicity/Toxicokinetics |
Toxicological data for Netazepide have been evaluated in preclinical safety studies supporting its clinical development. In animal studies, Netazepide has been generally well-tolerated at therapeutic doses. Common adverse effects may include gastrointestinal disturbances related to reduced gastric acid secretion. The compound has not been associated with significant organ toxicity or genotoxicity in preclinical studies. However, formal toxicology data are proprietary and not fully disclosed in public literature. Standard laboratory safety precautions should be followed when handling Netazepide: use of personal protective equipment (gloves, safety goggles, lab coat) and handling in a well-ventilated fume hood. The compound should be stored as recommended by the manufacturer. Researchers should consult the safety data sheet (SDS) before handling.
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| References |
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| Additional Infomation |
Additional information for Netazepide: The compound has a CAS number of 155488-25-8. Its molecular formula is C₂₈H₃₀N₆O₃ and molecular weight is 498.58-498.59 g/mol. Synonyms include Sograzepide. The compound is an orally active, selective CCKBR/CCK2R/gastrin receptor antagonist. It induces regression of type 1 gastric neuroendocrine tumors. The compound has been investigated in clinical trials for the treatment of gastric neuroendocrine tumors and hypergastrinemic conditions. It is an investigational drug and has not received FDA approval for clinical use. The compound is for research use only and is not approved for clinical applications outside of investigational studies.
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| Molecular Formula |
C28H30N6O3
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| Molecular Weight |
498.587
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| Exact Mass |
498.238
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| CAS # |
155488-25-8
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| Related CAS # |
(Rac)-Sograzepide;168161-71-5
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| PubChem CID |
9870520
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| Appearance |
Off-white to light yellow solid powder
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| Density |
1.25g/cm3
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| Boiling Point |
723.049ºC at 760 mmHg
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| Flash Point |
391.086ºC
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| LogP |
4.048
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
6
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
37
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| Complexity |
868
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| Defined Atom Stereocenter Count |
1
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| SMILES |
CC(C)(C)C(=O)CN1C2=CC=CC=C2C(=N[C@H](C1=O)NC(=O)NC3=CC=CC(=C3)NC)C4=CC=CC=N4
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| InChi Key |
YDZYKNJZCVIKPP-VWLOTQADSA-N
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| InChi Code |
InChI=1S/C28H30N6O3/c1-28(2,3)23(35)17-34-22-14-6-5-12-20(22)24(21-13-7-8-15-30-21)32-25(26(34)36)33-27(37)31-19-11-9-10-18(16-19)29-4/h5-16,25,29H,17H2,1-4H3,(H2,31,33,37)/t25-/m0/s1
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| Chemical Name |
1-[(3R)-1-(3,3-dimethyl-2-oxobutyl)-2-oxo-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]-3-[3-(methylamino)phenyl]urea
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| Synonyms |
YF 476; YF-476; YF476
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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 : ≥ 100 mg/mL (~200.57 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.17 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 20.8 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: ≥ 2.08 mg/mL (4.17 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in 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 20.8 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. View More
Solubility in Formulation 3: ≥ 2.08 mg/mL (4.17 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.0057 mL | 10.0283 mL | 20.0566 mL | |
| 5 mM | 0.4011 mL | 2.0057 mL | 4.0113 mL | |
| 10 mM | 0.2006 mL | 1.0028 mL | 2.0057 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.
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