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CCK-B Receptor Antagonist 2 (compound 15b) is a novel, potent and orally bioactive Gastrin/CCK-B antagonist with an IC50 value of 0.43 nM. CCK-B Receptor Antagonist 2 also inhibits gastrin/CCK-A activity with an IC50 of 1.82 μM.
| Targets |
CCK-B Receptor Antagonist 2 (YF476, CAS#: 155412-88-7) targets the gastrin/CCK-B receptor (also known as CCK-B receptor). In rat brain membranes, it displaces [125I]CCK-8 with an IC50 of 0.35–0.54 nM (95% confidence limits). It also binds to the CCK-A receptor from rat pancreas with lower affinity, displacing [3H]L-364,718 with an IC50 of 1699–1949 nM. [1]
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| ln Vivo |
CCK-B receptor antagonist 2 (0.1 μmol/kg; intravenous injection) inhibits the stomach acid production caused by pentagastrin in rats under anesthesia, with an ED50 of 8.3 nmol/kg[1].
In anesthetized rats, intravenous administration of CCK-B Receptor Antagonist 2 (YF476, CAS#: 155412-88-7) inhibited pentagastrin-induced gastric acid secretion with an ED50 of 0.0087 μmol/kg. [1] In Heidenhain pouch dogs, oral administration of CCK-B Receptor Antagonist 2 (YF476, CAS#: 155412-88-7) produced dose-dependent inhibition of pentagastrin-induced gastric acid secretion. At an oral dose of 0.1 μmol/kg, complete (100%) inhibition was observed; at 0.03 μmol/kg, 65% inhibition was observed. The oral ED50 was 0.021 μmol/kg (95% confidence limits: 0.013–0.029). Intravenous administration gave an ED50 of 0.018 μmol/kg (95% confidence limits: 0.013–0.033). The compound maintained complete inhibition of acid secretion for more than 6 hours after oral administration at 100 nmol/kg (0.1 μmol/kg). [1] |
| Enzyme Assay |
For CCK-B/gastrin receptor binding: Rat brains were homogenized in 0.32 M sucrose and centrifuged at 900g for 10 min. The supernatant was further centrifuged at 11500g for 15 min. The pellet was dispersed in 50 mM Tris-HCl (pH 7.4) containing 0.08% Triton X-100, allowed to stand for 30 min, and centrifuged again at 11500g for 15 min. The precipitate was washed twice with 5 mM Tris-HCl and twice with 50 mM Tris-HCl. The final membrane preparation was suspended in 50 mM Tris-HCl and stored at -80°C. For the assay, membranes were diluted with 10 mM HEPES buffer (containing 130 mM NaCl, 5 mM MgCl2, 1 mM EDTA, and 0.25 mg/mL bacitracin, pH 6.5), incubated at 25°C for 120 min with [125I]CCK-8 and the test compound, and then separated by suction filtration. Nonspecific binding was determined in the presence of 1 mM CCK-8. The IC50 was defined as the concentration of test compound required to inhibit specific binding by 50%. [1]
For CCK-A receptor binding: Rat pancreas was homogenized in 50 mM Tris-HCl (pH 7.7) using a Polytron homogenizer. The homogenate was centrifuged at 50000g for 10 min twice. The pellet was suspended in 50 mM Tris-HCl buffer containing 0.2% BSA, 5 mM MgCl2, 0.1 mg/mL bacitracin, and 5 mM DTT (pH 7.7). The membrane preparation was stored at -80°C. For the assay, membranes were warmed to room temperature, diluted 1:10 with the buffer, and incubated at 37°C for 30 min with [3H]L-364,718 and the test compound, then separated by suction filtration. Nonspecific binding was determined in the presence of 1 mM L-364,718. The IC50 was defined as the concentration of test compound required to inhibit specific binding by 50%. [1] |
| Animal Protocol |
Rat gastric acid secretion model: Male rats were anesthetized with urethane (1.25 g/kg intraperitoneally). A cannula was inserted into the trachea. After abdominal incision, the cardia was ligated and a polyethylene cannula was placed in the anterior stomach. The duodenum was incised and a cannula was inserted toward the stomach, with the pylorus ligated to fix the cannula. Physiological saline (adjusted to pH 7.0) was perfused from the anterior stomach toward the pylorus at a rate of 3 mL/min. Gastric acid secretion was measured by continuous titration of the perfusate using a pH-stat with 25 mM NaOH to pH 7.0. Pentagastrin was infused intravenously at 15 mg/kg/h. After stable maximal secretion (approximately 60 min), the test compound was administered intravenously. The ED50 was defined as the dose required to reduce gastric acid secretion to 50% of the maximal level. [1]
Heidenhain pouch dog model: Male beagle dogs with a Heidenhain pouch were used. One month after pouch preparation, secretory experiments were performed once a week. Dogs were fasted for 18 hours prior to experiments but allowed free access to water. A polyethylene tube was inserted into the femoral vein to infuse pentagastrin at a rate of 8 μmol/kg/h. Test compounds were administered orally or intravenously at 3 hours after the start of pentagastrin infusion. Gastric juice was collected every 15 minutes and the acidity was measured by automatic titration with 0.05 N NaOH to pH 7.0. For intravenous injection, test compounds were dissolved in DMF. [1] |
| ADME/Pharmacokinetics |
Oral bioavailability: CCK-B Receptor Antagonist 2 (YF476, CAS#: 155412-88-7) showed excellent oral bioavailability in dogs, as evidenced by a modest difference in activity between oral and intravenous administration (oral ED50 = 0.021 μmol/kg, intravenous ED50 = 0.018 μmol/kg). In contrast, the reference compound YM022 was approximately 70 times less potent orally than intravenously. [1]
Stability: The free base of CCK-B Receptor Antagonist 2 (YF476, CAS#: 155412-88-7) was obtained as a single-crystal form and remained stable after 3 months at 40°C and 75% relative humidity, with no observed imine bond tautomerization under these conditions. [1] |
| References | |
| Additional Infomation |
CCK-B Receptor Antagonist 2 (YF476, CAS#: 155412-88-7) is a potent and orally active gastrin/CCK-B receptor antagonist currently under clinical investigation for the treatment of gastro-oesophageal reflux disease (GORD). [1]
The compound was designed by combining structural modifications including a 1-(tert-butylcarbonyl)methyl group, a 5-(2-pyridyl) substituent, and a 3-(methylamino)phenyl urea moiety, which provided additive improvements in oral absorption and in vivo activity. [1] In Heidenhain pouch dogs, CCK-B Receptor Antagonist 2 (YF476, CAS#: 155412-88-7) was approximately 90 times more potent than YM022 after oral administration (oral ED50 = 21 nmol/kg for YF476 vs. 1.9 μmol/kg for YM022). [1] |
| Molecular Formula |
C27H28N6O3
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| Molecular Weight |
484.549625396729
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| Exact Mass |
484.222
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| CAS # |
155412-88-7
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| PubChem CID |
23844130
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| Appearance |
White to light yellow solid powder
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| LogP |
3.2
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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 |
6
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| Heavy Atom Count |
36
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| Complexity |
853
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| Defined Atom Stereocenter Count |
1
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| SMILES |
O=C(CN1C([C@H](NC(NC2C=CC=C(C=2)N)=O)N=C(C2C=CC=CN=2)C2C=CC=CC1=2)=O)C(C)(C)C
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| InChi Key |
ABJHMASUFPDZRW-DEOSSOPVSA-N
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| InChi Code |
InChI=1S/C27H28N6O3/c1-27(2,3)22(34)16-33-21-13-5-4-11-19(21)23(20-12-6-7-14-29-20)31-24(25(33)35)32-26(36)30-18-10-8-9-17(28)15-18/h4-15,24H,16,28H2,1-3H3,(H2,30,32,36)/t24-/m0/s1
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| Chemical Name |
1-(3-aminophenyl)-3-[(3R)-1-(3,3-dimethyl-2-oxobutyl)-2-oxo-5-pyridin-2-yl-3H-1,4-benzodiazepin-3-yl]urea
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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 : ~25 mg/mL (~51.59 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (4.29 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 (4.29 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 (4.29 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 | 2.0638 mL | 10.3189 mL | 20.6377 mL | |
| 5 mM | 0.4128 mL | 2.0638 mL | 4.1275 mL | |
| 10 mM | 0.2064 mL | 1.0319 mL | 2.0638 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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