Claziprotamidum
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Claziprotamidum (Claziprotamide; BBP-671) is a panthothenate kinase (PANK) activator with oral activity and blood-brain barrier permeability. Claziprotamidum binds to and activates all PANK isoforms, with the highest affinity for PANK3 (KD = 97 pM; IC50 = 1.39 nM). Claziprotamidum increases the intracellular biosynthesis of Coenzyme A (HY-128851) and restores mitochondrial function. Claziprotamidum can be used in the research of pantothenate kinase-associated neurodegeneration and propionic acidemia.
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- Pureza : 98.33%
- No. CAS: 2361124-03-8
- Fòrmula: C19H20ClFN4O
- Peso molecular:374.84
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Almacenamiento:Powder -20°C, 3 years ; In solvent -80°C, 6 months , -20°C, 1 month
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Actividad biológica
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Chemical Information
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Solvente y solubilidad
- Protocolo
- Pureza y Documentación
- Referencias
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Help & FAQs
Actividad biológica
Descripciòn
IC50 & Target
[3]|
PanK3 1.39 nM (Ki) |
PanK1β 2.02 nM (Ki) |
PanK2 102 nM (Ki) |
In Vitro
Claziprotamidum (10 μM; 24 h) increases total CoA levels by 244% in C3A human hepatocyte-like cells[1].
Claziprotamide (BBP-671) acts as an allosteric activator of recombinant PANK1β, PANK2, and PANK3 proteins by reducing their sensitivity to feedback inhibition by acetyl-CoA[2].
Claziprotamidum potently modulates the activity of recombinant human PANK1β, PANK2, and PANK3 proteins, with Ki values of 102 ± 21.4 nM, 2.02 ± 0.52 nM, and 1.39 ± 0.33 nM, respectively[3].
Claziprotamidum binds tightly to recombinant human PANK3 protein with a K0 of 97 ± 2 pM and a residence time of 21.4 minutes[3].
Claziprotamidum (2-7.5 μM) renders recombinant human PANK1β, PANK2, or PANK3 proteins, respectively, highly resistant to inhibition by propionyl-CoA[3].
Claziprotamidum (0.1-90 μM; 24 h) increases total intracellular CoA levels in human liver-derived C3A cells, with maximum elevation at 10 μM[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
Parmacokinetics
In Vivo
Claziprotamidum (0.1-10 mg/kg; p.o.; single administration) dose-dependently increases total CoA levels in the liver and forebrain of healthy C57BL/6J mice. At a single dose of 10 mg/kg, hepatic CoA levels increase by approximately 110%, and forebrain CoA levels increase by approximately 60%[2].
Claziprotamidum (0.1-30 mg/kg; p.o.; once daily; for 7 consecutive days) dose-dependently increases the drug concentrations in plasma, liver and forebrain of healthy C57BL/6J mice[2].
Claziprotamidum (10 mg/kg; p.o.; once daily; for 5 consecutive days) can cross the blood-brain barrier, increase the total CoA level in brain tissue, and also elevate the total CoA level in liver in healthy Sprague-Dawley rats treated with intracisternal catheterization[2].
Claziprotamidum (1 mg/kg; p.o.; once daily; for 3 consecutive days) transiently increases whole-blood acetyl-CoA levels in healthy C57BL/6J mice, with a peak reached at 4 h after the final administration[2].
Claziprotamidum (3 mg/kg/day; oral administration; via feed; once daily; for 5 consecutive days) doubles the whole-blood acetyl-CoA levels in healthy C57BL/6J mice[2].
Claziprotamidum (10 mg/kg per day; mixed into feed; ad libitum access; for 30 consecutive days) restores total brain CoA levels, increases body weight and improves motor function in Pank1fl/fl,Pank2fl/fl SynCre+ PKAN mice, but produces no statistically significant improvement in their survival rate[2].
Claziprotamidum (22.5 ppm; oral administration; continuous dosing) restores the survival rate of PA mice to 100%, normalizes hepatic CoA metabolite levels, reduces the levels of hallmark PA biomarkers in plasma and urine, and restores mitochondrial TCA cycle function[3].
Claziprotamidum (1 mg/kg; p.o.; single administration) increases the total hepatic CoA concentration in healthy C57BL/6J mice, with the peak observed at 4 h, and the elevated level persists for up to 24 h[3].
Claziprotamidum (11.25-45 ppm; oral administration; continuous dosing; 4 weeks) produces the maximal increase in total hepatic CoA concentration in healthy C57BL/6J mice at the dose of 22.5 ppm, with no additional benefit observed at the higher dose of 45 ppm[3].
Claziprotamidum (22.5 ppm; oral administration; continuous dosing) restores the survival rate of PA mice to 100%, normalizes hepatic CoA metabolite levels, reduces the levels of hallmark PA biomarkers in plasma and urine, and restores mitochondrial TCA cycle function[3].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57Bl6/J (6−8 weeks old)[1]
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Dosage:10 mg/kg
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Administration:oral gavage; every 12 hours; 5 doses
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Result:Significantly increased total CoA levels in mouse liver, forebrain, and hindbrain relative to vehicle control.
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Animal Model:C57BL/6J (male, 8-9 weeks old)[2]
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Dosage:0.1 mg/kg; 1 mg/kg; 3 mg/kg; 10 mg/kg
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Administration:p.o.; single dose
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Result:Left liver total CoA levels unchanged relative to controls at 0.1 mg/kg.
Increased liver total CoA to ~160 pmol/mg wet weight (a ~50% increase relative to controls) and forebrain total CoA to ~70 pmol/mg wet weight (a ~30% increase relative to controls) at 1 mg/kg.
Increased liver total CoA to ~190 pmol/mg wet weight (a ~80% increase relative to controls) and forebrain total CoA to ~78 pmol/mg wet weight (a ~45% increase relative to controls) at 3 mg/kg.
Increased liver total CoA to ~220 pmol/mg wet weight (a ~110% increase relative to controls) and forebrain total CoA to ~85 pmol/mg wet weight (a ~60% increase relative to controls) at 10 mg/kg.
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Animal Model:C57BL/6J (male, 8 weeks old)[2]
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Dosage:0.1 mg/kg; 1 mg/kg; 3 mg/kg; 30 mg/kg
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Administration:p.o.; once daily; 7 days
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Result:Increased plasma, liver, and forebrain concentrations proportionally to the administered dose.
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Animal Model:Sprague-Dawley (male, intracisternal cannulated)[2]
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Dosage:10 mg/kg
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Administration:p.o.; once daily; 5 days
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Result:Reached a Cmax of 0.12 pmol/μL and half-life of 1.6 hours in CSF.
Increased liver total CoA from a baseline of ~100 pmol/mg wet weight to a Cmax of ~142 pmol/mg wet weight at 2 hours postdose, with levels remaining elevated at 8 hours.
Increased brain total CoA from a baseline of ~40 pmol/mg wet weight to a Cmax of ~78 pmol/mg wet weight at 8 hours postdose.
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Animal Model:C57BL/6J (male, 8-9 weeks old)[2]
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Dosage:1 mg/kg
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Administration:p.o.; once daily; 3 days
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Result:Increased whole-blood acetyl-CoA levels from a baseline of ~0.3 pmol/μL blood to a peak of ~0.55 pmol/μL blood at 4 hours postdose, then decreased to ~0.3 pmol/μL blood at 8 hours postdose.
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Animal Model:C57BL/6J (8-10 weeks old)[2]
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Dosage:3 mg/kg/day
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Administration:p.o.; via chow; once daily; 5 days
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Result:Increased whole-blood acetyl-CoA levels by ~100% relative to untreated controls (from ~0.3 pmol/μL blood to ~0.6 pmol/μL blood).
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Animal Model:Pank1fl/fl,Pank2fl/fl SynCre+ (mixed gender, postnatal day 14 at study start, neuron-specific conditional deletion of Pank1 and Pank2 genes via SynCre promoter)[2]
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Dosage:10 mg/kg/day
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Administration:p.o.; via 75 ppm chow; ad libitum; 30 days starting at P14
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Result:Was detected in plasma, liver, forebrain, and hindbrain of treated mice.
Elevated forebrain total CoA levels, restoring ~70% of the deficit relative to untreated PKAN mice, and fully restored hindbrain total CoA levels to control levels.
Increased body weight significantly relative to untreated PKAN mice.
Enhanced locomotor function, with total distance traveled increased by ~300% and percentage of time moving increased by ~200% relative to untreated PKAN mice.
Showed no statistically significant improvement in survival probability relative to untreated PKAN mice.
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Animal Model:C57BL/6J mice (male and female, age postnatal day 19-21, genetic hypomorphic Propionic acidemia model with genotype Pcca^(-/-) PCCA(A138T)^(tg/0))[3]
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Dosage:22.5 ppm
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Administration:oral; continuous
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Result:Normalized hepatic nonesterified CoA (CoASH) and acetyl-CoA (C2-CoA) concentrations to near wild-type levels.
Reduced hepatic propionyl-CoA (C3-CoA) levels and significantly lowered the hepatic C3:C2-CoA ratio.
Significantly reduced elevated plasma C3:C2-carnitine ratio, methylcitrate, and methylmalonate.
Significantly reduced urinary malate, α-ketoglutarate, and C3:C2-carnitine ratio, while elevated urinary C2-carnitine.
Restored survival to wild-type levels, with 100% survival up to postnatal day 100.
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Animal Model:C57BL/6J mice (male, age 8 weeks)[3]
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Dosage:1 mg/kg
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Administration:p.o.; single dose
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Result:Increased liver total CoA concentrations to a maximum at 4 hours post-dosing.
Remained elevated through 12 hours post-dosing.
Were still higher than baseline at 24 hours post-dosing.
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Animal Model:C57BL/6J mice (male, age 8 weeks)[3]
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Dosage:11.25 ppm; 22.5 ppm; 45 ppm
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Administration:oral; continuous; 4 weeks
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Result:Elevated liver total CoA concentrations compared to control at 11.25 ppm.
Maximally elevated liver total CoA concentrations at 22.5 ppm.
Did not further increase liver total CoA concentrations at 45 ppm despite higher liver drug levels.
Chemical Information
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No. CAS 2361124-03-8
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Appearance Solid
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Peso molecular 374.84
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Fòrmula C19H20ClFN4O
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Color White to off-white
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SMILES
O=C(CC1=CC=C(C2CC2)C(F)=C1)N3CCN(CC3)C4=NN=C(C=C4)Cl
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Synonyms
Claziprotamide; BBP-671
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Envío
Room temperature in continental US; may vary elsewhere.
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Almacenamiento
Powder -20°C 3 years In solvent -80°C 6 months -20°C 1 month
Solvente y solubilidad
In Vitro:
DMSO : 100 mg/mL (266.78 mM; Need ultrasonic; Hygroscopic DMSO has a significant impact on the solubility of product, please use newly opened DMSO)
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
In Vivo:
Select the appropriate dissolution method based on your experimental animal and administration route.
- For the following dissolution methods, please ensure to first prepare a clear stock solution using an In Vitro approach and then sequentially add co-solvents:
- To ensure reliable experimental results, the clarified stock solution can be appropriately stored based on storage conditions. As for the working solution for In Vivo experiments, it is recommended to prepare freshly and use it on the same day.
- The percentages shown for the solvents indicate their volumetric ratio in the final prepared solution. If precipitation or phase separation occurs during preparation, heat and/or sonication can be used to aid dissolution.
Add each solvent one by one: 10% DMSO 40% PEG300 5% Tween-80 45% Saline
Solubility: ≥ 5 mg/mL (13.34 mM); Suspended solution
This protocol yields a suspended solution of ≥ 5 mg/mL (saturation unknown). Suspended solution can be used for oral and intraperitoneal injection.
Taking 1 mL working solution as an example, add 100 μL DMSO stock solution (50.0 mg/mL) to 400 μL PEG300, and mix evenly; then add 50 μL Tween-80 and mix evenly; then add 450 μL Saline to adjust the volume to 1 mL.
Preparation of Saline: Dissolve 0.9 g sodium chloride in ddH₂O and dilute to 100 mL to obtain a clear Saline solution.
In Vivo Dissolution Calculator
Please enter the basic information of animal experiments:
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Recommended: Prepare an additional quantity of animals to account for potential losses during experiments.
Please enter your animal formula composition:
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%DMSO +
Recommended: Keep the proportion of DMSO in working solution below 2% if your animal is weak.
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%+
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+%Tween-80 + +
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%Saline +
The co-solvents required include: DMSO, . All of co-solvents are available by MedChemExpress (MCE). , Tween 80. All of co-solvents are available by MedChemExpress (MCE).
Working solution concentration: 0.22 mg/mL
Method for preparing stock solution: mg drug dissolved in μL DMSO. Stock solution concentration: mg/mL.
1. Take μL DMSO stock solution;
2. Add μL .
μL , mix evenly;
3. Then add μL Tween 80, mix evenly;
4. Then add μL
Please ensure that the stock solution in the first step is dissolved to a clear state, and add co-solvents in sequence. You can use ultrasonic heating (ultrasonic cleaner, recommended frequency 20-40 kHz), vortexing, etc. to assist dissolution.
Pureza y Documentación
Referencias
[1]. Tangallapally R, et al. Development of Brain Penetrant Pyridazine Pantothenate Kinase Activators. J Med Chem. 2024;67(16):14432-14442. [Content Brief]
[2]. Subramanian C, et al. Pantothenate Kinase Activation Restores Brain Coenzyme A in a Mouse Model of Pantothenate Kinase-Associated Neurodegeneration. J Pharmacol Exp Ther. 2024;388(1):171-180. Published 2024 Jan 2. [Content Brief]
[3]. Subramanian C, et al. Relief of CoA sequestration and restoration of mitochondrial function in a mouse model of propionic acidemia. J Inherit Metab Dis. 2023;46(1):28-42. [Content Brief]
Complete Stock Solution Preparation Table
Please refer to the solubility information to select the appropriate solvent. Once prepared, please aliquot and store the solution to prevent product inactivation from repeated freeze-thaw cycles.
Storage method and period of stock solution: -80°C, 6 months; -20°C, 1 month. When stored at -80°C, please use it within 6 months. When stored at -20°C, please use it within 1 month.
| Optional Solvent | Concentration Solvent Mass | 1 mg | 5 mg | 10 mg | 25 mg |
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| DMSO | 1 mM | 2.6678 mL | 13.3390 mL | 26.6780 mL | 66.6951 mL |
| 5 mM | 0.5336 mL | 2.6678 mL | 5.3356 mL | 13.3390 mL | |
| 10 mM | 0.2668 mL | 1.3339 mL | 2.6678 mL | 6.6695 mL | |
| 15 mM | 0.1779 mL | 0.8893 mL | 1.7785 mL | 4.4463 mL | |
| 20 mM | 0.1334 mL | 0.6670 mL | 1.3339 mL | 3.3348 mL | |
| 25 mM | 0.1067 mL | 0.5336 mL | 1.0671 mL | 2.6678 mL | |
| 30 mM | 0.0889 mL | 0.4446 mL | 0.8893 mL | 2.2232 mL | |
| 40 mM | 0.0667 mL | 0.3335 mL | 0.6670 mL | 1.6674 mL | |
| 50 mM | 0.0534 mL | 0.2668 mL | 0.5336 mL | 1.3339 mL | |
| 60 mM | 0.0445 mL | 0.2223 mL | 0.4446 mL | 1.1116 mL | |
| 80 mM | 0.0333 mL | 0.1667 mL | 0.3335 mL | 0.8337 mL | |
| 100 mM | 0.0267 mL | 0.1334 mL | 0.2668 mL | 0.6670 mL |
Claziprotamidum Related Classifications
HY-159509 Related Classifications
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