A-8531
A-8531 is an orally active CD38 inhibitor with IC50 values of 1.10 nM against human CD38, IC50 values of 2.93 nM against mouse CD38, and a human Ka of 0.32 nM. A-8531 exerts its inhibitory activity via its 4-pyridine reactive warhead interacting with the CD38 substrate NAD+, and binds stably to CD38 only in the presence of NAD+, with a binding KD of 0.32 nM as detected by SPR. A-8531 dose-dependently increases NAD+ levels in mouse skin, lung and liver tissues, while simultaneously reducing the contents of NAM and ADPR in these tissues. A-8531 derivative A-3190 (HY-184206) has blood-brain barrier penetration. A-8531 can be used in studies related to neurodegenerative diseases.
For research use only. We do not sell to patients.
- Formula: C22H20N6O
- Molecular Weight:384.43
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Storage:
Please store the product under the recommended conditions in the Certificate of Analysis.
To place orders, for customer services and technical support, please contact: MedChemExpress USA
Tel: 609-228-6898 E-mail: [email protected] [email protected]
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Biological Activity
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Chemical Information
- Protocols
- Purity & Documentation
- References
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Help & FAQs
Biological Activity
Description
In Vitro
A-8531 (compound 25) (0-1 μM; 1-2 h) potently inhibits human CD38 NADase activity with an IC50 of 0.311 nM, and potently inhibits mouse CD38 NADase activity with an IC50 of 3.12 nM[1].
A-8531 binds tightly to human CD38 only in the presence of NAD+, with a KD value of 0.32 nM[1].
A-8531 significantly stabilizes human CD38 (ΔTm = 17.0 °C) only when incubated with 1 mM NAD+[1].
A-8531 is a non-competitive inhibitor of human CD38 hydrolase activity, with a Kiu of 0.6 nM[1].
A-8531 exhibits an apparent permeability coefficient of 51.3 × 10-6 cm/s in MDCK-MDR1 cells with a high efflux ratio of 5.8[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only. Further protocols information, click here.
In Vivo
A-8531 (30 mg/kg; p.o.; once; daily; 4 days) produces peak lung NAD+ elevation at 3 hours post-dose, with no compound or NAD+ accumulation after 4 days of daily dosing[1].
MedChemExpress (MCE) has not independently confirmed the accuracy of these methods. They are for reference only.
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Animal Model:C57Bl/6J (female, average 20 g, 11-14 weeks of age)[1]
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Dosage:1 mg/kg; 10 mg/kg; 30 mg/kg
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Administration:p.o.; daily; 4 days
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Result:Elevated NAD+ in skin, lung and liver at 1 mg/kg, with free tissue exposures ~10× (skin), ~10× (lung), ~12× (liver) mouse CD38 IC50.
Boosted NAD+ in skin, lung and liver at 10 mg/kg, with free tissue exposures >100× (skin), ~70× (lung), >100× (liver) mouse CD38 IC50.
Attained free brain concentrations 3.5× mouse CD38 IC50 at 30 mg/kg, yielding brain NAD+ comparable to 1 mg/kg A-3190.
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Animal Model:C57Bl/6J (female, average 20 g, 11-14 weeks of age)[1]
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Dosage:30 mg/kg
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Administration:p.o.; once; p.o.; daily; 4 days
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Result:Produced peak NAD+ levels in lung tissue at 3 hours post-dose for both single and 4-day daily dosing, with significant elevations.
Decreased NAD+ levels and unbound lung tissue concentrations sharply between 6 and 24 hours post-dose.
Showed no accumulation of compound or NAD+ between single and 4-day daily dosing.
Chemical Information
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Molecular Weight 384.43
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Formula C22H20N6O
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SMILES
NC1=C(C2=CC=NC=C2)N3N=C(C4=CC=C(C(N(C)C5CC5)=O)C=C4)C=CC3=N1
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Shipping
Room temperature in continental US; may vary elsewhere.
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Storage
Please store the product under the recommended conditions in the Certificate of Analysis.
Protocols
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Cell Cytotoxicity Assay
Cytotoxicity assays are usually based on the assessment of cell membrane damage, which can also be indirectly detected by measuring cell viability. Detection methods include MTT assay, CKK-8 assay, LDH assay and ATP assay, etc.
Purity & Documentation
References
Calculators
Concentration (start) × Volume (start) = Concentration (final) × Volume (final)
A-8531 Related Classifications
HY-184021 Related Classifications
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