2. Immunology/Inflammation
  3. CD38
  4. 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.

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A-8531

A-8531 Chemical Structure

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A-8531 Related Antibodies

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Description

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[1].

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.

A-8531 Related Antibodies
In Vivo

A-8531 (compound 25) (1-30 mg/kg; p.o.; daily; 4 days) dose-dependently increases NAD+ levels in mouse skin, lung, and liver, with significant elevations at 10 mg/kg, and achieves moderate brain exposure at 30 mg/kg[1].
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.

Animal Model: C57Bl/6J (female, average 20 g, 11-14 weeks of age)[1]
Dosage: 1 mg/kg; 10 mg/kg; 30 mg/kg
Administration: p.o.; daily; 4 days
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.
Animal Model: C57Bl/6J (female, average 20 g, 11-14 weeks of age)[1]
Dosage: 30 mg/kg
Administration: p.o.; once; p.o.; daily; 4 days
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.
Molecular Weight

384.43

Formula

C22H20N6O
SMILES

NC1=C(C2=CC=NC=C2)N3N=C(C4=CC=C(C(N(C)C5CC5)=O)C=C4)C=CC3=N1
Shipping

Room temperature in continental US; may vary elsewhere.
Storage

Please store the product under the recommended conditions in the Certificate of Analysis.
Purity & Documentation
References
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A-8531 Related Classifications

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Help & FAQs
  • Do most proteins show cross-species activity?

    Species cross-reactivity must be investigated individually for each product. Many human cytokines will produce a nice response in mouse cell lines, and many mouse proteins will show activity on human cells. Other proteins may have a lower specific activity when used in the opposite species.

Keywords:

A-8531A8531A 8531CD38NADase activitymouse CD38mouse skinMDCK-MDR1 cellshydrolase activitymouse lungmouse liver microsomeshuman CD38NAD+Inhibitorinhibitorinhibit

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