| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Purity: ≥98%
AZD9056 is a novel, potent, selective, orally bioavailable antagonist of P2X7 receptor which is an adenosine triphosphate (ATP)-gated cation channel expressed on a variety of cell types believed to play a role in inflammation. AZD9056 was an inhibitor of BCRP and weakly inhibited BCRP-mediated transport of methotrexate (IC(50)=92μM). Sulfasalazine inhibited methotrexate transport mediated by all transporters studied (IC(50)<5μM). Subsequent assessment of the in vitro data using [I]/IC(50) ratios indicated that both AZD9056 and sulfasalazine were unlikely to cause a DDI with methotrexate in vivo. In conclusion, to support rheumatoid arthritis drug development it is proposed that regulatory in vitro studies for OAT1, OAT3 and BCRP inhibition be routinely conducted to assess the potential for a transporter-mediated DDI with methotrexate in vivo.
| Targets |
P2X7 receptor – selective antagonist; inhibits BCRP-mediated methotrexate transport with IC50 = 92 μM; inhibits BCRP-mediated estrone 3-sulphate transport with IC50 = 32 μM; does not inhibit OAT1 or OAT3 transporters [1]
P2X7 receptor antagonist that suppresses NF-κB pathway activation and reduces inflammatory cytokine expression in osteoarthritis [2] |
|---|---|
| ln Vitro |
In Vitro: AZD9056 (0.3-100 μM) did not inhibit OAT1- or OAT3-mediated methotrexate uptake in oocyte assays. It inhibited BCRP-mediated methotrexate transport with an IC50 of 92 μM and BCRP-mediated estrone 3-sulphate transport with an IC50 of 32 μM. [1]
AZD9056 is a weakly basic secondary amine (pKa 9.77) with a hydrophobic adamantane moiety that is highly protein bound (97%). [1] |
| ln Vivo |
In Vivo: In a rat model of monosodium iodoacetate (MIA)-induced osteoarthritis, AZD9056 (12.5 mg/kg, injected every 2 days for 7 days starting 2 weeks after MIA injection) significantly reduced weight-bearing asymmetry, increased paw withdrawal thresholds, and decreased knee edema size compared to MIA-only group (p < 0.05). [2]
AZD9056 reversed the MIA-induced upregulation of IL-1β, IL-6, and TNF-α in both serum and knee joint cartilage tissues of rats with osteoarthritis. [2] AZD9056 significantly decreased the MIA-induced increase in P2X7 receptor, MMP-13, substance P (SP), and prostaglandin E2 (PGE2) expression in knee joint cartilage tissues. [2] AZD9056 reversed the MIA-induced upregulation of IKKα, IKKβ, IκBα, NF-κB p65 and their phosphorylated forms in the knee cartilage tissues of rats with OA. [2] In rheumatoid arthritis clinical studies, AZD9056 was evaluated for efficacy in patients with active disease despite treatment with methotrexate or sulphasalazine. [1] |
| Enzyme Assay |
Enzyme Assay: Oocyte uptake assays: Pools of 10 OAT1- or OAT3-expressing or water-injected oocytes were washed with sodium uptake buffer (pH 7.4). Uptake solutions contained radiolabelled compound and appropriate concentrations of non-radiolabelled compound in sodium uptake buffer. After 1 h incubation at room temperature, oocytes were washed 5 times with ice-cold buffer, lysed with 10% SDS, and analyzed by liquid scintillation counting. [1]
Vesicle uptake assays: MRP2- and BCRP-expressing membrane vesicles (0.67 mg/mL) were incubated with radiolabelled substrates in uptake buffer (250 mM sucrose, 10 mM MgCl₂, 10 mM Tris/HCl, pH 7.4) with or without 5 mM ATP. After 4 min incubation at 37°C, reactions were terminated by filtration through GF/B filter plates. Radioactivity was measured by liquid scintillation counting. [1] |
| Cell Assay |
Cell Assay: No cell-based assays (e.g., cell viability, antiproliferative, Western blot, PCR, immunohistochemistry, apoptosis, colony formation) were described for AZD9056 in these papers. Western blot analysis was performed on cartilage tissue samples, not on cultured cells. [2]
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| Animal Protocol |
Animal Protocol: Osteoarthritis rat model: Male Wistar rats received a single intra-articular injection of monosodium iodoacetate (MIA, 5 mg/kg) in sterile 0.9% saline into the left hind knee through the infrapatellar ligament using a 26G needle. AZD9056 (12.5 mg/kg) was injected every 2 days for 7 days starting 2 weeks after MIA injection. Behavioral tests (paw withdrawal threshold using Von Frey monofilaments, hindlimb weight-bearing asymmetry using Incapacitance Tester, and knee edema size using digital calipers) were evaluated at days 3, 7, 10, 14, 15, 17, 19, and 21 after MIA injection. Rats were sacrificed on days 7, 14, and 21 for tissue collection. [2]
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| ADME/Pharmacokinetics |
ADME/Pharmacokinetics: The therapeutic dose of AZD9056 is predicted to be 400 mg, giving a predicted total maximum plasma concentration of 2 μM. The theoretical intestinal concentration is calculated to be 3.5 mM. Unbound AZD9056 plasma concentration is 0.06 μM. The compound is highly protein bound (97%). [1]
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| Toxicity/Toxicokinetics |
Toxicity/Toxicokinetics: No specific toxicity data (LD50, hepatotoxicity, nephrotoxicity, drug-drug interactions) were described for AZD9056 in these papers. The compound was evaluated as a potential cause of drug-drug interaction with methotrexate via transporter inhibition. The [I₁]/IC₅₀ ratio for AZD9056 inhibition of BCRP-mediated estrone 3-sulphate transport was 0.06 (total concentration) or 0.002 (unbound concentration), and for BCRP-mediated methotrexate transport was 0.02 (total) or 0.0007 (unbound), indicating low risk of systemic DDI. The intestinal [I₂]/IC₅₀ ratio was 109, suggesting potential for intestinal DDI with BCRP substrates. [1]
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| References |
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| Additional Infomation |
AZD9056 is a purinergic P2X7 receptor antagonist that was being developed for the oral treatment of rheumatoid arthritis. It is a weakly basic secondary amine (pKa 9.77) with a hydrophobic adamantane moiety. In vitro studies showed that AZD9056 is neither an inhibitor of OAT1 nor OAT3 and is unlikely to cause a systemic transporter-mediated DDI with methotrexate. However, as a BCRP inhibitor, it has potential to perpetrate an intestinal DDI with co-administered BCRP substrate drugs. In an osteoarthritis rat model, AZD9056 exerted anti-inflammatory and pain-relieving effects by inhibiting P2X7R and the NF-κB signaling pathway, reducing the expression of IL-1β, IL-6, TNF-α, MMP-13, SP, and PGE2. The compound was evaluated in clinical trials for rheumatoid arthritis but did not meet efficacy endpoints. [1][2]
AZD9056 has been used in trials investigating the basic science and treatment of rheumatoid arthritis. |
| Molecular Formula |
C24H35CLN2O2
|
|---|---|
| Molecular Weight |
418.999905824661
|
| Exact Mass |
418.239
|
| Elemental Analysis |
C, 68.80; H, 8.42; Cl, 8.46; N, 6.69; O, 7.64
|
| CAS # |
345304-65-6
|
| Related CAS # |
345303-91-5 (HCl);345304-65-6;
|
| PubChem CID |
10161381
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| Appearance |
Typically exists as solid at room temperature
|
| LogP |
4.972
|
| Hydrogen Bond Donor Count |
3
|
| Hydrogen Bond Acceptor Count |
3
|
| Rotatable Bond Count |
10
|
| Heavy Atom Count |
29
|
| Complexity |
514
|
| Defined Atom Stereocenter Count |
0
|
| SMILES |
ClC1=CC=C(CCCNCCCO)C=C1C(NCC12CC3CC(CC(C3)C1)C2)=O
|
| InChi Key |
HSQAARMBHJCUOK-UHFFFAOYSA-N
|
| InChi Code |
InChI=1S/C24H35ClN2O2/c25-22-5-4-17(3-1-6-26-7-2-8-28)12-21(22)23(29)27-16-24-13-18-9-19(14-24)11-20(10-18)15-24/h4-5,12,18-20,26,28H,1-3,6-11,13-16H2,(H,27,29)
|
| Chemical Name |
Benzamide, 2-chloro-5-(3-((3-hydroxypropyl)amino)propyl)-N-(tricyclo(3.3.1.13,7)dec-1-ylmethyl)-
|
| Synonyms |
AZD-9056; AZD 9056; AZD-9，056; N-(1-adamantylmethyl)-2-chloro-5-[3-(3-hydroxypropylamino)propyl]benzamide; AZD9056; F13K378W4L; AZD9056.
|
| 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) |
May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples
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|---|---|
| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.3866 mL | 11.9332 mL | 23.8663 mL | |
| 5 mM | 0.4773 mL | 2.3866 mL | 4.7733 mL | |
| 10 mM | 0.2387 mL | 1.1933 mL | 2.3866 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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