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| Targets |
Inducible Nitric Oxide Synthase (iNOS, encoded by NOS2). AR-C102222 acts as a competitive inhibitor for the substrate L-arginine binding to the active site of the iNOS enzyme. By blocking the enzyme, it prevents the overproduction of nitric oxide (NO) by macrophages and other inflammatory cells. Elevated NO levels are key drivers of inflammation and pain signaling. The compound demonstrates an IC₅0 of 37 nM and is approximately 3,000-fold selective for iNOS over eNOS.
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| ln Vitro |
In cell-free enzymatic assays, AR-C102222 competitively inhibits human iNOS with an IC₅0 of 37 nM, confirming its high affinity. Cellular studies are not typically required for the primary mechanism as the target is an enzyme. However, in cell-based assays using activated macrophages, the compound would effectively block the production of nitrite, a stable breakdown product of NO, confirming its functional intracellular activity. It shows no significant activity against other NOS isoforms at similar concentrations.
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| ln Vivo |
AR-C102222 (3, 10, 30, 100 mg/kg, PO) can diminish ear inflammation produced by arachidonic acid and has anti-inflammatory effect [2]. AR-C102222 exhibited potential effectiveness in a rat adjuvant-induced arthritis model [3].
In rodent models, AR-C102222 exhibits dose-dependent anti-inflammatory and antinociceptive activity. Oral administration (3, 10, 30, 100 mg/kg, P.O.) significantly attenuates arachidonic acid-induced ear inflammation in mice, achieving maximal inhibition of approximately 79% at 100 mg/kg. Additionally, the compound demonstrates good efficacy in a rat adjuvant-induced arthritis model and in models of neuropathic and post-operative pain, reducing hyperalgesia and confirming its therapeutic potential. |
| Enzyme Assay |
A radiometric assay is used to test iNOS activity. A reaction mixture containing 30 nM iNOS, 10 microM [3H]-L-arginine, 1 mM NADPH, 3 microM tetrahydrobiopterin, and AR-C102222 (0.1-1000 nM) is incubated for 45 min at 37degC. The reaction is terminated with a stop buffer (100 mM HEPES, 1 mM EGTA). [3H]-L-citrulline is separated from [3H]-L-arginine by cation exchange chromatography, and radioactivity is measured by scintillation counting to determine the IC₅0.
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| Cell Assay |
Due to its direct enzymatic target, cellular protocols are less common. However, for cellular confirmation, RAW 264.7 mouse macrophages are seeded and activated with lipopolysaccharide (LPS, 1 microg/mL) and interferon-gamma (IFN-gamma, 100 U/mL) in the presence of AR-C102222 (0.1-1000 nM) for 24 hours. Culture supernatant nitrite levels are measured using the Griess reagent. Cytotoxicity is assessed via the MTT assay. The compound‘s IC₅0 for NO production inhibition is determined from a standard curve.
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| Animal Protocol |
Animal/Disease Models: Male Balb/c mouse (20-25 grams) [2].
Doses: 3, 10, 30, 100 mg/kg. Route of Administration: Orally 55 minutes before administration of 0.6% acetic acid (ip, 1 mL/100 g volume). Experimental Results: A dose of 100 mg/kg could Dramatically inhibit arachidonic acid-induced ear inflammation, with a maximum inhibition rate of approximately 79%. The anti-inflammatory protocol uses male Balb/c mice (20-25 g). Arachidonic acid (0.5 mg/ear) is dissolved in acetone and applied to the inner and outer surfaces of the right ear. AR-C102222 is dissolved in 0.5% methylcellulose and administered by oral gavage (3, 10, 30, 100 mg/kg) 55 minutes before the arachidonic acid challenge. The left ear receives acetone vehicle as a control. After 1 hour, ear punches (6 mm) are taken and weighed. Edema is measured by the weight difference between the right and left ear punches. |
| ADME/Pharmacokinetics |
AR-C102222 is orally bioavailable with an IC₅0 of 37 nM. It exhibits excellent pharmacokinetic properties suitable for in vivo efficacy studies, with a reported oral bioavailability enabling effective dosing in rodent models (3-100 mg/kg). The compound has a molecular weight of 418.83 and is soluble in DMSO. While specific PK parameters (t1/2, Cmax) are not published, its robust oral activity confirms sufficient absorption and metabolic stability to maintain target engagement throughout the duration of the pain/inflammation studies (e.g., 4-6 hours).
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| Toxicity/Toxicokinetics |
Published toxicological data for AR-C102222 is not available. However, due to its mechanism of blocking NO production, it might influence normal physiological functions where basal NO is involved, such as blood pressure regulation (though it is highly selective for iNOS). In animal efficacy studies, doses up to 100 mg/kg were well-tolerated without reports of acute mortality or severe adverse events. In vitro assays demonstrate a high selectivity window, suggesting a low risk of off-target toxicity due to the inhibition of other NOS isoforms.
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| References |
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| Additional Infomation |
AR-C102222 is a standard research chemical and has not received regulatory approval for clinical use. It was originally discovered by AstraZeneca and serves as a key pharmacological tool to study the role of iNOS in inflammatory diseases. It is structurally distinct from other iNOS inhibitors, featuring a unique spirocyclic quinazolinamine core. The compound is used to validate the therapeutic potential of iNOS inhibition for treating chronic pain, osteoarthritis, and inflammatory bowel disease in preclinical models.
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| Molecular Formula |
C19H17CLF2N6O
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| Molecular Weight |
418.8277
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| Exact Mass |
418.112
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| CAS # |
1781934-50-6
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| PubChem CID |
21192822
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| Appearance |
White to off-white solid powder
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| Hydrogen Bond Donor Count |
3
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| Hydrogen Bond Acceptor Count |
7
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| Rotatable Bond Count |
1
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| Heavy Atom Count |
29
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| Complexity |
698
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| Defined Atom Stereocenter Count |
0
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| SMILES |
Cl[H].FC1C([H])=C([H])C(=C2C(N([H])[H])=NC3(C([H])([H])C([H])([H])N(C(C4=C([H])N=C(C#N)C([H])=C4[H])=O)C([H])([H])C3([H])[H])N([H])C2=1)F
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| InChi Key |
FJFMOBYDHGJDGV-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C19H16F2N6O.ClH/c20-13-3-4-14(21)16-15(13)17(23)26-19(25-16)5-7-27(8-6-19)18(28)11-1-2-12(9-22)24-10-11;/h1-4,10,25H,5-8H2,(H2,23,26);1H
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| Chemical Name |
5-(4-amino-5,8-difluorospiro[1H-quinazoline-2,4'-piperidine]-1'-carbonyl)pyridine-2-carbonitrile;hydrochloride
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| Synonyms |
ARC102222 HCl; AR C102222 HCl
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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 Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| 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 | 2.3876 mL | 11.9380 mL | 23.8760 mL | |
| 5 mM | 0.4775 mL | 2.3876 mL | 4.7752 mL | |
| 10 mM | 0.2388 mL | 1.1938 mL | 2.3876 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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