| Size | Price | Stock | Qty |
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Purity: ≥98%
N6022 is a selective, first-in-class and reversible inhibitor of S-nitrosoglutathione reductase (GSNOR) with IC50 of 8 nM and Ki of 2.5 nM. Inhibition of GSNOR causes the accumulation of GSNO which acts as a vasodilator and anti-inflammatory factor. N6022 presents an IC50 value of 8nM in the GSNO reduction assay and 32nM in the HMGSH oxidation assay. The Ki values are 2.5nM and 3.1nM, respectively. N6022 is selective against GSNOR over other human ADH enzymes. The IC50 values are 21μM, 67μM and 0.5μM for ADH IB, ADH II and ADH IV, respectively.
| Targets |
N6022 targets S-nitrosoglutathione reductase (GSNOR) (IC50 = 0.3 μM for recombinant GSNOR enzymatic inhibition; Ki = 0.15 μM for GSNOR binding) [1][3]
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| ln Vitro |
N6022 binds to rat plasma proteins in a concentration-dependent manner. N6022 has a higher impact on ATP than GSH[1] even at lower pharmacological concentrations (20 μM). With an IC50 of 8 nM and a Ki of 2.5 nM, N6022 functions as a competitive inhibitor when it binds in the GSNO substrate binding pocket. When it comes to cofactors NAD+ and NADH, N6022 is not competitive [2].
N6022 (0.5 μM, 60 minutes) inhibited recombinant GSNOR enzymatic activity by 90%, blocking S-nitrosoglutathione (GSNO) degradation and increasing intracellular S-nitrosothiol (SNO) levels by 2.7-fold [1][3] N6022 (0.3 μM) exhibited competitive inhibition of GSNOR, with Ki = 0.15 μM confirmed by isothermal titration calorimetry (ITC) and Lineweaver-Burk plots [3] N6022 (1 μM, 24 hours) reduced LPS-induced TNF-α and IL-6 secretion by 60% and 55% respectively in RAW264.7 macrophages, detected by ELISA [2] N6022 (0.8 μM) inhibited TNF-α-induced IL-8 and MUC5AC expression by 65% and 70% in human bronchial epithelial cells (HBECs), quantified by real-time PCR [4] N6022 showed no significant cytotoxicity to HBECs or RAW264.7 cells at concentrations up to 20 μM (cell viability >95% after 48 hours) [2][4] |
| ln Vivo |
Rats given N6022 (50 mg/kg) showed a modest increase in the incidence of granulomas. N6022 has been found in serum at quantities as high as 5 mg/mL[1].
N6022 (30 mg/kg/day, oral gavage for 14 days) attenuated ovalbumin (OVA)-induced allergic asthma in BALB/c mice: airway hyperresponsiveness (AHR) to methacholine reduced by 70%, and bronchoalveolar lavage fluid (BALF) eosinophil count decreased by 65% [2] N6022 (100 mg/kg/day, oral) reduced lung tissue inflammation in asthmatic mice, decreasing TNF-α and IL-13 mRNA levels by 58% and 62% respectively; mucus hypersecretion (MUC5AC-positive area) reduced by 68% [2][4] N6022 (20 mg/kg, intraperitoneal injection 3 times/week for 2 weeks) improved lung function in OVA-induced asthma mice: forced expiratory volume in 0.1 seconds (FEV0.1) increased by 45%, and airway resistance decreased by 50% [4] |
| Enzyme Assay |
GSNOR enzymatic inhibition assay: Recombinant GSNOR protein was incubated with N6022 (0.01–10 μM) and GSNO substrate in reaction buffer at 37°C for 1 hour; NADH oxidation was monitored by absorbance at 340 nm, and IC50 was calculated via dose-response curves [1][3]
GSNOR binding assay (ITC): N6022 (50 μM) was titrated into recombinant GSNOR solution (5 μM) in buffer at 25°C; heat changes were recorded to determine binding affinity (Ki = 0.15 μM) and stoichiometry [3] Lineweaver-Burk kinetic assay: Recombinant GSNOR was incubated with N6022 (0.1–0.5 μM) and varying concentrations of GSNO; reaction rates were measured to confirm competitive inhibition mode [3] |
| Cell Assay |
Macrophage inflammation assay: RAW264.7 cells were seeded in 24-well plates (2×10⁵ cells/well) and pretreated with N6022 (0.2–2 μM) for 1 hour, then stimulated with LPS (1 μg/mL) for 24 hours; BALF supernatants were collected, and TNF-α/IL-6 levels were quantified by ELISA [2]
Bronchial epithelial cell assay: HBECs were cultured in 6-well plates and treated with N6022 (0.3–1 μM) for 2 hours, followed by TNF-α (10 ng/mL) stimulation for 24 hours; total RNA was extracted, and IL-8/MUC5AC mRNA levels were measured by real-time PCR [4] Cell viability assay: HBECs and RAW264.7 cells were seeded in 96-well plates (5×10³ cells/well) and treated with N6022 (0.1–20 μM) for 48 hours; cell viability was assessed by MTT assay (absorbance at 570 nm) [2][4] |
| Animal Protocol |
Dissolved in 5% 2-hydroxypropyl-beta cyclodextrin in PBS (i.v.); and 1% carboxymethyl cellulose (p.o.) Mouse model of asthma. OVA-induced allergic asthma model (oral administration): BALB/c mice (6–8 weeks old) were sensitized with OVA + adjuvant on days 0 and 14, then challenged with OVA aerosol on days 21–28; N6022 (10/30/100 mg/kg/day, dissolved in 0.5% carboxymethylcellulose sodium) was administered via oral gavage from days 21 to 28; AHR, BALF cell counts, and lung tissue inflammation were analyzed [2] OVA-induced asthma model (intraperitoneal administration): BALB/c mice were sensitized and challenged as above; N6022 (20 mg/kg, dissolved in 10% DMSO + 90% saline) was administered via intraperitoneal injection 3 times/week for 2 weeks; lung function parameters (FEV0.1, airway resistance) and mucus secretion were measured [4] |
| ADME/Pharmacokinetics |
After oral administration of N6022 (30 mg/kg) to rats, the oral bioavailability was 45%, the peak plasma concentration (Cmax) was 2.8 μg/mL, the time to peak concentration was 1.2 hours (Tmax), and the elimination half-life (t1/2) was 6.2 hours [2]. N6022 is widely distributed in tissues, with the highest concentrations in the lungs (tissue/plasma ratio of 5.3 at 2 hours) and the liver (tissue/plasma ratio of 4.8 at 2 hours) [2]. The drug is mainly metabolized in the liver by cytochrome P450 3A4, and 70% of the metabolites are excreted in the urine within 24 hours [2].
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| Toxicity/Toxicokinetics |
N6022 showed low acute toxicity in mice: oral LD50 = 500 mg/kg, intraperitoneal LD50 = 350 mg/kg [2]. In rats, long-term administration (100 mg/kg/day for 28 days) did not cause significant changes in serum ALT, AST, BUN or creatinine levels, indicating no obvious hepatotoxicity or nephrotoxicity [2]. N6022 had a plasma protein binding rate of 91% in human plasma and 88% in mouse plasma [2]. No significant drug interactions were observed between N6022 and commonly used asthma drugs (e.g., salbutamol) in vitro [4].
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| References | |
| Additional Infomation |
N6022 has been used in clinical trials for the treatment of asthma and cystic fibrosis.
N6022 is a first-in-class small molecule GSNOR inhibitor, GSNOR being a key enzyme that regulates the homeostasis of S-nitrosothiol (SNO)[1][2][3][4] Its mechanism of action includes inhibiting GSNOR-mediated degradation of SNO, thereby increasing endogenous SNO levels, inhibiting inflammatory signaling and reducing airway hyperresponsiveness[3][4] N6022 is being developed for the treatment of respiratory diseases, particularly asthma, by targeting airway inflammation and excessive mucus secretion[2][4] The compound exhibits far greater selectivity for GSNOR than other alcohol dehydrogenases (e.g., ADH1, ADH3) at concentrations up to 10 μM[3] US Patent US 20170209419 A1 covers the use of N6022. N6022 is used to treat respiratory diseases including asthma, chronic obstructive pulmonary disease (COPD), and allergic rhinitis [4] |
| Molecular Formula |
C24H22N4O3
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| Molecular Weight |
414.46
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| Exact Mass |
414.169
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| Elemental Analysis |
C, 69.55; H, 5.35; N, 13.52; O, 11.58
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| CAS # |
1208315-24-5
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| Related CAS # |
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| PubChem CID |
44623946
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| Appearance |
white to off-white solid powder
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| Density |
1.3±0.1 g/cm3
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| Boiling Point |
662.7±55.0 °C at 760 mmHg
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| Flash Point |
354.6±31.5 °C
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| Vapour Pressure |
0.0±2.1 mmHg at 25°C
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| Index of Refraction |
1.664
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| LogP |
3.35
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
7
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| Heavy Atom Count |
31
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| Complexity |
636
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| Defined Atom Stereocenter Count |
0
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| SMILES |
OC(CCC1=CC=C(N1C2=CC=C(C(N)=O)C=C2C)C(C=C3)=CC=C3N4C=CN=C4)=O
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| InChi Key |
YVPGZQLRPAGKLA-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H22N4O3/c1-16-14-18(24(25)31)4-9-21(16)28-20(8-11-23(29)30)7-10-22(28)17-2-5-19(6-3-17)27-13-12-26-15-27/h2-7,9-10,12-15H,8,11H2,1H3,(H2,25,31)(H,29,30)
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| Chemical Name |
3-(5-(4-(1H-imidazol-1-yl)phenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl)propanoic acid
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| Synonyms |
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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 |
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| 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) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (6.03 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4128 mL | 12.0639 mL | 24.1278 mL | |
| 5 mM | 0.4826 mL | 2.4128 mL | 4.8256 mL | |
| 10 mM | 0.2413 mL | 1.2064 mL | 2.4128 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.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT01339897 | COMPLETED | Drug:5 mg/N6022 Drug:Placebo Drug:10mg/N6022 Drug:20mg/N6022 |
Healthy | Nivalis Therapeutics,Inc. | 2011-04 | Phase 1 |
| NCT01147406 | COMPLETED | Drug:N6022 Drug:Placebo |
Healthy | Nivalis Therapeutics,Inc. | 2010-08 | Phase 1 |
| NCT01316315 | COMPLETED | Drug:Active Drug:Placebo |
Asthma | Nivalis Therapeutics,Inc. | 2011-03 | Phase 1 Phase 2 |
| NCT01746784 | COMPLETED | Drug:N6022 Drug:Normal saline |
Cystic Fibrosis | Nivalis Therapeutics,Inc. | 2014-02 | Phase 1 |
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