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Purity: ≥98%
Setanaxib (also known as GKT-137831; GTK831) is a novel, specific, potent, orally bioavailable, and dual inhibitor of NADPH oxidase NOX1/NOX4 with Ki of 110 nM and 140 nM, respectively. It was discovered by rational drug design following a campaign of high-throughput screening on several NOX isoforms. Initially, GKT137831 was developed to treat Idiopathic pulmonary fibrosis and obtained orphan drug designation from both FDA and EMEA in 2010. GKT137831 attenuates hypoxia-induced H2O2 release, cell proliferation, and TGF-β1 expression and blunted reductions in PPARγ in HPAECs and HPASMCs. GKT137831 also prevents oxidative stress in response to hyperglycemia in human aortic endothelial cells. In WT and SOD1mut mice, GKT137831 (60 mg/kg i.g.) prevents liver fibrosis and downregulates markers of oxidative stress, inflammation, and fibrosis.
| Targets |
Nox4 (Ki =140 nM); Nox1 (Ki =110 nM)
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| ln Vitro |
A strong Nox1/4 inhibitor, setanaxib (GKT137831) with a Kis of 140±40/110±30 nM[1]. Setanaxib (GKT137831) administration attenuates HPASMC proliferation under normoxic conditions at the 20 μM concentration during the 72-hour exposure to hypoxia or normoxia, but has no effect on proliferation in normoxic HPAECs. Setanaxib (GKT137831) inhibits the growth of HPASMC and HPAEC caused by hypoxia at concentrations of 5 and 20 μM in the preventive paradigm. The pulmonary vascular cell proliferation induced by hypoxia is inhibited by Setanaxib (GKT137831), according to complementary assays detecting PCNA expression or manual cell counting[2].
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| ln Vivo |
For the latter half of their CCl4 injections, some mice receive daily treatments of Setanaxib (GKT137831). Compared to WT mice, SOD1mu exhibit more severe hepatic fibrosis as a result of CCl4 exposure. Treating SOD1mu and WT mice with Setanaxib (GKT137831) reduces liver fibrosis. Setanaxib (GKT37831) treatment significantly reduces the elevated hepatic α-SMA expression in SOD1mu mice, bringing it down to a level comparable to WT animals given the NOX1/4 inhibitor[1].
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| Enzyme Assay |
Measurement of ROS Generation in HSCs[1]
HSCs were preincubated with the redox-sensitive dye DCFDA (10 μM) for 20 minutes and then stimulated with 10−6 M Ang II or vehicle (PBS) with 20 μM NOX1/4 inhibitor [Setanaxib (GKT137831)] or vehicle (PBS). DCFDA fluorescence was measured with a multiwall fluorescence scanner. Rac1 activity assay[1] Rac1 activity in HSCs was determined with the Rac1 G-LISA™ activation assay kit. (Cytoskelton, Inc.). Briefly, WT or SOD1 mutant HSCs were treated by 10−6 M Ang II (Sigma) or vehicle (PBS) with 20 μM NOX1/4 inhibitor[Setanaxib (GKT137831)] or vehicle (PBS) for 24 hours. According to the manufacturer’s protocol, protein lysate was extracted and Rac1 activity was determined by luminescence intensity. |
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| Cell Assay |
Monolayers of HPAECs and HPASMCs were propagated in culture and placed in normoxic (21% O2, 5% CO2) or hypoxic (1% O2, 5% CO2) conditions for 72 hours as previously reported. GKT137831 (0.1–20 μM), or vehicle (1% DMSO) were added to the culture medium at the onset (prevention regimen) or during the last 24 hours (intervention regimen) of a 72-hour hypoxia exposure regimen. More detailed information about GKT137831 dosing and specificity is provided in the online supplement[2].
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| Additional Infomation |
Setanaxib is an orally bioavailable inhibitor of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOX) 1 and 4, with potential anti-inflammatory, anti-fibrotic and antineoplastic activities. Upon oral administration, setanaxib targets, binds to and inhibits the activity of NOX1 and NOX4. This inhibits NOX1- and NOX4- mediated signal transduction pathways, thereby reducing inflammation and fibrosis. By targeting NOX4-overexpressing cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME), setanaxib may also inhibit myofibroblastic activation and enhance both the penetration of tumor-infiltrating lymphocytes (TILs) and antitumor T-cell immune responses. The NOX enzymes NOX1 and NOX4 primarily produce reactive oxygen species (ROS), which plays important roles in cellular signaling processes that regulate cell proliferation, differentiation and migration, and inflammation and fibrosis.
Drug Indication Treatment of primary biliary cholangitis |
| Molecular Formula |
C21H19CLN4O2
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| Molecular Weight |
394.85
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| Exact Mass |
394.119
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| Elemental Analysis |
C, 63.88; H, 4.85; Cl, 8.98; N, 14.19; O, 8.10
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| CAS # |
1218942-37-0
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| Related CAS # |
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| PubChem CID |
58496428
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| Appearance |
Typically exists as White to yellow solids at room temperature
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| Density |
1.4±0.1 g/cm3
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| Boiling Point |
560.5±60.0 °C at 760 mmHg
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| Flash Point |
292.8±32.9 °C
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| Vapour Pressure |
0.0±1.5 mmHg at 25°C
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| Index of Refraction |
1.713
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| LogP |
4.03
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| Hydrogen Bond Donor Count |
1
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| Hydrogen Bond Acceptor Count |
4
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| Rotatable Bond Count |
3
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| Heavy Atom Count |
28
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| Complexity |
732
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| Defined Atom Stereocenter Count |
0
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| SMILES |
ClC1=C([H])C([H])=C([H])C([H])=C1N1C(C2C(=C([H])C(N(C([H])([H])[H])C=2C2C([H])=C([H])C([H])=C(C=2[H])N(C([H])([H])[H])C([H])([H])[H])=O)N1[H])=O
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| InChi Key |
RGYQPQARIQKJKH-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C21H19ClN4O2/c1-24(2)14-8-6-7-13(11-14)20-19-16(12-18(27)25(20)3)23-26(21(19)28)17-10-5-4-9-15(17)22/h4-12,23H,1-3H3
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| Chemical Name |
2-(2-chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1,2-dihydro-3H-pyrazolo[4,3-c]pyridine-3,6(5H)-dione
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| Synonyms |
GTK831; GTK-831; GKT137831; Setanaxib; GKT-137831; 2-(2-Chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione; GKT-831; GKT831; 2-(2-Chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1H-pyrazolo(4,3-c)pyridine-3,6(2H,5H)-dione; GKT-137831; GKT137831; GKT 137831; GTK 831.
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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 (6.33 mM) (saturation unknown) in 5% DMSO + 40% PEG300 + 5% Tween80 + 50% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
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 (6.33 mM) in 5% DMSO + 95% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. 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. View More
Solubility in Formulation 3: ≥ 1.43 mg/mL (3.62 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. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.5326 mL | 12.6630 mL | 25.3261 mL | |
| 5 mM | 0.5065 mL | 2.5326 mL | 5.0652 mL | |
| 10 mM | 0.2533 mL | 1.2663 mL | 2.5326 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 |
| NCT06274489 | Recruiting | Drug: Setanaxib Drug: Placebo |
Alport Syndrome | Calliditas Therapeutics AB | November 27, 2023 | Phase 1 Phase 2 |
| NCT04327089 | Completed | Drug: Setanaxib | Phase 1 | Calliditas Therapeutics AB | June 24, 2020 | Phase 1 |
| NCT05014672 | Active, not recruiting | Drug: Setanaxib Drug: Placebo |
Primary Biliary Cholangitis Liver Stiffness |
Calliditas Therapeutics Suisse SA |
February 14, 2022 | Phase 2 |
| NCT05323656 | Active, not recruiting | Drug: Setanaxib Drug: Placebo |
Squamous Cell Carcinoma of Head and Neck |
Calliditas Therapeutics Suisse SA |
April 6, 2022 | Phase 2 |
| NCT03226067 | Completed | Drug: GKT137831 Drug: Placebo oral capsule |
Primary Biliary Cirrhosis | Calliditas Therapeutics AB | June 26, 2017 | Phase 2 |
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