Synonym
GKT137831; GKT-137831; GKT 137831; GTK831; GTK-831; GTK 831; Setanaxib;
IUPAC/Chemical Name
2-(2-chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1,2-dihydro-3H-pyrazolo[4,3-c]pyridine-3,6(5H)-dione
InChi Key
RGYQPQARIQKJKH-UHFFFAOYSA-N
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
SMILES Code
CN(C)C1=CC(C2=C(C(N(C3=CC=CC=C3Cl)N4)=O)C4=CC(N2C)=O)=CC=C1
Appearance
light yellow to yellow solid powder
Purity
>98% (or refer to the Certificate of Analysis)
Shipping Condition
Shipped under ambient temperature as non-hazardous chemical. This product is stable enough for a few weeks during ordinary shipping and time spent in Customs.
Storage Condition
Dry, dark and at 0 - 4 C for short term (days to weeks) or -20 C for long term (months to years).
Solubility
Soluble in DMSO, not in water
Shelf Life
>2 years if stored properly
Drug Formulation
This drug may be formulated in DMSO
Stock Solution Storage
0 - 4 C for short term (days to weeks), or -20 C for long term (months).
HS Tariff Code
2934.99.9001
Biological target:
Setanaxib (GKT137831, GKT831) is a potent, dual NADPH oxidase NOX1/NOX4 inhibitor with Ki of 110 nM and 140 nM, respectively.
In vitro activity:
In an effort to discover new selective modulators of Nox enzymes, cell free assays were developed using membranes prepared from cells heterologously over-expressing a specific Nox enzyme isoform. GKT137831 (Fig. 2A) is a potent Nox4 inhibitor (Ki =120 ± 30 nM) with an affinity similar to the irreversible and unspecific flavoprotein inhibitor Diphenyliodonium (DPI; Ki =70±10 nM) (Fig. 2B). As expected, DPI showed complete non-selectivity, and the same potency was recorded on all four Noxes probed (Fig. 2B). On the other hand, GKT137831 had a better potency both on human Nox4 (Ki =140 ± 40 nM) and human Nox1 (Ki =110± 30 nM) and was found 15-fold less potent on Nox2 (Ki = 1750 ± 700 nM) and 3-fold less potent on Nox5 (Ki =410±100 nM). Moreover, GKT137831 did not significantly inhibit a highly-specific NOX2-driven response, i.e. neutrophil oxidative burst up to 100uM, as measured by flow cytometry in human whole blood. To further demonstrate the specificity of GKT137831 for Nox enzymes, the candidate drug was subjected to an extensive in vitro off-target pharmacological profile on 170 different proteins including ROS producing and redox-sensitive enzymes, as well as representative proteins of well recognized drug target families such as GPCRs, kinases, ion channels and others enzymes. GKT137831 when tested at 10 μM did not show any significant inhibition of any tested target protein, demonstrating the excellent specificity of this compound (see supplementary Table 2).
Reference: Hepatology. 2012 Dec;56(6):2316-27. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22806357/
In vivo activity:
To investigate the role of SOD1 and the effect of NOX1/4 inhibition on liver fibrosis, liver fibrosis was induced in SOD1mu (with increased catalytic activity) and WT mice by 12 consecutive CCl4 injections over a 6-week period. During the last half of CCl4 injections, some mice were treated with GKT137831 daily. CCl4-induced liver fibrosis was more pronounced in SOD1mu compared to WT mice. Liver fibrosis in both SOD1mu and WT mice was attenuated by GKT137831 treatment. The NOX1/4 inhibitor reduced the levels of hepatic collagen deposition in CCl4 induced fibrosis in SOD1mu and WT mice to the same low level, as assessed by Sirius red staining and its quantification (Fig. 3A,B). Hepatic α-SMA expression, a marker for HSC activation, was enhanced in SOD1mu mice after CCl4 injections compared to WT mice, as assessed by immunohistochemistry and immunoblotting. The increased hepatic α-SMA expression was markedly decreased in SOD1mu mice treated with GKT137831, to a level similar to that of WT mice given the NOX1/4 inhibitor (Fig. 3C,D). The mRNAs of fibrogenic markers, including collagen α1(I), tissue inhibitor of metalloprotease 1 (TIMP-1), and TGF-β were increased in SOD1mu mice to higher levels than in WT mice after CCl4 injections, but treatment with GKT137831 reduced the induction of those genes to the same lower levels (Fig. 3E). Similarly, BDL-induced hepatic fibrosis in both WT and SOD1mu mice was decreased by treatment with GK137831 (Supplemental Figure 1). Thus, both hepatotoxin (CCl4) (this study) and cholestasis (BDL) (this study and REFA) induced liver fibrosis is suppressed by blocking NOX1 and NOX4.
Reference: Hepatology. 2012 Dec;56(6):2316-27. https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22806357/
|
Solvent |
mg/mL |
mM |
| Solubility |
| DMSO |
14.3 |
36.19 |
Note: There can be variations in solubility for the same chemical from different vendors or different batches from the same vendor. The following factors can affect the solubility of the same chemical: solvent used for crystallization, residual solvent content, polymorphism, salt versus free form, degree of hydration, solvent temperature. Please use the solubility data as a reference only. Warming and sonication will facilitate dissolving. Still have questions? Please contact our Technical Support scientists.
Preparing Stock Solutions
The following data is based on the
product
molecular weight
394.85
Batch specific molecular weights may vary
from batch to batch
due to the degree of hydration, which will
affect the solvent
volumes required to prepare stock solutions.
| Concentration / Solvent Volume / Mass |
1 mg |
5 mg |
10 mg |
| 1 mM |
1.15 mL |
5.76 mL |
11.51 mL |
| 5 mM |
0.23 mL |
1.15 mL |
2.3 mL |
| 10 mM |
0.12 mL |
0.58 mL |
1.15 mL |
| 50 mM |
0.02 mL |
0.12 mL |
0.23 mL |
In vitro protocol:
1. Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C, Page P, Brenner DA. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology. 2012 Dec;56(6):2316-27. doi: 10.1002/hep.25938. PMID: 22806357; PMCID: PMC3493679.
2. Green DE, Murphy TC, Kang BY, Kleinhenz JM, Szyndralewiez C, Page P, Sutliff RL, Hart CM. The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol. 2012 Nov;47(5):718-26. doi: 10.1165/rcmb.2011-0418OC. Epub 2012 Aug 16. PMID: 22904198; PMCID: PMC3547100.
In vivo protocol:
1. Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C, Page P, Brenner DA. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology. 2012 Dec;56(6):2316-27. doi: 10.1002/hep.25938. PMID: 22806357; PMCID: PMC3493679.
2. Zhao QD, Viswanadhapalli S, Williams P, Shi Q, Tan C, Yi X, Bhandari B, Abboud HE. NADPH oxidase 4 induces cardiac fibrosis and hypertrophy through activating Akt/mTOR and NFκB signaling pathways. Circulation. 2015 Feb 17;131(7):643-55. doi: 10.1161/CIRCULATIONAHA.114.011079. Epub 2015 Jan 14. PMID: 25589557; PMCID: PMC4568756.
1: Deliyanti D, Wilkinson-Berka JL. Inhibition of NOX1/4 with GKT137831: a potential novel treatment to attenuate neuroglial cell inflammation in the retina. J Neuroinflammation. 2015 Jul 30;12:136. doi: 10.1186/s12974-015-0363-z. PubMed PMID: 26219952; PubMed Central PMCID: PMC4518508.
2: Green DE, Murphy TC, Kang BY, Kleinhenz JM, Szyndralewiez C, Page P, Sutliff RL, Hart CM. The Nox4 inhibitor GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation. Am J Respir Cell Mol Biol. 2012 Nov;47(5):718-26. doi: 10.1165/rcmb.2011-0418OC. Epub 2012 Aug 16. PubMed PMID: 22904198; PubMed Central PMCID: PMC3547100.
3: Aoyama T, Paik YH, Watanabe S, Laleu B, Gaggini F, Fioraso-Cartier L, Molango S, Heitz F, Merlot C, Szyndralewiez C, Page P, Brenner DA. Nicotinamide adenine dinucleotide phosphate oxidase in experimental liver fibrosis: GKT137831 as a novel potential therapeutic agent. Hepatology. 2012 Dec;56(6):2316-27. doi: 10.1002/hep.25938. PubMed PMID: 22806357; PubMed Central PMCID: PMC3493679.
4: Jiang JX, Chen X, Serizawa N, Szyndralewiez C, Page P, Schröder K, Brandes RP, Devaraj S, Török NJ. Liver fibrosis and hepatocyte apoptosis are attenuated by GKT137831, a novel NOX4/NOX1 inhibitor in vivo. Free Radic Biol Med. 2012 Jul 15;53(2):289-96. doi: 10.1016/j.freeradbiomed.2012.05.007. Epub 2012 May 19. PubMed PMID: 22618020; PubMed Central PMCID: PMC3392471.
