GKT137831, also known as GTK831, is a novel and potent Nox4 inhibitor. GKT137831 reduced the increased leukocyte adherence to the vasculature, the pro-inflammatory phenotype of microglia and macroglia, the increased gene and protein expression of vascular endothelial growth factor, monocyte chemoattractant protein-1, and leukocyte adhesion molecules as well as vascular leakage. In all cultured cell types, GKT137831 reduced the hypoxia-induced increase in ROS levels and protein expression of various inflammatory mediators. GKT137831 may be potentially useful as a treatment for a variety of vision-threatening retinopathies.
CAS Number: 1218942-37-0
Molecular Weight: 394.85
Chemical Name: 2-(2-chlorophenyl)-4-(3-(dimethylamino)phenyl)-5-methyl-1,2-dihydro-3H-pyrazolo[4,3-c]pyridine-3,6(5H)-dione
Appearance: Solid Power
Purity: ≥98% (or refer to the Certificate of Analysis)
Solubility: Soluble in DMSO, not in water
Shipping Condition: Shipped under ambient temperature as non-hazardous chemical or refer to Certificate of Analysis
Storage Condition: Dry, dark and -20 oC for 1 year or refer to the Certificate of Analysis.
Shelf Life: ≥12 months if stored properly.
Stock Solution Storage: 0 - 4 oC for 1 month or refer to the Certificate of Analysis.
Drug Formulation: To be determined.
HS Tariff Code: 382200
How to use
GKT137831 is a potent Nox1/4 inhibitor (Kis=140±40/110±30 nM). Administration of GKT137831 throughout the 72-hour period of normoxia or hypoxia exposure attenuates HPASMC proliferation under normoxic conditions at the 20 μM concentration but had no effect on proliferation in normoxic HPAECs. In the prevention paradigm, GKT137831 attenuates hypoxia-induced HPASMC and HPAEC proliferation at 5 and 20 μM. Complementary assays of cell proliferation measuring the expression of PCNA or manual cell counting confirmed that GKT137831 attenuates hypoxia-induced pulmonary vascular cell proliferation.
During the last half of CCl4 injections, some mice are treated with GKT137831 daily. CCl4-induced liver fibrosis is more pronounced in SOD1mu compared to WT mice. Liver fibrosis in both SOD1mu and WT mice is attenuated by GKT137831 treatment. The increased hepatic α-SMA expression is markedly decreased in SOD1mu mice treated with GKT137831, to a level similar to that of WT mice given the NOX1/4 inhibitor.
- 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.
- 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.
- 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.
- 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.
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