Uses

GKT136901 is a potent, selective and orally active inhibitor of NADPH oxidase (NOX1/4), with Kis of 160 and 165 nM, respectively. GKT136901 is also a selective and direct scavenger of peroxynitrite. GKT136901 can be used for the research of diabetic nephropathy, stroke, and neurodegeneration. GKT136901 also has anti-inflammatory activity[1][2][3].

Biological Activity

Cell permeable: yes', 'Primary Target
NOX1- and NOX4-containing NADPH oxidase activity', 'Reversible: yes

Synthesis

1217897-99-8

955272-06-7

d) Synthesis of 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione (Compound (Ia) of formula (II), Scheme 1): an isopropanol solution of sodium isopropoxide was prepared by dissolving sodium (0.082 g, 3.57 mmol, 1 equiv.) in isopropanol (75 mL). To this solution was added methyl [(4E)-1-(2-chlorophenyl)-5-oxo-4-{[(pyridin-2-ylmethyl)amino]ethylidene}-4,5-dihydro-1H-pyrazol-3-yl]acetate (compound of formula (VIII), 1.42 g, 3.57 mmol). The reaction mixture was refluxed for 1 hour and subsequently cooled to room temperature. It was neutralized with 20% aqueous hydrochloric acid (0.59 mL) to pH 7. After removing 50 mL of isopropanol by distillation under reduced pressure, 25 mL of water was added. The reaction flask was placed in a refrigerator overnight and a white precipitate was precipitated. The precipitate was collected by filtration, washed sequentially with water (2 x 5 mL) and cyclohexane, and dried under vacuum to afford the pure product 2-(2-chlorophenyl)-4-methyl-5-(pyridin-2-ylmethyl)-1H-pyrazolo[4,3-c]pyridine-3,6(2H,5H)-dione 1.07 g in 82% yield.1H-NMR (500 MHz, DMSO-d6, ppm) : 2.78 (s, 3H), 5.41 (s, 2H), 5.66 (s, 1H), 7.31-7.28 (m, 1H), 7.32 (d, J=7.9 Hz, 1H), 7.50-7.47 (m, 2H), 7.60-7.56 (m, 1H), 7.66-7.64 (m, 1H), 7.79 (td, J=7.6 ,1.9 Hz, 1H), 8.48 (m, 1H), 10.73 (s, br, 1H).MS (ESI+): 367.9; MS (ESI-): 365.7.

in vivo

IC 50

NOX1; NOX4

References

[1] Laleu B, et, al. First in class, potent, and orally bioavailable NADPH oxidase isoform 4 (Nox4) inhibitors for the treatment of idiopathic pulmonary fibrosis. J Med Chem. 2010 Nov 11;53(21):7715-30. DOI:10.1021/jm100773e
[2] Teixeira G, et, al. Therapeutic potential of NADPH oxidase 1/4 inhibitors. Br J Pharmacol. 2017 Jun;174(12):1647-1669. DOI:10.1111/bph.13532
[3] Schildknecht S, et, al. The NOX1/4 inhibitor GKT136901 as selective and direct scavenger of peroxynitrite. Curr Med Chem. 2014;21(3):365-76. DOI:10.2174/09298673113209990179
[4] Sedeek M, et, al. Critical role of Nox4-based NADPH oxidase in glucose-induced oxidative stress in the kidney: implications in type 2 diabetic nephropathy. Am J Physiol Renal Physiol. 2010 Dec;299(6):F1348-58. DOI:10.1152/ajprenal.00028.2010
[5] Hwang JS, et, al. GKT136901 protects primary human brain microvascular endothelial cells against methamphetamine-induced blood-brain barrier dysfunction. Life Sci. 2020 Sep 1;256:117917. DOI:10.1016/j.lfs.2020.117917
[6] Sedeek M, et, al. Renoprotective effects of a novel Nox1/4 inhibitor in a mouse model of Type 2 diabetes. Clin Sci (Lond). 2013 Feb;124(3):191-202. DOI:10.1042/CS20120330