GKT137831

GKT137831 (Setanaxib, GKT-137831) is a potent, selective, dual NADPH oxidase Nox1/4 inhibitor with Ki of 110/140 nM, 15-fold less potent on Nox2 and 3-fold less potent on Nox5, and no affinity for xanthine oxidase; attenuates liver fibrosis and ROS production in both SOD1mu and WT mice, suppresses ROS production and NOX and fibrotic gene expression, but not Rac1 activity, in SOD1mut and WT in hepatic stellate cells (HSCs) . Diabetes Phase 2 Clinical (In Vitro) :Setanaxib (GKT137831) is a potent Nox1/4 inhibitor (Kis=140±40/110±30 nM) . Administration of Setanaxib (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, Setanaxib (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 Setanaxib (GKT137831) attenuates hypoxia-induced pulmonary vascular cell proliferation. (In Vivo) :During the last half of CCl4 injections, some mice are treated with Setanaxib (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 Setanaxib (GKT137831) treatment. The increased hepatic α-SMA expression is markedly decreased in SOD1mu mice treated with Setanaxib (GKT137831), to a level similar to that of WT mice given the NOX1/4 inhibitor.