SGK1-IN-8

SGK1-IN-8 (compound 55) is an inhibitor of SGK1 and GSK3β, exhibiting an IC50 of 0.11 μM for human SGK1 and 3.39 μM for human GSK3β. It reduces the catalytic activity of both SGK1 and GSK3β and decreases the phosphorylation level of TAU protein at the Ser214 site. SGK1-IN-8 is applicable in Alzheimer's disease research.

SGK1-IN-8 effectively inhibits human recombinant SGK1 with an IC50 of 0.11 μM at varying concentrations for one hour. It shows no toxicity to SH-SY5Y cells at 1 μM with one-hour pre-incubation and 24-hour total exposure with OA, and provides statistically significant neuroprotection against okadaic acid-induced toxicity. At 1 μM, SGK1-IN-8 does not alter total TAU levels but significantly reduces phosphorylation at Ser396 and Ser214 in SH-SY5Y cells. As a P-glycoprotein substrate, SGK1-IN-8 at 10 μM for 120 minutes has an efflux ratio of 2.90 in MDCKII cells transfected with MDR1, and this efflux can be reversed by the P-gp inhibitor Zosuquidar. Additionally, SGK1-IN-8 weakly inhibits human recombinant GSK3β with an IC50 of 3.39 μM at various concentrations for 30 minutes.

SGK1-IN-8 (compound 55)(5-10 mg/kg; Intraperitoneal injection, oral administration; single-dose administration) demonstrates rapid absorption following a single intraperitoneal or oral administration in male BALB/c mice; however, it exhibits low brain penetration, with a brain-Kp (AUC last) of 0.04 for both administration routes.