AS-1842856

A novel transcription factor Foxo1 inhibitor that potently and selectively inhibits Foxo1-mediated transactivation with IC50 of 33 nM, with no significant activity on Foxo3a and Foxo4; reduces glucose production through the inhibition of G6pase and phosphoenolpyruvate carboxykinase (PEPCK) mRNA levels in a rat hepatic cell line; decreases fasting plasma glucose level in diabetic db/db mice. (In Vitro) :AS1842856 potently inhibits human Foxo1 transactivation and reduces glucose production through the inhibition of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase mRNA levels in a rat hepatic cell line. After AS1842856 treatment, there is no significant difference in the protein expression of p-FoxO1 and FoxO1 compared with the control group, but the expression of p-Akt is decreased compared with the control group. (In Vivo) :Oral administration of AS1842856 to diabetic db/db mice leads to a drastic decrease in fasting plasma glucose level via the inhibition of hepatic gluconeogenic genes, whereas administration to normal mice has no effect on the fasting plasma glucose level. Treatment with AS1842856 also suppresses an increase in plasma glucose level caused by pyruvate injection in both normal and db/db mice.