AS1842856 is a novel potent, orally active and cell-permeable small-molecule inhibitor of Foxo1 (forkhead transcription factor forkhead box O1) with an IC50 of 30 nM. Excessive hepatic glucose production through the gluconeogenesis pathway is partially responsible for the elevated glucose levels observed in patients with type 2 diabetes mellitus (T2DM). The forkhead transcription factor forkhead box O1 (Foxo1) plays a crucial role in mediating the effect of insulin on hepatic gluconeogenesis. 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. Oral administration of AS1842856 to diabetic db/db mice led to a drastic decrease in fasting plasma glucose level via the inhibition of hepatic gluconeogenic genes, whereas administration to normal mice had no effect on the fasting plasma glucose level. Treatment with AS1842856 also suppressed an increase in plasma glucose level caused by pyruvate injection in both normal and db/db mice. Taken together, these findings indicate that the Foxo1 inhibitor represents a new class of drugs for use in treating T2DM.

Physicochemical Properties

Molecular Formula	C18H22FN3O3
Molecular Weight	347.39
Exact Mass	347.165
CAS #	836620-48-5
Related CAS #	836620-48-5
PubChem CID	72193864
Appearance	White to light yellow solid powder
LogP	3.839
Hydrogen Bond Donor Count	3
Hydrogen Bond Acceptor Count	7
Rotatable Bond Count	4
Heavy Atom Count	25
Complexity	562
Defined Atom Stereocenter Count	0
InChi Key	MOMCHYGXXYBDCD-UHFFFAOYSA-N
InChi Code	InChI=1S/C18H22FN3O3/c1-2-22-9-11(18(24)25)17(23)14-13(22)8-12(15(19)16(14)20)21-10-6-4-3-5-7-10/h8-10,21H,2-7,20H2,1H3,(H,24,25)
Chemical Name	5-amino-7-(cyclohexylamino)-1-ethyl-6-fluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid
Synonyms	AS1842856; AS-1842856; AS 1842856
HS Tariff Code	2934.99.9001
Storage	Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month
Shipping Condition	Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Biological Activity

ln Vitro	In a rat hepatic cell line, AS1842856 potently inhibits human Foxo1 transactivation and decreases glucose synthesis via inhibiting the amounts of phosphoenolpyruvate carboxykinase and glucose-6 phosphatase mRNA[1]. Following AS1842856 therapy, there is a decrease in p-Akt expression relative to the control group, but there is no discernible difference in the protein expression of FoxO1 and p-FoxO1[2].
ln Vivo	By inhibiting hepatic gluconeogenic genes, oral administration of AS1842856 to diabetic db/db mice causes a significant reduction in fasting plasma glucose levels; however, delivery to normal mice has little effect on fasting plasma glucose levels. In both normal and db/db mice, treatment with AS1842856 also reduces an increase in plasma glucose level brought on by pyruvate injection[1].
Animal Protocol	AS1842856 is dissolved in 6% cyclodextrin for oral administration. Diabetic db/db mice
References	[1]. Discovery of novel forkhead box O1 inhibitors for treating type 2 diabetes: improvement of fasting glycemia in diabetic db/db mice. Mol Pharmacol. 2010 Nov;78(5):961-70. [2]. The resistant effect of SIRT1 in oxidative stress-induced senescence of rat nucleus pulposus cell is regulated by Akt-FoxO1 pathway. Biosci Rep. 2019 May 10;39(5). pii: BSR20190112.
Additional Infomation	AS1842856 is a quinolone that is 4-quinolone substituted at positions 1, 3, 5, 6 and 7 by ethyl, carboxy, amino, fluorine, and cyclohexylamino groups, respectively. It can directly bind to and block the transcription activity of the active forkhead box protein O1 (Foxo1), but not the Ser256-phosphorylated form. It induces cell death and growth arrest in Burkitt lymphoma cell lines at low concentrations. It has a role as a hypoglycemic agent, an anti-obesity agent, an autophagy inhibitor, an antineoplastic agent, an apoptosis inducer and a forkhead box protein O1 inhibitor. It is a quinolinemonocarboxylic acid, a quinolone, an organofluorine compound, a primary amino compound, a secondary amino compound and a tertiary amino compound.

Solubility Data

Solubility (In Vitro)

DMSO:≥ 5 mg/mL Water:N/A Ethanol:N/A

Solubility (In Vivo)

Solubility in Formulation 1: ≥ 1.67 mg/mL (4.81 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 16.7 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. Solubility in Formulation 2: 1 mg/mL (2.88 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 400 μL of PEG300 and mix evenly; then add 50 μL of Tween-80 to the above solution and mix evenly; then add 450 μL of normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 3: ≥ 1 mg/mL (2.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 10.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 4: 10 mg/mL (28.79 mM) in 6% HP-β-CD in Saline (add these co-solvents sequentially from left to right, and one by one), Suspension solution; with ultrasonication. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.  (Please use freshly prepared in vivo formulations for optimal results.)

Preparing Stock Solutions		1 mg	5 mg	10 mg
	1 mM	2.8786 mL	14.3930 mL	28.7861 mL
	5 mM	0.5757 mL	2.8786 mL	5.7572 mL
	10 mM	0.2879 mL	1.4393 mL	2.8786 mL

*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.