A-769662 844499-71-4

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Molecular Weight: 360.39 A-769662 is a potent, reversible AMPK activator with EC50 of 0.8 μM, little effect on GPPase/FBPase activity.


A-769662 stimulates partially purified rat liver AMPK with EC50 with 0.8
μM. A-769662 activates AMPK purified from multiple tissues and species
in a dose-responsive manner with modest variations in observed EC50s.
EC50s determined for A-769662 using partially purified AMPK extracts
from rat heart, rat muscle, or human embryonic kidney cells (HEKs) are
2.2 mM, 1.9 mM, or 1.1 mM, respectively.


A 4 hours treatment of primary
rat hepatocytes with A-769662 dose-dependently increases ACC
phosphorylation, which correlated inhibition of fatty acid synthesis
with IC50 of 3.2 μM. A-769662 also inhibits fatty acid sythesis in mouse
hepatocytes with IC50 with 3.6 μM [1] A-769662 activates
AMPK both allosterically and by inhibiting dephosphorylation of AMPK on
Thr-172, similar to the effects of AMP. A-769662 inhibits
proteasomal function by an AMPK-independent mechanism. A-769662 affects
the in vitro activity of purified 26S proteasomes but not the in vitro
activity of purified 20S proteasomes. A-769662 has toxic effects on MEF
cells. A recent research shows A-769662 inhibited cell proliferation and DNA synthesis.


Short-term treatment of normal Sprague Dawley rats with A-769662
decreases liver malonyl CoA levels and the respiratory exchange ratio,
VCO2/VO2, indicating an increased rate of whole-body fatty acid
oxidation. Treatment of ob/ob mice with 30 mg/kg b.i.d. A-769662
decreases hepatic expression of PEPCK, G6Pase, and FAS, lowers plasma
glucose by 40%, reduced body weight gain and significantly decreases
both plasma and liver triglyceride levels.


Protocol(Only for Reference)


Kinase Assay:


[1]

96-well AMPK assay

AMPK activity is measured by monitoring phosphorylation of the SAMS peptide substrate (20 mM in standard assays and 100 mM in additivity assays) following a previously described protocol (Anderson et al., 2004). To determine whether A-769662-induced AMPK activation occurs in a reversible manner, AMP or A-769662 are preincubated with rat liver AMPK for 10 minutes at 20 times standard assay concentrations prior to dilution and measurement of AMPK activity.

Fatty Acid Synthesis Assay

Primary rat hepatocytes are isolated and plated at 5 × 104 cells per well on BioCoat, collagen-coated, black-walled 96-well plates in DMEM supplemented with 10% FBS, 5 mM glucose, 1 mM sodium pyruvate, 2 mM L-glutamine, 25 mM HEPES, 0.1 m

Cell Assay:


[3]

Cell lines	MEF cells
Concentrations	300 μM
Incubation Time	24 hours
Method	Cell viability of MEF cells treated or not with A-769662 is performed as follows: cells are harvested by trypsinization and incubated with 0.5 mg/mL RNase and 50 μg/mL propidium iodine at room temperature in the dark; cell viability is analyzed by flow cytometry using a FACScanto flow cytometer, using an excitation laser at 488 nm and a propidium iodine fluorescence detection at 600 nm. To determine the proportion of cells in each phase of the Cell Cycle, cells are harvested by trypsinization, collected by centrifugation, washed in PBS and fixed overnight in 80% ethanol at -20 °C. Subsequently, these fixed cells are centrifuged to remove the fixative and incubated for 20 minutes in the dark at room temperature in PBS containing 0.5 mg/mL RNase and 50 μg/mL propidium iodine. Flow cytometry analysis is performed as above. The proportion of cells in G1, S, and G2 is determined using the MODFIT program. Cell culture pictures are taken at the indicated times using a camera coupled to an inverted microscope with a 20 × objective.

Animal Study:


[1]

Animal Models	Sprague Dawley rats
Formulation	A-769662 is dissolved in DMSO.
Dosages	30 mg/kg
Administration	Administered via i.p.
Solubility	1% DMSO/30% polyethylene glycol/1% Tween 80, 30 mg/mL
* Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Conversion of different model animals based on BSA (Value based on data from FDA Draft Guidelines)

Species	Baboon	Dog	Monkey	Rabbit	Guinea pig	Rat	Hamster	Mouse
Weight (kg)	12	10	3	1.8	0.4	0.15	0.08	0.02
Body Surface Area (m2)	0.6	0.5	0.24	0.15	0.05	0.025	0.02	0.007
Km factor	20	20	12	12	8	6	5	3

Animal A (mg/kg) = Animal B (mg/kg) multiplied by	Animal B Km
	Animal A Km

For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.

Rat dose (mg/kg) = mouse dose (22.4 mg/kg) ×	mouse Km(3)	= 11.2 mg/kg
	rat Km(6)

Chemical Information

Molecular Weight (MW)	360.39
Formula	C20H12N2O3S
CAS No.	844499-71-4

Storage	3 years -20℃Powder
	6 months-80℃in solvent (DMSO, water, etc.)
Synonyms

Solubility (25°C) *	In vitro	DMSO	72 mg/mL (199.78 mM)
		Water	<1 mg/mL (
		Ethanol	<1 mg/mL (
	In vivo	1% DMSO/30% polyethylene glycol/1% Tween 80	30 mg/mL
* <1 mg/ml means slightly soluble or insoluble. * Please note that Selleck tests the solubility of all compounds in-house, and the actual solubility may differ slightly from published values. This is normal and is due to slight batch-to-batch variations.

Chemical Name	Thieno[2,3-b]pyridine-5-carbonitrile, 6,7-dihydro-4-hydroxy-3-(2'-hydroxy[1,1'-biphenyl]-4-yl)-6-oxo-

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