A-769662

• CAT Number: I005049
• CAS Number: 844499-71-4
• Molecular Formula: C20H12N2O3S
• Molecular Weight: 360.4
• Purity: ≥95%
• Target: AMPK
• Solubility: DMSO: ≤ 24 mg/mL
• Storage: 3 years -20C powder
• IC50: 8 uM (EC50) [1]
• InChI: InChI=1S/C20H12N2O3S/c21-9-14-18(24)17-15(10-26-20(17)22-19(14)25)12-7-5-11(6-8-12)13-3-1-2-4-16(13)23/h1-8,10,23H,(H2,22,24,25)
• InChIKey: CTESJDQKVOEUOY-UHFFFAOYSA-N
• SMILES: OC1=CC=CC=C1C2=CC=C(C3=CSC(N4)=C3C(O)=C(C#N)C4=O)C=C2

A-769662 is a potent, reversible AMPK activator with EC50 of 0.8 μM, little effect on GPPase/FBPase activity.IC50 value: 8 uM (EC50) [1]Target: AMPKin vitro: 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 [2]. 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 [3].in vivo: 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 [1].

Reference

1:AMP-activated protein kinase (AMPK) activator A-769662 increases intracellular calcium and ATP release from astrocytes in an AMPK-independent manner. Vlachaki Walker JM, Robb JL, Cruz AM, Malhi A, Weightman Potter PG, Ashford MLJ, McCrimmon RJ, Ellacott KLJ, Beall C.Diabetes Obes Metab. 2017 Feb 17. doi: 10.1111/dom.12912. [Epub ahead of print] PMID: 28211632 2:Effect of A-769662, a direct AMPK activator, on Tlr-4 expression and activity in mice heart tissue. Rameshrad M, Maleki-Dizaji N, Soraya H, Toutounchi NS, Barzegari A, Garjani A.Iran J Basic Med Sci. 2016 Dec;19(12):1308-1317. doi: 10.22038/ijbms.2016.7917. PMID: 28096963 Free PMC Article3:A-769662, a direct AMPK activator, attenuates lipopolysaccharide-induced acute heart and lung inflammation in rats. Rameshrad M, Soraya H, Maleki-Dizaji N, Vaez H, Garjani A.Mol Med Rep. 2016 Mar;13(3):2843-9. doi: 10.3892/mmr.2016.4821. Epub 2016 Jan 28. PMID: 26820069 4:AMPK Activation by A-769662 Controls IL-6 Expression in Inflammatory Arthritis. Guma M, Wang Y, Viollet B, Liu-Bryan R.PLoS One. 2015 Oct 16;10(10):e0140452. doi: 10.1371/journal.pone.0140452. eCollection 2015. PMID: 26474486 Free PMC Article5:A-769662 protects osteoblasts from hydrogen dioxide-induced apoptosis through activating of AMP-activated protein kinase (AMPK). Zhu Y, Zhou J, Ao R, Yu B.Int J Mol Sci. 2014 Jun 23;15(6):11190-203. doi: 10.3390/ijms150611190. PMID: 24960362 Free PMC Article6:A-769662 potentiates the effect of other AMP-activated protein kinase activators on cardiac glucose uptake. Timmermans AD, Balteau M, Gélinas R, Renguet E, Ginion A, de Meester C, Sakamoto K, Balligand JL, Bontemps F, Vanoverschelde JL, Horman S, Beauloye C, Bertrand L.Am J Physiol Heart Circ Physiol. 2014 Jun 15;306(12):H1619-30. doi: 10.1152/ajpheart.00965.2013. Epub 2014 Apr 18. PMID: 24748590 Free Article7:Small molecule drug A-769662 and AMP synergistically activate naive AMPK independent of upstream kinase signaling. Scott JW, Ling N, Issa SM, Dite TA, O/’Brien MT, Chen ZP, Galic S, Langendorf CG, Steinberg GR, Kemp BE, Oakhill JS.Chem Biol. 2014 May 22;21(5):619-27. doi: 10.1016/j.chembiol.2014.03.006. Epub 2014 Apr 17. PMID: 24746562 Free Article8:AMP-activated protein kinase activator A-769662 is an inhibitor of the Na(+)-K(+)-ATPase. Benziane B, Björnholm M, Lantier L, Viollet B, Zierath JR, Chibalin AV.Am J Physiol Cell Physiol. 2009 Dec;297(6):C1554-66. doi: 10.1152/ajpcell.00010.2009. Epub 2009 Oct 14. PMID: 19828836 Free Article9:A-769662 activates AMPK beta1-containing complexes but induces glucose uptake through a PI3-kinase-dependent pathway in mouse skeletal muscle. Treebak JT, Birk JB, Hansen BF, Olsen GS, Wojtaszewski JF.Am J Physiol Cell Physiol. 2009 Oct;297(4):C1041-52. doi: 10.1152/ajpcell.00051.2009. Epub 2009 Aug 5. PMID: 19657063 Free Article10:Inhibitory effects of A-769662, a novel activator of AMP-activated protein kinase, on 3T3-L1 adipogenesis. Zhou Y, Wang D, Zhu Q, Gao X, Yang S, Xu A, Wu D.Biol Pharm Bull. 2009 Jun;32(6):993-8. PMID: 19483304 Free Article