A-769662   Click here for help

GtoPdb Ligand ID: 10069

Synonyms: A769662
PDB Ligand
Compound class: Synthetic organic
Comment: A-769662 is a small molecule activator of AMP-activated protein kinase (AMPK). Its chemical structure was originally disclosed by Cool et al. (2006) [1], in which it was used to demonstrate that AMPK activation is a feasible approach for the treatment of the metabolic syndrome and type 2 diabetes. A-769662 activates AMPK both allosterically (as evidenced by its ability to activate a mutant AMPK γ subunit that is resistant to endogenous AMP-induced activation) and by inhibiting dephosphorylation of AMPK on Thr172 [3]. A-769662 is suitable as as experimental tool to understand the physiological roles of AMPK in vitro and in vivo. Use of A-769662 has also confirmed AMPK's role as an autophagy target, whose activation is able to ameliorate neurodegeneration in animal models [4]. AMPK activation induces autophagy in an mTOR-independent manner, so limits the risk of the potentially detrimental effects that mTOR inhibition may have on important cellular pathways in addition to autophagy.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 2
Hydrogen bond donors 3
Rotatable bonds 2
Topological polar surface area 125.35
Molecular weight 360.06
XLogP 4.39
No. Lipinski's rules broken 0
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Canonical SMILES N#Cc1c(=O)[nH]c2c(c1O)c(cs2)c1ccc(cc1)c1ccccc1O
Isomeric SMILES N#Cc1c(=O)[nH]c2c(c1O)c(cs2)c1ccc(cc1)c1ccccc1O
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)
Bioactivity Comments
In assays using partially purified rat AMPK A-769662 was around 50-fold more potent than AMP by EC50 and produced a greater maximum activation level (4.1-fold vs. 0.5-fold) [2].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
AMP kinase Rn Activator Activation 6.2 – 6.9 pEC50 - 1-2
pEC50 6.9 (EC50 1.16x10-7 M) [2]
Description: Activation of AMPK purified from rat liver, which contains α1 and α2 catalytic subunits, with β1 and γ1 regulatory subunits.
pEC50 6.2 (EC50 7x10-7 M) [1]
Description: Activation of baculovirus expressed α1,β1,&gamma1 recombinant isoform of AMPK.
AMP kinase Hs Activator Activation 6.0 pEC50 - 1
pEC50 6.0 (EC50 1.1x10-6 M) [1]
Description: Activation of AMPK partially purified from HEK cells.