compound 86 [PMID: 26982234]   

GtoPdb Ligand ID: 9251

Compound class: Synthetic organic
Comment: Compound 86 is reported as a selective inhibitor of sirtuin 2 (SIRT2) [1], a NAD-dependent protein deacetylase with protective effects neurodegenerative disease. Compound 86 is shown to be competitive with NAD+ and the enzyme's peptide substrate, with acceptable blood-brain barrier penetrance (a property essential for any drug being developed for neuroprotective activity).

Drug-like SIRT2 inhibitors are being developed to determine if SIRT2 blockade could be of clinical benefit in Parkinson's disease [2].
2D Structure
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Physico-chemical Properties
Hydrogen bond acceptors 7
Hydrogen bond donors 2
Rotatable bonds 8
Topological polar surface area 106.78
Molecular weight 432.18
XLogP 2.18
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Canonical SMILES O=C(c1ccc(cc1)N1CCOCC1)Nc1cccc(c1)COc1cncc(c1)C(=O)N
Isomeric SMILES O=C(c1ccc(cc1)N1CCOCC1)Nc1cccc(c1)COc1cncc(c1)C(=O)N
InChI InChI=1S/C24H24N4O4/c25-23(29)19-13-22(15-26-14-19)32-16-17-2-1-3-20(12-17)27-24(30)18-4-6-21(7-5-18)28-8-10-31-11-9-28/h1-7,12-15H,8-11,16H2,(H2,25,29)(H,27,30)
InChI Key VKLKXFOZNHEBSW-UHFFFAOYSA-N
Bioactivity Comments
Compound 86 is around 70-fold selective for SIRT2 compared to SIRT1 and SIRT3 in a biochemical enzyme activity assay [1]. In vitro, compound 86 protects SH-SY5Y cells against oligomeric α-synuclein toxicity, which is a cellular model of Parkinson's disease neurodegeneration [3-4].
Selectivity at enzymes
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Target Sp. Type Action Value Parameter Concentration range (M) Reference
sirtuin 2 Hs Inhibitor Inhibition 7.1 pKi - 1
pKi 7.1 (Ki 7.3x10-8 M) [1]