AMG-8718   Click here for help

GtoPdb Ligand ID: 9639

PDB Ligand
Compound class: Synthetic organic
Comment: This Amgen BACE1 inhibitor for Alzheimer's disease, AMG-8718, had a balanced profile of potency, hERG binding affinity, and Pgp recognition. It also produced robust and sustained reductions of CSF and brain Aβ levels in a rat pharmacodynamic model [1]. However, retinal thinning was observed in a 1-month toxicity study in the rat and further studies suggested this to be an off-target effect where, in the rat, AMG-8718 impairs phagolysosomal function, leading to photoreceptor dysfunction and ultimately loss of photoreceptors [2]. The compound is example 288 in [3] from over 1000 analogues, but only binned activity data is provided. While the PubChem Bioassay data and other sources link to this structure note that MMDB and PubMed link their PDB structure to a different tautomeric representation as PubChem CID 86580376.
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2D Structure
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Physico-chemical Properties
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Hydrogen bond acceptors 6
Hydrogen bond donors 1
Rotatable bonds 1
Topological polar surface area 91.85
Molecular weight 442.14
XLogP 3.48
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
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Canonical SMILES NC1=NC2(CO1)c1cc(C#CC3(C)COC3)cnc1Oc1c2cc(cc1)c1cccnc1F
Isomeric SMILES NC1=N[C@]2(CO1)c1cc(C#CC3(C)COC3)cnc1Oc1c2cc(cc1)c1cccnc1F
InChI InChI=1S/C25H19FN4O3/c1-24(12-31-13-24)7-6-15-9-19-22(29-11-15)33-20-5-4-16(17-3-2-8-28-21(17)26)10-18(20)25(19)14-32-23(27)30-25/h2-5,8-11H,12-14H2,1H3,(H2,27,30)/t25-/m0/s1
InChI Key GKKFBOARESVMBW-VWLOTQADSA-N
Classification Click here for help
Compound class Synthetic organic
Database Links Click here for help
GtoPdb PubChem SID 340590269
PubChem CID 45254510
RCSB PDB Ligand 3LL
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SynPHARM 84541 (in complex with beta-secretase 1)