atabecestat   Click here for help

GtoPdb Ligand ID: 9963

Synonyms: JNJ-54861911 | JNJ-54861911-AAA | RSC-385896
PDB Ligand
Compound class: Synthetic organic
Comment: JNJ-54861911 was originally discovered at Shionogi in 2008 as a BACE1 inhibitor. Clinical development was progressed by Janssen as atabecestat [1]. The compound is orally active with good brain penetration and low P-gp substrate characteristic, which reflects in vivo Aβ reduction in brain and CSF for rat, monkey, and dog. However, serious elevations of liver enzymes were observed in the Phase 2b/3 study patients, causing the trial to be stopped in May 2018. The Phase 1 results were published in Sept 2018 [4].
Click here for help

Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

✖

View interactive charts of activity data across species
2D Structure
Click here for help

2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

✖
Click here for structure editor
Physico-chemical Properties
Click here for help

Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the CDK toolkit. All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

✖
Hydrogen bond acceptors 6
Hydrogen bond donors 2
Rotatable bonds 4
Topological polar surface area 129.46
Molecular weight 367.09
XLogP 2.31
No. Lipinski's rules broken 0
SMILES / InChI / InChIKey
Click here for help

SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

✖
Canonical SMILES N#Cc1ccc(nc1)C(=O)Nc1ccc(c(c1)C1(C)C=CSC(=N1)N)F
Isomeric SMILES N#Cc1ccc(nc1)C(=O)Nc1ccc(c(c1)[C@]1(C)C=CSC(=N1)N)F
InChI InChI=1S/C18H14FN5OS/c1-18(6-7-26-17(21)24-18)13-8-12(3-4-14(13)19)23-16(25)15-5-2-11(9-20)10-22-15/h2-8,10H,1H3,(H2,21,24)(H,23,25)/t18-/m0/s1
InChI Key VLLFGVHGKLDDLW-SFHVURJKSA-N
No information available.
Summary of Clinical Use Click here for help
The Phase 2/3 study that was terminated due to unacceptable liver toxicity was NCT02569398, which was desigend to evaluate JNJ-54861911's ability to slow cognitive decline in subjects with late-onset preclinical stage Alzheimer's disease. Janssen's online statement outlining their reasons for stopping the trial can be viewed here.
Clinical Trials
Clinical Trial ID Title Type Source Comment References
NCT02569398 An Efficacy and Safety Study of Atabecestat in Participants Who Are Asymptomatic at Risk for Developing Alzheimer's Dementia Phase 2/Phase 3 Interventional Janssen Research & Development, LLC This trial was terminated due to significant elevation of liver enzymes in participants in the treatment arm. Subsequent analysis showed dose-related cognitive worsening. 3