4AZY

Design and Synthesis of BACE1 Inhibitors with In Vivo Brain Reduction of beta-Amyloid Peptides (COMPOUND 10)


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Design and synthesis of beta-site amyloid precursor protein cleaving enzyme (BACE1) inhibitors with in vivo brain reduction of beta-amyloid peptides.

Swahn, B.M.Kolmodin, K.Karlstrom, S.von Berg, S.Soderman, P.Holenz, J.Berg, S.Lindstrom, J.Sundstrom, M.Turek, D.Kihlstrom, J.Slivo, C.Andersson, L.Pyring, D.Rotticci, D.Ohberg, L.Kers, A.Bogar, K.von Kieseritzky, F.Bergh, M.Olsson, L.L.Janson, J.Eketjall, S.Georgievska, B.Jeppsson, F.Falting, J.

(2012) J Med Chem 55: 9346-9361

  • DOI: https://doi.org/10.1021/jm3009025
  • Primary Citation of Related Structures:  
    4AZY, 4B00

  • PubMed Abstract: 

    The evaluation of a series of aminoisoindoles as β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors and the discovery of a clinical candidate drug for Alzheimer's disease, (S)-32 (AZD3839), are described. The improvement in permeability properties by the introduction of fluorine adjacent to the amidine moiety, resulting in in vivo brain reduction of Aβ40, is discussed. Due to the basic nature of these compounds, they displayed affinity for the human ether-a-go-go related gene (hERG) ion channel. Different ways to reduce hERG inhibition and increase hERG margins for this series are described, culminating in (S)-16 and (R)-41 showing large in vitro margins with BACE1 cell IC(50) values of 8.6 and 0.16 nM, respectively, and hERG IC(50) values of 16 and 2.8 μM, respectively. Several compounds were advanced into pharmacodynamic studies and demonstrated significant reduction of β-amyloid peptides in mouse brain following oral dosing.


  • Organizational Affiliation

    Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85, Södertälje, Sweden. brittmarieswahn@gmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-SECRETASE 1411Homo sapiensMutation(s): 2 
EC: 3.4.23.46
UniProt & NIH Common Fund Data Resources
Find proteins for P56817 (Homo sapiens)
Explore P56817 
Go to UniProtKB:  P56817
PHAROS:  P56817
GTEx:  ENSG00000186318 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP56817
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
7F3 Binding MOAD:  4AZY IC50: 125 (nM) from 1 assay(s)
BindingDB:  4AZY IC50: min: 22, max: 204 (nM) from 5 assay(s)
PDBBind:  4AZY IC50: 198 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.79 Å
  • R-Value Free: 0.210 
  • R-Value Work: 0.176 
  • R-Value Observed: 0.177 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.54α = 90
b = 76.39β = 90
c = 104.34γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-17
    Type: Initial release
  • Version 1.1: 2012-11-21
    Changes: Database references
  • Version 1.2: 2018-02-14
    Changes: Database references, Structure summary
  • Version 1.3: 2023-12-20
    Changes: Data collection, Database references, Derived calculations, Other, Refinement description