4B1C

New Aminoimidazoles as BACE-1 Inhibitors: From Rational Design to Ab- lowering in Brain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.191 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

New aminoimidazoles as beta-secretase (BACE-1) inhibitors showing amyloid-beta (A beta ) lowering in brain.

Gravenfors, Y.Viklund, J.Blid, J.Ginman, T.Karlstrom, S.Kihlstrom, J.Kolmodin, K.Lindstrom, J.von Berg, S.von Kieseritzky, F.Bogar, K.Slivo, C.Swahn, B.M.Olsson, L.L.Johansson, P.Eketjall, S.Falting, J.Jeppsson, F.Stromberg, K.Janson, J.Rahm, F.

(2012) J Med Chem 55: 9297-9311

  • DOI: https://doi.org/10.1021/jm300991n
  • Primary Citation of Related Structures:  
    4B1C, 4B1D, 4B1E

  • PubMed Abstract: 

    Amino-2H-imidazoles are described as a new class of BACE-1 inhibitors for the treatment of Alzheimer's disease. Synthetic methods, crystal structures, and structure-activity relationships for target activity, permeability, and hERG activity are reported and discussed. Compound (S)-1m was one of the most promising compounds in this report, with high potency in the cellular assay and a good overall profile. When guinea pigs were treated with compound (S)-1m, a concentration and time dependent decrease in Aβ40 and Aβ42 levels in plasma, brain, and CSF was observed. The maximum reduction of brain Aβ was 40-50%, 1.5 h after oral dosing (100 μmol/kg). The results presented highlight the potential of this new class of BACE-1 inhibitors with good target potency and with low effect on hERG, in combination with a fair CNS exposure in vivo.


  • Organizational Affiliation

    Department of Medicinal Chemistry, AstraZeneca R&D Södertälje, SE-151 85 Södertälje, Sweden. ylva.gravenfors@hotmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-SECRETASE 1375Homo sapiensMutation(s): 0 
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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
1B1
Query on 1B1

Download Ideal Coordinates CCD File 
C [auth A](2R)-2-cyclopropyl-5-methyl-2-[3-(5-prop-1-yn-1-ylpyridin-3-yl)phenyl]-2H-imidazol-4-amine
C21 H20 N4
TWHSRVVFCICXII-OAQYLSRUSA-N
DMS
Query on DMS

Download Ideal Coordinates CCD File 
B [auth A]DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
1B1 PDBBind:  4B1C IC50: 79 (nM) from 1 assay(s)
Binding MOAD:  4B1C IC50: 79 (nM) from 1 assay(s)
BindingDB:  4B1C IC50: min: 79, max: 190 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.95 Å
  • R-Value Free: 0.245 
  • R-Value Work: 0.188 
  • R-Value Observed: 0.191 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.96α = 90
b = 75.596β = 90
c = 104.523γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2012-10-10
    Type: Initial release
  • Version 1.1: 2012-11-21
    Changes: Database references
  • Version 1.2: 2018-02-14
    Changes: Database references, Structure summary