4B72

Aminoimidazoles as BACE-1 Inhibitors: From De Novo Design to Ab- lowering in Brain


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


This is version 1.1 of the entry. See complete history


Literature

Core Refinement Toward Permeable Beta-Secretase (Bace-1) Inhibitors with Low Herg Activity.

Ginman, T.Viklund, J.Malmstrom, J.Blid, J.Emond, R.Forsblom, R.Johansson, A.Kers, A.Lake, F.Sehgelmeble, F.Sterky, K.J.Bergh, M.Lindgren, A.Johansson, P.Jeppsson, F.Falting, J.Gravenfors, Y.Rahm, F.

(2013) J Med Chem 56: 4181

  • DOI: https://doi.org/10.1021/jm3011349
  • Primary Citation of Related Structures:  
    4B70, 4B72, 4B77, 4B78

  • PubMed Abstract: 

    By use of iterative design aided by predictive models for target affinity, brain permeability, and hERG activity, novel and diverse compounds based on cyclic amidine and guanidine cores were synthesized with the goal of finding BACE-1 inhibitors as a treatment for Alzheimer's disease. Since synthesis feasibility had low priority in the design of the cores, an extensive synthesis effort was needed to make the relevant compounds. Syntheses of these compounds are reported, together with physicochemical properties and structure-activity relationships based on in vitro data. Four crystal structures of diverse amidines binding in the active site are deposited and discussed. Inhibitors of BACE-1 with 3 μM to 32 nM potencies in cells are shown, together with data on in vivo brain exposure levels for four compounds. The results presented show the importance of the core structure for the profile of the final compounds.


  • Organizational Affiliation

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


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
BETA-SECRETASE 1388Homo 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2FB
Query on 2FB

Download Ideal Coordinates CCD File 
B [auth A](6R)-6-(4-methoxyphenyl)-2-methyl-6-(3-pyrimidin-5-ylphenyl)pyrrolo[3,4-d][1,3]thiazol-4-amine
C23 H19 N5 O S
YQFNSFOVYAQJAF-HSZRJFAPSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2FB BindingDB:  4B72 IC50: min: 32, max: 630 (nM) from 2 assay(s)
Binding MOAD:  4B72 IC50: 630 (nM) from 1 assay(s)
PDBBind:  4B72 IC50: 630 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.60 Å
  • R-Value Free: 0.229 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 47.99α = 90
b = 75.15β = 90
c = 104.61γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
MOSFLMdata reduction
SCALAdata scaling
PHASERphasing

Structure Validation

View Full Validation Report



Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2013-06-26
    Type: Initial release
  • Version 1.1: 2013-07-03
    Changes: Database references