5CLM

1,4-Oxazine BACE1 inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

1,4-Oxazine beta-Secretase 1 (BACE1) Inhibitors: From Hit Generation to Orally Bioavailable Brain Penetrant Leads.

Rombouts, F.J.Tresadern, G.Delgado, O.Martinez-Lamenca, C.Van Gool, M.Garcia-Molina, A.Alonso de Diego, S.A.Oehlrich, D.Prokopcova, H.Alonso, J.M.Austin, N.Borghys, H.Van Brandt, S.Surkyn, M.De Cleyn, M.Vos, A.Alexander, R.Macdonald, G.Moechars, D.Gijsen, H.Trabanco, A.A.

(2015) J Med Chem 58: 8216-8235

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01101
  • Primary Citation of Related Structures:  
    5CLM

  • PubMed Abstract: 

    1,4-Oxazines are presented, which show good in vitro inhibition in enzymatic and cellular BACE1 assays. We describe lead optimization focused on reducing the amidine pKa while optimizing interactions in the BACE1 active site. Our strategy permitted modulation of properties such as permeation and especially P-glycoprotein efflux. This led to compounds which were orally bioavailable, centrally active, and which demonstrated robust lowering of brain and CSF Aβ levels, respectively, in mouse and dog models. The amyloid lowering potential of these molecules makes them valuable leads in the search for new BACE1 inhibitors for the treatment of Alzheimer's disease.


  • Organizational Affiliation

    Neuroscience Medicinal Chemistry, Janssen Research & Development, Janssen Pharmaceutica NV , Turnhoutseweg 30, B-2340 Beerse, Belgium.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1401Homo sapiensMutation(s): 2 
Gene Names: BACE1BACEKIAA1149
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
52K BindingDB:  5CLM IC50: min: 7.4, max: 240 (nM) from 4 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.61 Å
  • R-Value Free: 0.250 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.193 
  • Space Group: P 61 2 2
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 100.824α = 90
b = 100.824β = 90
c = 170.104γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
XSCALEdata scaling
REFMACrefinement
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Revision History  (Full details and data files)

  • Version 1.0: 2015-09-30
    Type: Initial release
  • Version 1.1: 2015-11-04
    Changes: Database references