3QI1

Design and synthesis of hydroxyethylamine (hea) BACE-1 inhibitors: prime side chromane-containing inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.202 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Design and synthesis of hydroxyethylamine (HEA) BACE-1 inhibitors: prime side chromane-containing inhibitors.

Ng, R.A.Sun, M.Bowers, S.Hom, R.K.Probst, G.D.John, V.Fang, L.Y.Maillard, M.Gailunas, A.Brogley, L.Neitz, R.J.Tung, J.S.Pleiss, M.A.Konradi, A.W.Sham, H.L.Dappen, M.S.Adler, M.Yao, N.Zmolek, W.Nakamura, D.Quinn, K.P.Sauer, J.M.Bova, M.P.Ruslim, L.Artis, D.R.Yednock, T.A.

(2013) Bioorg Med Chem Lett 23: 4674-4679

  • DOI: https://doi.org/10.1016/j.bmcl.2013.06.006
  • Primary Citation of Related Structures:  
    3QI1

  • PubMed Abstract: 

    The structure activity relationship of the prime region of conformationally restricted hydroxyethylamine (HEA) BACE inhibitors is described. Variation of the P1' region provided selectivity over Cat-D with a series of 2,2-dioxo-isothiochromanes and optimization of the P2' substituent of chromane-HEA(s) with polar substituents provided improvements in the compound's in vitro permeability. Significant potency gains were observed with small aliphatic substituents such as methyl, n-propyl, and cyclopropyl when placed at the C-2 position of the chromane.


  • Organizational Affiliation

    Department of Chemical Sciences, Elan Pharmaceuticals, 180 Oyster Point Boulevard, South San Francisco, CA 94080, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1408Homo sapiensMutation(s): 2 
Gene Names: BACEBACE1KIAA1149
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
C6A
Query on C6A

Download Ideal Coordinates CCD File 
B [auth A]N-[(2S,3R)-4-{[(2R,4S)-2-cyclopropyl-6-(2,2-dimethylpropyl)-3,4-dihydro-2H-chromen-4-yl]amino}-1-(3,5-difluorophenyl)-3-hydroxybutan-2-yl]acetamide
C29 H38 F2 N2 O3
IBLLHMQPQAMFLM-WDTRASESSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
C6A PDBBind:  3QI1 IC50: 22 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.30 Å
  • R-Value Free: 0.269 
  • R-Value Work: 0.198 
  • R-Value Observed: 0.202 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 72.174α = 90
b = 75.506β = 90
c = 80.236γ = 90
Software Package:
Software NamePurpose
MOLREPphasing
REFMACrefinement
CrystalCleardata reduction
CrystalCleardata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-03-28 
  • Deposition Author(s): Yao, N.

Revision History  (Full details and data files)

  • Version 1.0: 2012-03-28
    Type: Initial release
  • Version 1.1: 2013-12-18
    Changes: Database references