4N00

Discovery of 7-THP chromans: BACE1 inhibitors that reduce A-beta in the CNS


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of 7-tetrahydropyran-2-yl chromans: beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors that reduce amyloid beta-protein (A beta ) in the central nervous system.

Thomas, A.A.Hunt, K.W.Volgraf, M.Watts, R.J.Liu, X.Vigers, G.Smith, D.Sammond, D.Tang, T.P.Rhodes, S.P.Metcalf, A.T.Brown, K.D.Otten, J.N.Burkard, M.Cox, A.A.Do, M.K.Dutcher, D.Rana, S.DeLisle, R.K.Regal, K.Wright, A.D.Groneberg, R.Scearce-Levie, K.Siu, M.Purkey, H.E.Lyssikatos, J.P.Gunawardana, I.W.

(2014) J Med Chem 57: 878-902

  • DOI: https://doi.org/10.1021/jm401635n
  • Primary Citation of Related Structures:  
    4N00

  • PubMed Abstract: 

    In an attempt to increase selectivity vs Cathepsin D (CatD) in our BACE1 program, a series of 1,3,4,4a,10,10a-hexahydropyrano[4,3-b]chromene analogues was developed. Three different Asp-binding moieties were examined: spirocyclic acyl guanidines, aminooxazolines, and aminothiazolines in order to modulate potency, selectivity, efflux, and permeability. Using structure-based design, substitutions to improve binding to both the S3 and S2' sites of BACE1 were explored. An acyl guanidine moiety provided the most potent analogues. These compounds demonstrated 10-420 fold selectivity for BACE1 vs CatD, and were highly potent in a cell assay measuring Aβ1-40 production (5-99 nM). They also suffered from high efflux. Despite this undesirable property, two of the acyl guanidines achieved free brain concentrations (Cfree,brain) in a guinea pig PD model sufficient to cover their cell IC50s. Moreover, a significant reduction of Aβ1-40 in guinea pig, rat, and cyno CSF (58%, 53%, and 63%, respectively) was observed for compound 62.


  • Organizational Affiliation

    Array BioPharma , 3200 Walnut Street, Boulder, Colorado 80301, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1406Homo sapiensMutation(s): 0 
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
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
2EX
Query on 2EX

Download Ideal Coordinates CCD File 
C [auth A](4R,4a'S,10a'S)-2-amino-8'-(2-fluoropyridin-3-yl)-1-methyl-3',4',4a',10a'-tetrahydro-1'H-spiro[imidazole-4,10'-pyrano[4,3-b]chromen]-5(1H)-one
C20 H19 F N4 O3
DWEUDIDNAOSEBW-UVFQYZLESA-N
NI
Query on NI

Download Ideal Coordinates CCD File 
B [auth A]NICKEL (II) ION
Ni
VEQPNABPJHWNSG-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
2EX Binding MOAD:  4N00 IC50: 9.5 (nM) from 1 assay(s)
BindingDB:  4N00 IC50: 9.9 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.80 Å
  • R-Value Free: 0.235 
  • R-Value Work: 0.196 
  • R-Value Observed: 0.198 
  • Space Group: C 2 2 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.99α = 90
b = 103.91β = 90
c = 100.42γ = 90
Software Package:
Software NamePurpose
CrystalCleardata collection
MOLREPphasing
REFMACrefinement
MOSFLMdata reduction
SCALAdata scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-05-14
    Type: Initial release
  • Version 1.1: 2018-01-24
    Changes: Structure summary
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description