5HDZ

BACE-1 in complex with (7aR)-7a-(5-cyanothiophen-2-yl)-6-(5-fluoro-4-methyl-6-(methylthio)pyrimidin-2-yl)-3-methyl-4-oxooctahydro-2H-pyrrolo[3,4-d]pyrimidin-2-iminium


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.49 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Structure-Based Design of an Iminoheterocyclic beta-Site Amyloid Precursor Protein Cleaving Enzyme (BACE) Inhibitor that Lowers Central A beta in Nonhuman Primates.

Mandal, M.Wu, Y.Misiaszek, J.Li, G.Buevich, A.Caldwell, J.P.Liu, X.Mazzola, R.D.Orth, P.Strickland, C.Voigt, J.Wang, H.Zhu, Z.Chen, X.Grzelak, M.Hyde, L.A.Kuvelkar, R.Leach, P.T.Terracina, G.Zhang, L.Zhang, Q.Michener, M.S.Smith, B.Cox, K.Grotz, D.Favreau, L.Mitra, K.Kazakevich, I.McKittrick, B.A.Greenlee, W.Kennedy, M.E.Parker, E.M.Cumming, J.N.Stamford, A.W.

(2016) J Med Chem 59: 3231-3248

  • DOI: https://doi.org/10.1021/acs.jmedchem.5b01995
  • Primary Citation of Related Structures:  
    5HD0, 5HDU, 5HDV, 5HDX, 5HDZ, 5HE4, 5HE5, 5HE7

  • PubMed Abstract: 

    We describe successful efforts to optimize the in vivo profile and address off-target liabilities of a series of BACE1 inhibitors represented by 6 that embodies the recently validated fused pyrrolidine iminopyrimidinone scaffold. Employing structure-based design, truncation of the cyanophenyl group of 6 that binds in the S3 pocket of BACE1 followed by modification of the thienyl group in S1 was pursued. Optimization of the pyrimidine substituent that binds in the S2'-S2″ pocket of BACE1 remediated time-dependent CYP3A4 inhibition of earlier analogues in this series and imparted high BACE1 affinity. These efforts resulted in the discovery of difluorophenyl analogue 9 (MBi-4), which robustly lowered CSF and cortex Aβ40 in both rats and cynomolgus monkeys following a single oral dose. Compound 9 represents a unique molecular shape among BACE inhibitors reported to potently lower central Aβ in nonrodent preclinical species.


  • Organizational Affiliation

    Department of Global Chemistry, ‡Department of Neuroscience, §Department of Safety Assessment and Laboratory Animal Research, ∥Department of Discovery Pharmaceutical Sciences, and ⊥Department of Pharmacokinetics, Pharmacodynamics, and Drug Metabolism, Merck Research Laboratories , 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Beta-secretase 1
A, B
414Homo 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 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
954
Query on 954

Download Ideal Coordinates CCD File 
C [auth A],
D [auth B]
5-{(2E,4aR,7aR)-6-[5-fluoro-4-methyl-6-(methylsulfanyl)pyrimidin-2-yl]-2-imino-3-methyl-4-oxooctahydro-7aH-pyrrolo[3,4-d]pyrimidin-7a-yl}thiophene-2-carbonitrile
C18 H18 F N7 O S2
RVOBSBJZKQOYEK-VOJFVSQTSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
954 BindingDB:  5HDZ Ki: 45 (nM) from 1 assay(s)
IC50: 36 (nM) from 1 assay(s)
Binding MOAD:  5HDZ Ki: 45 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.49 Å
  • R-Value Free: 0.207 
  • R-Value Work: 0.194 
  • R-Value Observed: 0.195 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 86.303α = 90
b = 89.914β = 90
c = 131.554γ = 90
Software Package:
Software NamePurpose
PDB_EXTRACTdata extraction
XDSdata reduction
SCALAdata scaling
BUSTERrefinement
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2016-03-16 
  • Deposition Author(s): Orth, P.

Revision History  (Full details and data files)

  • Version 1.0: 2016-03-16
    Type: Initial release
  • Version 1.1: 2016-04-27
    Changes: Database references