5KYJ

Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Brain penetrant liver X receptor (LXR) modulators based on a 2,4,5,6-tetrahydropyrrolo[3,4-c]pyrazole core.

Tice, C.M.Noto, P.B.Fan, K.Y.Zhao, W.Lotesta, S.D.Dong, C.Marcus, A.P.Zheng, Y.J.Chen, G.Wu, Z.Van Orden, R.Zhou, J.Bukhtiyarov, Y.Zhao, Y.Lipinski, K.Howard, L.Guo, J.Kandpal, G.Meng, S.Hardy, A.Krosky, P.Gregg, R.E.Leftheris, K.McKeever, B.M.Singh, S.B.Lala, D.McGeehan, G.M.Zhuang, L.Claremon, D.A.

(2016) Bioorg Med Chem Lett 26: 5044-5050

  • DOI: https://doi.org/10.1016/j.bmcl.2016.08.089
  • Primary Citation of Related Structures:  
    5KYA, 5KYJ

  • PubMed Abstract: 

    Liver X receptor (LXR) agonists have been reported to lower brain amyloid beta (Aβ) and thus to have potential for the treatment of Alzheimer's disease. Structure and property based design led to the discovery of a series of orally bioavailable, brain penetrant LXR agonists. Oral administration of compound 18 to rats resulted in significant upregulation of the expression of the LXR target gene ABCA1 in brain tissue, but no significant effect on Aβ levels was detected.


  • Organizational Affiliation

    Vitae Pharmaceuticals, 502 West Office Center Drive, Fort Washington, PA 19034, USA.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Oxysterols receptor LXR-betaA,
C [auth E]
287Homo sapiensMutation(s): 6 
Gene Names: NR1H2LXRBNERUNR
UniProt & NIH Common Fund Data Resources
Find proteins for P55055 (Homo sapiens)
Explore P55055 
Go to UniProtKB:  P55055
PHAROS:  P55055
GTEx:  ENSG00000131408 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP55055
Sequence Annotations
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  • Reference Sequence
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Retinoic acid receptor RXR-betaB,
D [auth F]
256Homo sapiensMutation(s): 1 
Gene Names: RXRBNR2B2
UniProt & NIH Common Fund Data Resources
Find proteins for P28702 (Homo sapiens)
Explore P28702 
Go to UniProtKB:  P28702
PHAROS:  P28702
GTEx:  ENSG00000204231 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28702
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 1 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6Y8
Query on 6Y8

Download Ideal Coordinates CCD File 
E [auth A],
F [auth E]
(6~{R})-5-(5-fluoranyl-2-methoxy-pyrimidin-4-yl)-2-(3-methylsulfonylphenyl)-6-propan-2-yl-4,6-dihydropyrrolo[3,4-c]pyrazole
C20 H22 F N5 O3 S
HDDKTNCZLILPNB-GOSISDBHSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6Y8 BindingDB:  5KYJ Ki: 13 (nM) from 1 assay(s)
EC50: 15 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.253 
  • R-Value Work: 0.199 
  • R-Value Observed: 0.201 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 69.92α = 90
b = 100.93β = 90
c = 145.9γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
MOLREPphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-09-21
    Type: Initial release
  • Version 1.1: 2016-10-19
    Changes: Database references
  • Version 1.2: 2017-08-09
    Changes: Database references, Derived calculations
  • Version 1.3: 2017-11-01
    Changes: Author supporting evidence
  • Version 1.4: 2023-10-04
    Changes: Data collection, Database references, Refinement description