3BGL

Hepatoselectivity of Statins: Design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 

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Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Hepatoselectivity of statins: design and synthesis of 4-sulfamoyl pyrroles as HMG-CoA reductase inhibitors.

Park, W.K.Kennedy, R.M.Larsen, S.D.Miller, S.Roth, B.D.Song, Y.Steinbaugh, B.A.Sun, K.Tait, B.D.Kowala, M.C.Trivedi, B.K.Auerbach, B.Askew, V.Dillon, L.Hanselman, J.C.Lin, Z.Lu, G.H.Robertson, A.Sekerke, C.

(2008) Bioorg Med Chem Lett 18: 1151-1156

  • DOI: https://doi.org/10.1016/j.bmcl.2007.11.124
  • Primary Citation of Related Structures:  
    3BGL

  • PubMed Abstract: 

    4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.


  • Organizational Affiliation

    Department of Chemistry, CVMED, Pfizer Global Research and Development, Michigan Laboratories, Ann Arbor, MI, USA. wkcpark@gmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
3-hydroxy-3-methylglutaryl-coenzyme A reductase
A, B, C, D
441Homo sapiensMutation(s): 1 
Gene Names: HMGCR
EC: 1.1.1.34
UniProt & NIH Common Fund Data Resources
Find proteins for P04035 (Homo sapiens)
Explore P04035 
Go to UniProtKB:  P04035
PHAROS:  P04035
GTEx:  ENSG00000113161 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04035
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
RID PDBBind:  3BGL IC50: 4.5 (nM) from 1 assay(s)
Binding MOAD:  3BGL IC50: 4.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.23 Å
  • R-Value Free: 0.251 
  • R-Value Work: 0.208 
  • R-Value Observed: 0.210 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 71.588α = 90
b = 172.156β = 117.24
c = 75.148γ = 90
Software Package:
Software NamePurpose
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction
HKL-2000data 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: 2008-01-29
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2017-10-25
    Changes: Refinement description
  • Version 1.3: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.4: 2024-02-21
    Changes: Data collection