4HX5

Crystal structure of 11 beta-HSD1 in complex with SAR184841


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.19 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.163 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of SAR184841, a potent and long-lasting inhibitor of 11beta-hydroxysteroid dehydrogenase type 1, active in a physiopathological animal model of T2D

Venier, O.Pascal, C.Braun, A.Namane, C.Mougenot, P.Crespin, O.Pacquet, F.Mougenot, C.Monseau, C.Onofri, B.Dadji-Faihun, R.Leger, C.Ben-Hassine, M.Van-Pham, T.Ragot, J.L.Philippo, C.Farjot, G.Noah, L.Maniani, K.Boutarfa, A.Nicolai, E.Guillot, E.Pruniaux, M.P.Gussregen, S.Engel, C.Coutant, A.L.de Miguel, B.Castro, A.

(2013) Bioorg Med Chem Lett 23: 2414-2421

  • DOI: https://doi.org/10.1016/j.bmcl.2013.02.018
  • Primary Citation of Related Structures:  
    4HX5

  • PubMed Abstract: 

    Starting from 11β-HSD1 inhibitors that were active ex vivo but with Cyp 3A4 liability, we obtained a new series of adamantane ureas displaying potent inhibition of both human and rodent 11β-HSD1 enzymes, devoid of Cyp 3A4 interactions, and rationally designed to provide long-lasting inhibition in target tissues. Final optimizations lead to SAR184841 with good oral pharmacokinetic properties showing in vivo activity and improvement of metabolic parameters in a physiopathological model of type 2 diabetes.


  • Organizational Affiliation

    Sanofi R&D, 1 Avenue Pierre Brossolette, 91385 Chilly-Mazarin, France. olivier.venier@sanofi-aventis.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Corticosteroid 11-beta-dehydrogenase isozyme 1
A, B, C, D
286Homo sapiensMutation(s): 1 
Gene Names: HSD11B1HSD11HSD11L
EC: 1.1.1.146
UniProt & NIH Common Fund Data Resources
Find proteins for P28845 (Homo sapiens)
Explore P28845 
Go to UniProtKB:  P28845
PHAROS:  P28845
GTEx:  ENSG00000117594 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP28845
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
NDP
Query on NDP

Download Ideal Coordinates CCD File 
F [auth A],
H [auth B],
J [auth C],
L [auth D]
NADPH DIHYDRO-NICOTINAMIDE-ADENINE-DINUCLEOTIDE PHOSPHATE
C21 H30 N7 O17 P3
ACFIXJIJDZMPPO-NNYOXOHSSA-N
19V
Query on 19V

Download Ideal Coordinates CCD File 
E [auth A],
G [auth B],
I [auth C],
K [auth D]
4-[5-(4-tert-butylpiperazin-1-yl)pyridin-2-yl]-N-[(1R,2S,3S,5S,7s)-5-carbamoyltricyclo[3.3.1.1~3,7~]dec-2-yl]-3,4-dihydroquinoxaline-1(2H)-carboxamide
C33 H45 N7 O2
RZUKTDWPBQOSBE-PKZLOJIYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
19V Binding MOAD:  4HX5 IC50: 4 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.19 Å
  • R-Value Free: 0.199 
  • R-Value Work: 0.163 
  • Space Group: P 1 21 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 56.399α = 90
b = 153.491β = 92.89
c = 73.755γ = 90
Software Package:
Software NamePurpose
PHASERphasing
BUSTERrefinement
XDSdata reduction
XSCALEdata 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: 2013-05-08
    Type: Initial release
  • Version 1.1: 2013-06-12
    Changes: Other
  • Version 1.2: 2023-09-20
    Changes: Data collection, Database references, Derived calculations, Refinement description