4P38

Human 11beta-Hydroxysteroid Dehydrogenase Type 1 in complex with AZD8329


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.229 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Novel acidic 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) inhibitor with reduced acyl glucuronide liability: the discovery of 4-[4-(2-adamantylcarbamoyl)-5-tert-butyl-pyrazol-1-yl]benzoic acid (AZD8329).

Scott, J.S.deSchoolmeester, J.Kilgour, E.Mayers, R.M.Packer, M.J.Hargreaves, D.Gerhardt, S.Ogg, D.J.Rees, A.Selmi, N.Stocker, A.Swales, J.G.Whittamore, P.R.

(2012) J Med Chem 55: 10136-10147

  • DOI: https://doi.org/10.1021/jm301252n
  • Primary Citation of Related Structures:  
    4P38

  • PubMed Abstract: 

    Inhibition of 11β-HSD1 is viewed as a potential target for the treatment of obesity and other elements of the metabolic syndrome. We report here the optimization of a carboxylic acid class of inhibitors from AZD4017 (1) to the development candidate AZD8329 (27). A structural change from pyridine to pyrazole together with structural optimization led to an improved technical profile in terms of both solubility and pharmacokinetics. The extent of acyl glucuronidation was reduced through structural optimization of both the carboxylic acid and amide substituents, coupled with a reduction in lipophilicity leading to an overall increase in metabolic stability.


  • Organizational Affiliation

    Cardiovascular & Gastrointestinal Innovative Medicines Unit, AstraZeneca Mereside , Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom. jamie.scott@astrazeneca.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
265Homo sapiensMutation(s): 0 
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
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  • Reference Sequence
Small Molecules
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.80 Å
  • R-Value Free: 0.272 
  • R-Value Work: 0.227 
  • R-Value Observed: 0.229 
  • Space Group: P 31 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 103.516α = 90
b = 103.516β = 90
c = 134.78γ = 120
Software Package:
Software NamePurpose
BUSTERrefinement
d*TREKdata scaling
CrystalCleardata collection
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-04-30
    Type: Initial release
  • Version 1.1: 2014-11-12
    Changes: Structure summary
  • Version 1.2: 2017-11-01
    Changes: Author supporting evidence, Database references, Derived calculations, Other, Refinement description, Source and taxonomy
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Refinement description