3BYZ

2-Amino-1,3-thiazol-4(5H)-ones as Potent and Selective 11-Hydroxysteroid Dehydrogenase Type 1 Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.69 Å
  • R-Value Free: 0.293 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.222 

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Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

2-amino-1,3-thiazol-4(5H)-ones as potent and selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitors: enzyme-ligand co-crystal structure and demonstration of pharmacodynamic effects in C57Bl/6 mice.

Johansson, L.Fotsch, C.Bartberger, M.D.Castro, V.M.Chen, M.Emery, M.Gustafsson, S.Hale, C.Hickman, D.Homan, E.Jordan, S.R.Komorowski, R.Li, A.McRae, K.Moniz, G.Matsumoto, G.Orihuela, C.Palm, G.Veniant, M.Wang, M.Williams, M.Zhang, J.

(2008) J Med Chem 51: 2933-2943

  • DOI: https://doi.org/10.1021/jm701551j
  • Primary Citation of Related Structures:  
    3BYZ

  • PubMed Abstract: 

    11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) has attracted considerable attention during the past few years as a potential target for the treatment of diseases associated with metabolic syndrome. In our ongoing work on 11beta-HSD1 inhibitors, a series of new 2-amino-1,3-thiazol-4(5 H)-ones were explored. By inserting various cycloalkylamines at the 2-position and alkyl groups or spirocycloalkyl groups at the 5-position of the thiazolone, several potent 11beta-HSD1 inhibitors were identified. An X-ray cocrystal structure of human 11beta-HSD1 with compound 6d (Ki=28 nM) revealed a large lipophilic pocket accessible by substitution off the 2-position of the thiazolone. To increase potency, analogues were prepared with larger lipophilic groups at this position. One of these compounds, the 3-noradamantyl analogue 8b, was a potent inhibitor of human 11beta-HSD1 (Ki=3 nM) and also inhibited 11beta-HSD1 activity in lean C57Bl/6 mice when evaluated in an ex vivo adipose and liver cortisone to cortisol conversion assay.


  • Organizational Affiliation

    Biovitrum AB, Stockholm, Sweden. lars.johansson@biovitrum.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
275Homo 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
Binding Affinity Annotations 
IDSourceBinding Affinity
H11 BindingDB:  3BYZ Ki: 28 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.69 Å
  • R-Value Free: 0.293 
  • R-Value Work: 0.218 
  • R-Value Observed: 0.222 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.036α = 90
b = 138.48β = 90
c = 155.022γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
ADSCdata collection
HKL-2000data reduction
SCALEPACKdata 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: 2008-02-12
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2021-10-20
    Changes: Database references, Derived calculations
  • Version 1.3: 2024-02-21
    Changes: Data collection