3G49

N-(Pyridin-2-yl) Arylsulfonamide Inhibitors of 11b-Hydroxysteroid Dehydrogenase Type 1: Discovery of PF-915275

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 

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Ligand Structure Quality Assessment 


This is version 1.5 of the entry. See complete history. 


Literature

N-(Pyridin-2-yl) arylsulfonamide inhibitors of 11beta-hydroxysteroid dehydrogenase type 1: Discovery of PF-915275.

Siu, M., Johnson, T.O., Wang, Y., Nair, S.K., Taylor, W.D., Cripps, S.J., Matthews, J.J., Edwards, M.P., Pauly, T.A., Ermolieff, J., Castro, A., Hosea, N.A., LaPaglia, A., Fanjul, A.N., Vogel, J.E.

(2009) Bioorg Med Chem Lett 19: 3493-3497

  • DOI: https://doi.org/10.1016/j.bmcl.2009.05.011
  • Primary Citation of Related Structures:  
    3G49

  • PubMed Abstract: 

    N-(Pyridin-2-yl) arylsulfonamides are identified as inhibitors of 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1), an enzyme that catalyzes the reduction of the glucocorticoid cortisone to cortisol. Dysregulation of glucocorticoids has been implicated in the pathogenesis of diabetes and the metabolic syndrome. In this Letter, we present the development of an initial lead to an efficient ligand with improved physiochemical properties using a deletion strategy. This strategy allowed for further optimization of potency leading to the discovery of the clinical candidate PF-915275.

    • Organizational Affiliation: 

    Discovery Chemistry, Pfizer Global Research and Development, 10770 Science Center Drive, San Diego, CA 92121, United States. siu.michael@gene.com


Macromolecules
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(by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
11-beta-hydroxysteroid dehydrogenase 1
A, B, C, D
277Cavia porcellusMutation(s): 0 
Gene Names: HSD11B1
EC: 1.1.1.146
Membrane Entity: Yes 
UniProt
Find proteins for Q6QLL4 (Cavia porcellus)
Explore Q6QLL4 
Go to UniProtKB:  Q6QLL4
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ6QLL4
Sequence Annotations
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
3G4 Binding MOAD:  3G49 Ki: 287 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.50 Å
  • R-Value Free: 0.225 
  • R-Value Work: 0.189 
  • R-Value Observed: 0.191 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.207α = 90
b = 83.599β = 90
c = 179.202γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
CNSrefinement
MAR345data collection
HKL-2000data reduction
HKL-2000data scaling
CNSphasing

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

  • Released Date: 2009-08-04 
    • Deposition Author(s): Pauly, T.A.

Revision History  (Full details and data files)

  • Version 1.0: 2009-08-04
    Type: Initial release
  • Version 1.1: 2011-07-13
    Changes: Version format compliance
  • Version 1.2: 2012-03-21
    Changes: Database references
  • Version 1.3: 2017-11-01
    Changes: Refinement description
  • Version 1.4: 2019-07-24
    Changes: Data collection, Refinement description
  • Version 1.5: 2024-02-21
    Changes: Data collection, Database references, Derived calculations