5PGU

CRYSTAL STRUCTURE OF 11BETA-HSD1 DOUBLE MUTANT (L262R, F278E) COMPLEXED WITH 2-[2-(4-fluorophenyl)-2-adamantyl]-1-(3-methoxyazetidin-1-yl)ethanone


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.231 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of Clinical Candidate 2-((2S,6S)-2-Phenyl-6-hydroxyadamantan-2-yl)-1-(3'-hydroxyazetidin-1-yl)ethanone [BMS-816336], an Orally Active Novel Selective 11 beta-Hydroxysteroid Dehydrogenase Type 1 Inhibitor.

Ye, X.Y.Chen, S.Y.Wu, S.Yoon, D.S.Wang, H.Hong, Z.O'Connor, S.P.Li, J.Li, J.J.Kennedy, L.J.Walker, S.J.Nayeem, A.Sheriff, S.Camac, D.M.Ramamurthy, V.Morin, P.E.Zebo, R.Taylor, J.R.Morgan, N.N.Ponticiello, R.P.Harrity, T.Apedo, A.Golla, R.Seethala, R.Wang, M.Harper, T.W.Sleczka, B.G.He, B.Kirby, M.Leahy, D.K.Li, J.Hanson, R.L.Guo, Z.Li, Y.X.DiMarco, J.D.Scaringe, R.Maxwell, B.Moulin, F.Barrish, J.C.Gordon, D.A.Robl, J.A.

(2017) J Med Chem 60: 4932-4948

  • DOI: https://doi.org/10.1021/acs.jmedchem.7b00211
  • Primary Citation of Related Structures:  
    5PGU, 5PGV, 5PGW, 5PGX, 5PGY, 5PGZ

  • PubMed Abstract: 

    BMS-816336 (6n-2), a hydroxy-substituted adamantyl acetamide, has been identified as a novel, potent inhibitor against human 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme (IC 50 3.0 nM) with >10000-fold selectivity over human 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2). 6n-2 exhibits a robust acute pharmacodynamic effect in cynomolgus monkeys (ED 50 0.12 mg/kg) and in DIO mice. It is orally bioavailable (%F ranges from 20 to 72% in preclinical species) and has a predicted pharmacokinetic profile of a high peak to trough ratio and short half-life in humans. This ADME profile met our selection criteria for once daily administration, targeting robust inhibition of 11β-HSD1 enzyme for the first 12 h period after dosing followed by an "inhibition holiday" so that the potential for hypothalamic-pituitary-adrenal (HPA) axis activation might be mitigated. 6n-2 was found to be well-tolerated in phase 1 clinical studies and represents a potential new treatment for type 2 diabetes, metabolic syndrome, and other human diseases modulated by glucocorticoid control.


  • Organizational Affiliation

    Discovery Chemistry, ‡Pharmaceutical Candidate Optimization, §Computer-Assisted Drug Design, ∥Metabolic Diseases Biology, ⊥Lead Evaluation, #Process Chemistry, ∇Chemical Synthesis, ○Discovery Toxicology, Research and Development, Bristol-Myers Squibb , 350 Carter Road, Princeton, New Jersey 08540, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Corticosteroid 11-beta-dehydrogenase isozyme 1A,
B,
C [auth D],
D [auth E]
286Homo sapiensMutation(s): 2 
Gene Names: HSD11B1HSD11HSD11LSDR26C1
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
8K4 Binding MOAD:  5PGU IC50: 1 (nM) from 1 assay(s)
BindingDB:  5PGU IC50: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.35 Å
  • R-Value Free: 0.254 
  • R-Value Work: 0.230 
  • R-Value Observed: 0.231 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 74.3α = 90
b = 93.8β = 90
c = 168.1γ = 90
Software Package:
Software NamePurpose
HKL-2000data collection
HKL-2000data scaling
AMoREphasing
BUSTERrefinement
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2017-11-01 
  • Deposition Author(s): Sheriff, S.

Revision History  (Full details and data files)

  • Version 1.0: 2017-11-01
    Type: Initial release
  • Version 1.1: 2018-02-21
    Changes: Structure summary
  • Version 1.2: 2024-03-06
    Changes: Data collection, Database references