4Y8X

Factor XIa in complex with the inhibitor methyl (4-{4-chloro-2-[(1S)-1-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.164 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.158 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a Potent Parenterally Administered Factor XIa Inhibitor with Hydroxyquinolin-2(1H)-one as the P2' Moiety.

Hu, Z.Wong, P.C.Gilligan, P.J.Han, W.Pabbisetty, K.B.Bozarth, J.M.Crain, E.J.Harper, T.Luettgen, J.M.Myers, J.E.Ramamurthy, V.Rossi, K.A.Sheriff, S.Watson, C.A.Wei, A.Zheng, J.J.Seiffert, D.A.Wexler, R.R.Quan, M.L.

(2015) ACS Med Chem Lett 6: 590-595

  • DOI: https://doi.org/10.1021/acsmedchemlett.5b00066
  • Primary Citation of Related Structures:  
    4Y8X, 4Y8Y, 4Y8Z

  • PubMed Abstract: 

    Structure-activity relationship optimization of phenylalanine P1' and P2' regions with a phenylimidazole core resulted in a series of potent FXIa inhibitors. Introducing 4-hydroxyquinolin-2-one as the P2' group enhanced FXIa affinity and metabolic stability. Incorporation of an N-methyl piperazine amide group to replace the phenylalanine improved both FXIa potency and aqueous solubility. Combination of the optimization led to the discovery of FXIa inhibitor 13 with a FXIa K i of 0.04 nM and an aPTT EC2x of 1.0 μM. Dose-dependent efficacy (EC50 of 0.53 μM) was achieved in the rabbit ECAT model with minimal bleeding time prolongation.


  • Organizational Affiliation

    Research and Development, Bristol-Myers Squibb , Princeton, New Jersey 08543, United States.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor XIa244Homo sapiensMutation(s): 2 
Gene Names: F11
EC: 3.4.21.27
UniProt & NIH Common Fund Data Resources
Find proteins for P03951 (Homo sapiens)
Explore P03951 
Go to UniProtKB:  P03951
PHAROS:  P03951
GTEx:  ENSG00000088926 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP03951
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
4GR
Query on 4GR

Download Ideal Coordinates CCD File 
B [auth A]methyl (4-{4-chloro-2-[(1S)-1-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-2-phenylethyl]-1H-imidazol-5-yl}phenyl)carbamate
C29 H24 Cl2 N8 O3
GLCBWRQIUCCILC-PZVJUEDKSA-N
SO4
Query on SO4

Download Ideal Coordinates CCD File 
C [auth A],
D [auth A]
SULFATE ION
O4 S
QAOWNCQODCNURD-UHFFFAOYSA-L
EDO
Query on EDO

Download Ideal Coordinates CCD File 
E [auth A]
F [auth A]
G [auth A]
H [auth A]
I [auth A]
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A],
K [auth A],
L [auth A],
M [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.164 
  • R-Value Work: 0.158 
  • R-Value Observed: 0.158 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.78α = 90
b = 78.78β = 90
c = 106.32γ = 120
Software Package:
Software NamePurpose
BUSTER-TNTrefinement
PDB_EXTRACTdata extraction
XDSdata reduction
SCALAdata scaling
AMoREphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2015-05-27 
  • Deposition Author(s): Sheriff, S.

Revision History  (Full details and data files)

  • Version 1.0: 2015-05-27
    Type: Initial release
  • Version 1.1: 2018-04-18
    Changes: Data collection, Database references, Derived calculations, Source and taxonomy, Structure summary
  • Version 1.2: 2023-09-27
    Changes: Data collection, Database references, Derived calculations, Refinement description, Structure summary