5QTX

FACTOR XIA IN COMPLEX WITH THE INHIBITOR ethyl (2R,7S)-7-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-14-[(methoxycarbonyl)amino]-1,2,3,4,5,6,7,9-octahydro-11,8-(azeno)-1,9-benzodiazacyclotridecine-2-carboxylate


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.4 of the entry. See complete history


Literature

Orally bioavailable amine-linked macrocyclic inhibitors of factor XIa.

Fang, T.Corte, J.R.Gilligan, P.J.Jeon, Y.Osuna, H.Rossi, K.A.Myers Jr., J.E.Sheriff, S.Lou, Z.Zheng, J.J.Harper, T.W.Bozarth, J.M.Wu, Y.Luettgen, J.M.Seiffert, D.A.Wexler, R.R.Lam, P.Y.S.

(2020) Bioorg Med Chem Lett 30: 126949-126949

  • DOI: https://doi.org/10.1016/j.bmcl.2020.126949
  • Primary Citation of Related Structures:  
    5QTV, 5QTW, 5QTX, 5QTY

  • PubMed Abstract: 

    The discovery of orally bioavailable FXIa inhibitors has been a challenge. Herein, we describe our efforts to address this challenge by optimization of our imidazole-based macrocyclic series. Our optimization strategy focused on modifications to the P2 prime, macrocyclic amide linker, and the imidazole scaffold. Replacing the amide of the macrocyclic linker with amide isosteres led to the discovery of substituted amine linkers which not only maintained FXIa binding affinity but also improved oral exposure in rats. Combining the optimized macrocyclic amine linker with a pyridine scaffold afforded compounds 23 and 24 that were orally bioavailable, single-digit nanomolar FXIa inhibitors with excellent selectivity against relevant blood coagulation enzymes.


  • Organizational Affiliation

    Bristol-Myers Squibb Company, Research and Development, 350 Carter Road, Hopewell, NJ 08540, United States. Electronic address: [email protected].


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor XI244Homo sapiensMutation(s): 0 
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

Find similar proteins by:  Sequence   |   3D Structure  

Entity ID: 2
MoleculeChains Sequence LengthOrganismDetailsImage
Coagulation factor XIB [auth H]18Homo sapiensMutation(s): 0 
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
QLD
Query on QLD

Download Ideal Coordinates CCD File 
C [auth A]ethyl (2R,7S)-7-({(2E)-3-[5-chloro-2-(1H-tetrazol-1-yl)phenyl]prop-2-enoyl}amino)-14-[(methoxycarbonyl)amino]-1,2,3,4,5,6,7,9-octahydro-11,8-(azeno)-1,9-benzodiazacyclotridecine-2-carboxylate
C30 H32 Cl N9 O5
BNKJNEZXZHRTHJ-GGRGIUQZSA-N
SO4
Query on SO4

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

Download Ideal Coordinates CCD File 
F [auth A]
G [auth A]
H [auth A]
I [auth A]
J [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],
N [auth A],
O [auth A],
P [auth A],
Q [auth A],
R [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
QLD BindingDB:  5QTX Ki: min: 0.22, max: 203 (nM) from 2 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.07 Å
  • R-Value Free: 0.178 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 
  • Space Group: P 32 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 78.85α = 90
b = 78.85β = 90
c = 105.88γ = 120
Software Package:
Software NamePurpose
XDSdata reduction
SCALAdata scaling
AMoREphasing
BUSTERrefinement
PDB_EXTRACTdata extraction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2020-01-29 
  • Deposition Author(s): Sheriff, S.

Revision History  (Full details and data files)

  • Version 1.0: 2020-01-29
    Type: Initial release
  • Version 1.1: 2020-02-26
    Changes: Data collection, Database references
  • Version 1.2: 2020-03-18
    Changes: Data collection, Database references
  • Version 1.3: 2021-05-12
    Changes: Structure summary
  • Version 1.4: 2024-10-23
    Changes: Data collection, Database references, Structure summary