4PF3

Mineralocorticoid receptor ligand-binding domain with compuond 37a


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.177 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of 6-[5-(4-fluorophenyl)-3-methyl-pyrazol-4-yl]-benzoxazin-3-one derivatives as novel selective nonsteroidal mineralocorticoid receptor antagonists

Hasui, T.Ohyabu, N.Ohra, T.Fuji, K.Sugimoto, T.Fujimoto, J.Asano, K.Oosawa, M.Shiotani, S.Nishigaki, N.Kusumoto, K.Matsui, H.Mizukami, A.Habuka, N.Sogabe, S.Endo, S.Ono, M.Siedem, C.S.Tang, T.P.Gauthier, C.De Meese, L.A.Boyd, S.A.Fukumoto, S.

(2014) Bioorg Med Chem 22: 5428-5445

  • DOI: https://doi.org/10.1016/j.bmc.2014.07.038
  • Primary Citation of Related Structures:  
    4PF3

  • PubMed Abstract: 

    In the course of our study on selective nonsteroidal mineralocorticoid receptor (MR) antagonists, a series of novel benzoxazine derivatives possessing an azole ring as the core scaffold was designed for the purpose of attenuating the partial agonistic activity of the previously reported dihydropyrrol-2-one derivatives. Screening of alternative azole rings identified 1,3-dimethyl pyrazole 6a as a lead compound with reduced partial agonistic activity. Subsequent replacement of the 1-methyl group of the pyrazole ring with larger lipophilic side chains or polar side chains targeting Arg817 and Gln776 increased MR binding activity while maintaining the agonistic response at the lower level. Among these compounds, 6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one (37a) showed highly potent in vitro activity, high selectivity versus other steroid hormone receptors, and good pharmacokinetic profiles. Oral administration of 37a in deoxycorticosterone acetate-salt hypertensive rats showed a significant blood pressure-lowering effect with no signs of antiandrogenic effects.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 26-1, Muraoka-higashi, 2-Chome, Fujisawa, Kanagawa 251-8555, Japan. Electronic address: tomoaki.hasui@takeda.com.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Mineralocorticoid receptor275Homo sapiensMutation(s): 3 
Gene Names: NR3C2MCRMLR
UniProt & NIH Common Fund Data Resources
Find proteins for P08235 (Homo sapiens)
Explore P08235 
Go to UniProtKB:  P08235
PHAROS:  P08235
GTEx:  ENSG00000151623 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP08235
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 2 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
HFN
Query on HFN

Download Ideal Coordinates CCD File 
B [auth A]6-[1-(2,2-difluoro-3-hydroxypropyl)-5-(4-fluorophenyl)-3-methyl-1H-pyrazol-4-yl]-2H-1,4-benzoxazin-3(4H)-one
C21 H18 F3 N3 O3
YPCPZZOTKIPGMW-UHFFFAOYSA-N
EDO
Query on EDO

Download Ideal Coordinates CCD File 
C [auth A]
D [auth A]
E [auth A]
F [auth A]
G [auth A]
C [auth A],
D [auth A],
E [auth A],
F [auth A],
G [auth A],
H [auth A],
I [auth A],
J [auth A]
1,2-ETHANEDIOL
C2 H6 O2
LYCAIKOWRPUZTN-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
HFN BindingDB:  4PF3 IC50: min: 51, max: 71 (nM) from 2 assay(s)
Binding MOAD:  4PF3 IC50: 51 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.10 Å
  • R-Value Free: 0.177 
  • R-Value Work: 0.154 
  • R-Value Observed: 0.155 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 58.05α = 90
b = 66.365β = 90
c = 74.908γ = 90
Software Package:
Software NamePurpose
REFMACrefinement

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2014-11-26
    Type: Initial release
  • Version 1.1: 2020-01-22
    Changes: Advisory, Data collection, Database references, Derived calculations, Source and taxonomy, Structure summary
  • Version 1.2: 2023-11-08
    Changes: Data collection, Database references, Refinement description