5KOS

Discovery of TAK-272: A Novel, Potent and Orally Active Renin In-hibitor


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.41 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.1 of the entry. See complete history


Literature

Discovery of TAK-272: A Novel, Potent, and Orally Active Renin Inhibitor.

Imaeda, Y.Tokuhara, H.Fukase, Y.Kanagawa, R.Kajimoto, Y.Kusumoto, K.Kondo, M.Snell, G.Behnke, C.A.Kuroita, T.

(2016) ACS Med Chem Lett 7: 933-938

  • DOI: https://doi.org/10.1021/acsmedchemlett.6b00251
  • Primary Citation of Related Structures:  
    5KOS

  • PubMed Abstract: 

    The aspartic proteinase renin is an attractive target for the treatment of hypertension and cardiovascular/renal disease such as chronic kidney disease and heart failure. We introduced an S1' site binder into the lead compound 1 guided by structure-based drug design (SBDD), and further optimization of physicochemical properties led to the discovery of benzimidazole derivative 10 (1-(4-methoxybutyl)- N -(2-methylpropyl)- N -[(3 S ,5 R )-5-(morpholin-4-yl)carbonylpiperidin-3-yl]-1 H- benzimidazole-2-carboxamide hydrochloride, TAK-272) as a highly potent and orally active renin inhibitor. Compound 10 demonstrated good oral bioavailability (BA) and long-lasting efficacy in rats. Compound 10 is currently in clinical trials.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited , 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
Renin
A, B
337Homo sapiensMutation(s): 0 
Gene Names: REN
EC: 3.4.23.15
UniProt & NIH Common Fund Data Resources
Find proteins for P00797 (Homo sapiens)
Explore P00797 
Go to UniProtKB:  P00797
PHAROS:  P00797
GTEx:  ENSG00000143839 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP00797
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
6VS
Query on 6VS

Download Ideal Coordinates CCD File 
D [auth A],
P [auth B]
2-~{tert}-butyl-4-(3-methoxypropylamino)-~{N}-(2-methylpropyl)-~{N}-[(3~{S},5~{R})-5-morpholin-4-ylcarbonylpiperidin-3-yl]pyrimidine-5-carboxamide
C27 H46 N6 O4
ISBMTDVOSWIALV-RTWAWAEBSA-N
NAG
Query on NAG

Download Ideal Coordinates CCD File 
C [auth A],
O [auth B]
2-acetamido-2-deoxy-beta-D-glucopyranose
C8 H15 N O6
OVRNDRQMDRJTHS-FMDGEEDCSA-N
PEG
Query on PEG

Download Ideal Coordinates CCD File 
M [auth A],
N [auth A],
Q [auth B]
DI(HYDROXYETHYL)ETHER
C4 H10 O3
MTHSVFCYNBDYFN-UHFFFAOYSA-N
DMS
Query on DMS

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],
R [auth B],
S [auth B]
DIMETHYL SULFOXIDE
C2 H6 O S
IAZDPXIOMUYVGZ-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
6VS BindingDB:  5KOS IC50: min: 0.38, max: 1.5 (nM) from 3 assay(s)
Binding MOAD:  5KOS IC50: 1.5 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.41 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.185 
  • R-Value Observed: 0.187 
  • Space Group: P 21 3
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 137.077α = 90
b = 137.077β = 90
c = 137.077γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
HKL-2000data scaling
MOLREPphasing
PDB_EXTRACTdata extraction
HKL-2000data reduction

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2016-11-16
    Type: Initial release
  • Version 1.1: 2020-07-29
    Type: Remediation
    Reason: Carbohydrate remediation
    Changes: Data collection, Derived calculations, Structure summary