5VP1

Discovery of Clinical Candidate N-{(1S)-1-[3-Fluoro-4-(trifluoromethoxy)phenyl]-2-methoxyethyl}-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), A Highly Potent, Selective, and Brain-Penetrating Phosphodiesterase 2A Inhibitor for the Treatment of Cognitive Disorders


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.225 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history


Literature

Discovery of a Novel Series of Pyrazolo[1,5-a]pyrimidine-Based Phosphodiesterase 2A Inhibitors Structurally Different from N-((1S)-1-(3-Fluoro-4-(trifluoromethoxy)phenyl)-2-methoxyethyl)-7-methoxy-2-oxo-2,3-dihydropyrido[2,3-b]pyrazine-4(1H)-carboxamide (TAK-915), for the Treatment of Cognitive Disorders.

Mikami, S.Kawasaki, M.Ikeda, S.Negoro, N.Nakamura, S.Nomura, I.Ashizawa, T.Kokubo, H.Hoffman, I.D.Zou, H.Oki, H.Uchiyama, N.Hiura, Y.Miyamoto, M.Itou, Y.Nakashima, M.Iwashita, H.Taniguchi, T.

(2017) Chem Pharm Bull (Tokyo) 65: 1058-1077

  • DOI: https://doi.org/10.1248/cpb.c17-00564
  • Primary Citation of Related Structures:  
    5VP1

  • PubMed Abstract: 

    It has been hypothesized that selective inhibition of phosphodiesterase (PDE) 2A could potentially be a novel approach to treat cognitive impairment in neuropsychiatric and neurodegenerative disorders through augmentation of cyclic nucleotide signaling pathways in brain regions associated with learning and memory. Following our earlier work, this article describes a drug design strategy for a new series of lead compounds structurally distinct from our clinical candidate 2 (TAK-915), and subsequent medicinal chemistry efforts to optimize potency, selectivity over other PDE families, and other preclinical properties including in vitro phototoxicity and in vivo rat plasma clearance. These efforts resulted in the discovery of N-((1S)-2-hydroxy-2-methyl-1-(4-(trifluoromethoxy)phenyl)propyl)-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (20), which robustly increased 3',5'-cyclic guanosine monophosphate (cGMP) levels in the rat brain following an oral dose, and moreover, attenuated MK-801-induced episodic memory deficits in a passive avoidance task in rats. These data provide further support to the potential therapeutic utility of PDE2A inhibitors in enhancing cognitive performance.


  • Organizational Affiliation

    Pharmaceutical Research Division, Takeda Pharmaceutical Company, Limited.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cGMP-dependent 3',5'-cyclic phosphodiesterase
A, B, C
345Homo sapiensMutation(s): 0 
Gene Names: PDE2A
EC: 3.1.4.17
UniProt & NIH Common Fund Data Resources
Find proteins for O00408 (Homo sapiens)
Explore O00408 
Go to UniProtKB:  O00408
PHAROS:  O00408
GTEx:  ENSG00000186642 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupO00408
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 3 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
9GA
Query on 9GA

Download Ideal Coordinates CCD File 
G [auth A],
J [auth B],
M [auth C]
N-{(1S)-2-hydroxy-2-methyl-1-[4-(trifluoromethoxy)phenyl]propyl}-6-methyl-5-(3-methyl-1H-1,2,4-triazol-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide
C22 H22 F3 N7 O3
HXMZXPQNCNEBPD-KRWDZBQOSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B],
K [auth C]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
MG
Query on MG

Download Ideal Coordinates CCD File 
E [auth A],
F [auth A],
I [auth B],
L [auth C]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
9GA Binding MOAD:  5VP1 IC50: 0.51 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.86 Å
  • R-Value Free: 0.243 
  • R-Value Work: 0.225 
  • R-Value Observed: 0.225 
  • Space Group: C 1 2 1
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 165.129α = 90
b = 72.712β = 109.15
c = 90.061γ = 90
Software Package:
Software NamePurpose
REFMACrefinement
Aimlessdata scaling
PDB_EXTRACTdata extraction
HKL-2000data reduction
PHASERphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2017-12-27
    Type: Initial release
  • Version 1.1: 2018-05-23
    Changes: Data collection, Structure summary
  • Version 1.2: 2024-03-13
    Changes: Data collection, Database references, Derived calculations, Refinement description