3SN7

Highly Potent, Selective, and Orally Active Phosphodiestarase 10A Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.82 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.247 
  • R-Value Observed: 0.248 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Highly Potent, Selective, and Orally Active Phosphodiesterase 10A Inhibitors.

Malamas, M.S.Ni, Y.Erdei, J.Stange, H.Schindler, R.Lankau, H.J.Grunwald, C.Fan, K.Y.Parris, K.Langen, B.Egerland, U.Hage, T.Marquis, K.L.Grauer, S.Brennan, J.Navarra, R.Graf, R.Harrison, B.L.Robichaud, A.Kronbach, T.Pangalos, M.N.Hoefgen, N.Brandon, N.J.

(2011) J Med Chem 54: 7621-7638

  • DOI: https://doi.org/10.1021/jm2009138
  • Primary Citation of Related Structures:  
    3SN7, 3SNI, 3SNL

  • PubMed Abstract: 

    The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.


  • Organizational Affiliation

    Pfizer Neuroscience Princeton, NJ 08852, USA. malamas.michael@gmail.com


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
cAMP and cAMP-inhibited cGMP 3',5'-cyclic phosphodiesterase 10A
A, B
345Homo sapiensMutation(s): 0 
Gene Names: PDE10A
EC: 3.1.4.17 (PDB Primary Data), 3.1.4.35 (PDB Primary Data)
UniProt & NIH Common Fund Data Resources
Find proteins for Q9Y233 (Homo sapiens)
Explore Q9Y233 
Go to UniProtKB:  Q9Y233
PHAROS:  Q9Y233
GTEx:  ENSG00000112541 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupQ9Y233
Sequence Annotations
Expand
  • Reference Sequence
Small Molecules
Ligands 4 Unique
IDChains Name / Formula / InChI Key2D Diagram3D Interactions
540
Query on 540

Download Ideal Coordinates CCD File 
D [auth A],
H [auth B]
8-fluoro-6-methoxy-3,4-dimethyl-1-(3-methylpyridin-4-yl)imidazo[1,5-a]quinoxaline
C19 H17 F N4 O
JGRMMBRYUDVUAI-UHFFFAOYSA-N
ZN
Query on ZN

Download Ideal Coordinates CCD File 
E [auth A],
I [auth B]
ZINC ION
Zn
PTFCDOFLOPIGGS-UHFFFAOYSA-N
CL
Query on CL

Download Ideal Coordinates CCD File 
C [auth A],
G [auth B]
CHLORIDE ION
Cl
VEXZGXHMUGYJMC-UHFFFAOYSA-M
MG
Query on MG

Download Ideal Coordinates CCD File 
F [auth A],
J [auth B]
MAGNESIUM ION
Mg
JLVVSXFLKOJNIY-UHFFFAOYSA-N
Binding Affinity Annotations 
IDSourceBinding Affinity
540 PDBBind:  3SN7 IC50: 0.7 (nM) from 1 assay(s)
BindingDB:  3SN7 IC50: 0.7 (nM) from 1 assay(s)
Binding MOAD:  3SN7 IC50: 0.7 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.82 Å
  • R-Value Free: 0.276 
  • R-Value Work: 0.247 
  • R-Value Observed: 0.248 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 50.641α = 90
b = 81.465β = 90
c = 158.044γ = 90
Software Package:
Software NamePurpose
MAR345data collection
SHARPphasing
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2011-10-26 
  • Deposition Author(s): Parris, K.D.

Revision History  (Full details and data files)

  • Version 1.0: 2011-10-26
    Type: Initial release
  • Version 1.1: 2011-11-16
    Changes: Database references
  • Version 1.2: 2017-11-08
    Changes: Refinement description
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations