4FCD

Potent and Selective Phosphodiesterase 10A Inhibitors


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.300 
  • R-Value Work: 0.257 
  • R-Value Observed: 0.259 

wwPDB Validation   3D Report Full Report


Ligand Structure Quality Assessment 


This is version 1.3 of the entry. See complete history


Literature

Novel triazines as potent and selective phosphodiesterase 10A inhibitors.

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

(2012) Bioorg Med Chem Lett 22: 5876-5884

  • DOI: https://doi.org/10.1016/j.bmcl.2012.07.076
  • Primary Citation of Related Structures:  
    4FCB, 4FCD

  • PubMed Abstract: 

    The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).


  • Organizational Affiliation

    Pfizer Neuroscience Princeton, 865 Ridge Road, Monmouth Junction, 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
Binding Affinity Annotations 
IDSourceBinding Affinity
0T6 Binding MOAD:  4FCD IC50: 0.28 (nM) from 1 assay(s)
BindingDB:  4FCD IC50: 0.28 (nM) from 1 assay(s)
PDBBind:  4FCD IC50: 0.28 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.02 Å
  • R-Value Free: 0.300 
  • R-Value Work: 0.257 
  • R-Value Observed: 0.259 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 51.453α = 90
b = 81.503β = 90
c = 157.787γ = 90
Software Package:
Software NamePurpose
MAR345data collection
REFMACrefinement
HKL-2000data reduction
HKL-2000data scaling
REFMACphasing

Structure Validation

View Full Validation Report



Ligand Structure Quality Assessment 


Entry History 

Deposition Data

  • Released Date: 2012-09-05 
  • Deposition Author(s): Parris, K.D.

Revision History  (Full details and data files)

  • Version 1.0: 2012-09-05
    Type: Initial release
  • Version 1.1: 2013-01-02
    Changes: Database references
  • Version 1.2: 2017-11-15
    Changes: Refinement description
  • Version 1.3: 2024-02-28
    Changes: Data collection, Database references, Derived calculations