4DFF

The SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 

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This is version 1.1 of the entry. See complete history. 


Literature

The SAR development of dihydroimidazoisoquinoline derivatives as phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Ho, G.D., Michael Seganish, W., Bercovici, A., Tulshian, D., Greenlee, W.J., Van Rijn, R., Hruza, A., Xiao, L., Rindgen, D., Mullins, D., Guzzi, M., Zhang, X., Bleickardt, C., Hodgson, R.

(2012) Bioorg Med Chem Lett 22: 2585-2589

  • DOI: https://doi.org/10.1016/j.bmcl.2012.01.113
  • Primary Citation of Related Structures:  
    4DFF

  • PubMed Abstract: 

    The identification of potent and orally active dihydroimidazoisoquinolines as PDE 10A inhibitors is reported. The SAR development led to the discovery of compound 35 as a potent, selective, and orally active PDE10A inhibitor. Compound 35 inhibited MK-801-induced hyperactivity at 3mg/kg and displayed a 10-fold separation between the minimal effective doses for inhibition of MK-801-induced hyperactivity and hypolocomotion in rats.

    • Organizational Affiliation: 

    Department of Medicinal Chemistry, Merck Research Laboratories, Kenilworth, NJ 07033, United States. ginny.ho@merck.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
352Homo 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
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  • Reference Sequence
Small Molecules
Binding Affinity Annotations 
IDSourceBinding Affinity
0JP BindingDB:  4DFF Ki: 35 (nM) from 1 assay(s)
Binding MOAD:  4DFF Ki: 35 (nM) from 1 assay(s)
PDBBind:  4DFF Ki: 35 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.11 Å
  • R-Value Free: 0.223 
  • R-Value Work: 0.190 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 48.654α = 90
b = 81.177β = 90
c = 153.323γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
HKL-2000data reduction
HKL-2000data scaling

Structure Validation

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Ligand Structure Quality Assessment 


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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2012-03-14
    Type: Initial release
  • Version 1.1: 2012-04-04
    Changes: Database references