3UI7

Discovery of orally active pyrazoloquinoline as a potent PDE10 inhibitor for the management of schizophrenia

Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 

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Ligand Structure Quality Assessment 


This is version 1.2 of the entry. See complete history. 


Literature

Discovery of orally active pyrazoloquinolines as potent PDE10 inhibitors for the management of schizophrenia.

Yang, S.W., Smotryski, J., McElroy, W.T., Tan, Z., Ho, G., Tulshian, D., Greenlee, W.J., Guzzi, M., Zhang, X., Mullins, D., Xiao, L., Hruza, A., Chan, T.M., Rindgen, D., Bleickardt, C., Hodgson, R.

(2012) Bioorg Med Chem Lett 22: 235-239

  • DOI: https://doi.org/10.1016/j.bmcl.2011.11.023
  • Primary Citation of Related Structures:  
    3UI7

  • PubMed Abstract: 

    A series of pyrazoloquinoline analogs have been synthesized and shown to bind to PDE10 with high affinity. From the SAR study and our lead optimization efforts, compounds 16 and 27 were found to possess potent oral antipsychotic activity in the MK-801 induced hyperactive rat model.

    • Organizational Affiliation: 

    Department of Medicinal Chemistry, Merck Research Laboratories, 2015 Galloping Hill Road, Kenilworth, NJ 07033, United States. shu-wei.yang@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
333Homo 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
C1L Binding MOAD:  3UI7 Ki: 1 (nM) from 1 assay(s)
BindingDB:  3UI7 Ki: 1 (nM) from 1 assay(s)
PDBBind:  3UI7 Ki: 1 (nM) from 1 assay(s)
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 2.28 Å
  • R-Value Free: 0.240 
  • R-Value Work: 0.195 
  • R-Value Observed: 0.197 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 49.539α = 90
b = 81.611β = 90
c = 158.577γ = 90
Software Package:
Software NamePurpose
BUSTERrefinement
autoPROCdata scaling
XDSdata reduction
SCALAdata 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: 2011-12-21
    Type: Initial release
  • Version 1.1: 2012-01-11
    Changes: Database references
  • Version 1.2: 2024-02-28
    Changes: Data collection, Database references, Derived calculations, Refinement description