PF-04859989   Click here for help

GtoPdb Ligand ID: 9038

Synonyms: compound 1 [PMID: 23466229]
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: PF-04859989 was identified as a potent, irreversable and selective inhibitor of human and rat kynurenine aminotransferase II (KATII; a.k.a. aminoadipate aminotransferase AADAT) [1-2] . An X-ray crystal structure of the enzyme co-crystalised with an inhibitor has been reported [1]. In vivo pharmacokinetic and efficacy studies in rat show it to be brain-penetrant, reducing brain kynurenic acid by 50%. KAT inhibitors are expected to exhibit neuroprotective effects, that may be beneficial for the treatment of neurodegenerative and cognitive impairment disorders [3].
2D Structure
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2D Structure

An image of the ligand's 2D structure. For small molecules with SMILES these are drawn using the NCI/CADD Chemical Identifier Resolver. Click on the image to access the chemical structure search tool with the ligand pre-loaded in the structure editor. For other types of ligands, e.g. longer nucleotides and peptides, a manually drawn representation of the molecule may be provided.

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Physico-chemical Properties
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Physico-chemical Properties

Calculated molecular properties are available for small molecules and natural products (not peptides). Properties were generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/). All properties were selected to enable the prediction of the Lipinski Rule-of-Five profile or ‘druglikeness’ for each ligand. For more info on each category see the help pages.

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Hydrogen bond acceptors 2
Hydrogen bond donors 2
Rotatable bonds 0
Topological polar surface area 66.56
Molecular weight 178.07
XLogP 0.43
No. Lipinski's rules broken 0

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
SMILES / InChI / InChIKey
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SMILES / InChI / InChIKey

SMILES (Simplified Molecular Input Line Entry Specification) A specification for unambiguously describing the structure of chemical molecules using short ASCII strings. Canonical SMILES specify a unique representation of the 2D structure without chiral or isotopic specifications. Isomeric SMILES include chiral specification and isotopes.

Standard InChI (IUPAC International Chemical Identifier) and InChIKey InChI is a non-proprietary, standard, textual identifier for chemical substances designed to facilitate linking of information and database searching. An InChIKey is a simplified version of a full InChI, designed for easier web searching.

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)

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Canonical SMILES O=C1C(N)Cc2c(N1O)cccc2
Isomeric SMILES O=C1[C@@H](N)Cc2c(N1O)cccc2
InChI InChI=1S/C9H10N2O2/c10-7-5-6-3-1-2-4-8(6)11(13)9(7)12/h1-4,7,13H,5,10H2/t7-/m0/s1
InChI Key HYTRYTZFJVVZAF-ZETCQYMHSA-N

Generated using the Chemistry Development Kit (CDK) (Willighagen EL et al. Journal of Cheminformatics vol. 9:33. 2017, doi:10.1186/s13321-017-0220-4; https://cdk.github.io/)
References
1. Dounay AB, Anderson M, Bechle BM, Campbell BM, Claffey MM, Evdokimov A, Evrard E, Fonseca KR, Gan X, Ghosh S et al.. (2012)
Discovery of Brain-Penetrant, Irreversible Kynurenine Aminotransferase II Inhibitors for Schizophrenia.
ACS Med Chem Lett, 3 (3): 187-92. [PMID:24900455]
2. Dounay AB, Anderson M, Bechle BM, Evrard E, Gan X, Kim JY, McAllister LA, Pandit J, Rong S, Salafia MA et al.. (2013)
PF-04859989 as a template for structure-based drug design: identification of new pyrazole series of irreversible KAT II inhibitors with improved lipophilic efficiency.
Bioorg Med Chem Lett, 23 (7): 1961-6. [PMID:23466229]
3. Nematollahi A, Sun G, Jayawickrama GS, Church WB. (2016)
Kynurenine Aminotransferase Isozyme Inhibitors: A Review.
Int J Mol Sci, 17 (6). [PMID:27314340]
4. Nguyen NT, Kimura A, Nakahama T, Chinen I, Masuda K, Nohara K, Fujii-Kuriyama Y, Kishimoto T. (2010)
Aryl hydrocarbon receptor negatively regulates dendritic cell immunogenicity via a kynurenine-dependent mechanism.
Proc Natl Acad Sci USA, 107 (46): 19961-6. [PMID:21041655]
5. Wang Y, Liu H, McKenzie G, Witting PK, Stasch JP, Hahn M, Changsirivathanathamrong D, Wu BJ, Ball HJ, Thomas SR et al.. (2010)
Kynurenine is an endothelium-derived relaxing factor produced during inflammation.
Nat Med, 16 (3): 279-85. [PMID:20190767]