MK-0359   Click here for help

GtoPdb Ligand ID: 9852

Synonyms: L-454,560 [1] | L-454560 | MK0359
Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: MK-0359 is a potent and selective, oral PDE4 inhibitor that has a competitive and reversible mode of interaction. MK-0359 is identified as L-454,560 [1] by citation in [2]. MK-0359 inhibits both the apo- (Mg2+ free) and holoenzyme ((Mg2+-bound) states of PDE4 [1].
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Ligand Activity Visualisation Charts

These are box plot that provide a unique visualisation, summarising all the activity data for a ligand taken from ChEMBL and GtoPdb across multiple targets and species. Click on a plot to see the median, interquartile range, low and high data points. A value of zero indicates that no data are available. A separate chart is created for each target, and where possible the algorithm tries to merge ChEMBL and GtoPdb targets by matching them on name and UniProt accession, for each available species. However, please note that inconsistency in naming of targets may lead to data for the same target being reported across multiple charts.

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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 6
Hydrogen bond donors 0
Rotatable bonds 7
Topological polar surface area 136.85
Molecular weight 587.15
XLogP 6.09
No. Lipinski's rules broken 1

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 Cc1noc(n1)C(=Cc1cccc(c1)c1cc(cc2c1nccc2)C(S(=O)(=O)C)(C)C)c1ccc(cc1)S(=O)(=O)C
Isomeric SMILES Cc1noc(n1)/C(=C/c1cccc(c1)c1cc(cc2c1nccc2)C(S(=O)(=O)C)(C)C)/c1ccc(cc1)S(=O)(=O)C
InChI InChI=1S/C31H29N3O5S2/c1-20-33-30(39-34-20)28(22-11-13-26(14-12-22)40(4,35)36)17-21-8-6-9-23(16-21)27-19-25(31(2,3)41(5,37)38)18-24-10-7-15-32-29(24)27/h6-19H,1-5H3/b28-17+
InChI Key YYGZHVJDHMMABU-OGLMXYFKSA-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/)
Bioactivity Comments
MK-0359 is active in vitro and in vivo [1]. It blocks LPS-induced TNF-α formation in whole blood assays with a potency similar to that exhibited by roflumilast. Evidence suggest that majority of the anti-inflammatory effect of PDE4 inhibition is through PDE4B and PDE4D isozymes, and that PDE4D, as the major isoform in the brain responsible for emesis [3], is associated with the adverse gastrointestinal (GI) events associated with PDE4 inhibition. MK-0359 inhibits the hydrolysis of cAMP by PDE4A, 4B and 4D with similar potencies, which accounts for the adverse GI effects observed in clinical trial [2].
Selectivity at enzymes
Key to terms and symbols Click column headers to sort
Target Sp. Type Action Value Parameter Concentration range (M) Reference
phosphodiesterase 4B Hs Inhibitor Inhibition 9.3 pIC50 - 1
⤷ pIC50 9.3 (IC50 5x10-10 M) [1]
phosphodiesterase 4D Hs Inhibitor Inhibition 8.9 pIC50 - 1
⤷ pIC50 8.9 (IC50 1.2x10-9 M) [1]
phosphodiesterase 4A Hs Inhibitor Inhibition 8.8 pIC50 - 1
⤷ pIC50 8.8 (IC50 1.6x10-9 M) [1]
phosphodiesterase 4C Hs Inhibitor Inhibition 8.0 pIC50 - 1
⤷ pIC50 8.0 (IC50 9.1x10-9 M) [1]