CBS-3595   Click here for help

GtoPdb Ligand ID: 9610

Immunopharmacology Ligand
Compound class: Synthetic organic
Comment: CBS-3595 is a dual inhibitor of p38α MAPK (MAPK14) and phosphodiesterase 4 (PDE-4) [1], a mechanism that represents a novel approach that may be useful for the treatment of pulmonary diseases (e.g. asthma and COPD) as well as other inflammatory diseases, for which there still exists a high level of unmet clinical need. The term Cytokine-Suppressive Anti-Inflammatory Drugs (CSAIDs) has been coined to describe compounds exploiting molecular mechanisms such as that targeted by CBS-3595.
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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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View interactive charts of activity data across species
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 4
Hydrogen bond donors 1
Rotatable bonds 5
Topological polar surface area 85.11
Molecular weight 356.11
XLogP 4.13
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 CSc1nc(c(n1C)c1ccnc(c1)NC(=O)C)c1ccc(cc1)F
Isomeric SMILES CSc1nc(c(n1C)c1ccnc(c1)NC(=O)C)c1ccc(cc1)F
InChI InChI=1S/C18H17FN4OS/c1-11(24)21-15-10-13(8-9-20-15)17-16(22-18(25-3)23(17)2)12-4-6-14(19)7-5-12/h4-10H,1-3H3,(H,20,21,24)
InChI Key CJKGORBZVWDVRY-UHFFFAOYSA-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/)
No information available.
Summary of Clinical Use Click here for help
Dose-limiting adverse events associated with inhibition of PDE-4 (nausea, vomiting and malaise, 1−2 h postdose) experienced by four first-in-human test subjects led to discontinuation of the clinical study of CBS-3595. This was determined to be due to high levels of active metabolite CBS-3728 (PubChem CID 11012474) in humans (less of this metabolite was measured in preclinical monkey studies) and this metabolite appeared to be selective for the PDE4D3 isoform, which is considered to be responsible for the nausea/vomiting side effects of PDE4 inhibitors. Therefore, isoform selectivity is an essential consideration for the development of future clinical candidates.