Tricyclic 3,4-dihydropyrimidine-2-thione derivatives as potent TRPA1 antagonists

The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throug...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2012-01, Vol.22 (2), p.797-800
Main Authors: Gijsen, Harrie J.M., Berthelot, Didier, De Cleyn, Michel A.J., Geuens, Ivo, Brône, Bert, Mercken, Marc
Format: Article
Language:English
Subjects:
Animals
Antagonist
antagonists
Biginelli
Biological and medical sciences
Calcium Channels
derivatization
Humans
Medical sciences
Molecular Structure
Nerve Tissue Proteins - antagonists & inhibitors
pain
Pharmacology. Drug treatments
Pyrimidines - chemical synthesis
Pyrimidines - chemistry
Pyrimidines - pharmacology
Rats
receptors
Stereoisomerism
Structure-Activity Relationship
Thiones - chemical synthesis
Thiones - chemistry
Thiones - pharmacology
Transient Receptor Potential Channels - antagonists & inhibitors
TRPA1
TRPA1 Cation Channel
TRPC Cation Channels - antagonists & inhibitors
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Summary:The transient receptor potential A1 (TRPA1) channel has been implicated in a number of inflammatory and nociceptive processes, and antagonists of the TRPA1 receptor could offer a potential treatment for conditions such as inflammatory or neuropathic pain, airway disorders, and itch. In a high throughput screen aimed at the identification of TRPA1 antagonists, 4-phenyl-2-thioxo-1,2,3,4-tetrahydro-indeno[1,2-d]pyrimidin-5-one (1) was identified as a potent TRPA1 receptor antagonist. A series of analogous tricyclic 3,4-dihydropyrimidine-2-thiones has been prepared via the multi-component Biginelli reaction and subsequent derivatization. This has led to TRPA1 antagonists with potencies around 10nM for both rat and human derived TRPA1 receptors. The activity was shown to reside exclusively in the 4R-enantiomers.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.12.068