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 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.
Neuroscience, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium. hgijsen@its.jnj.com
Harrie J M
HJ
Gijsen
Didier
D
Berthelot
Michel A J
MA
De Cleyn
Ivo
I
Geuens
Bert
B
Brône
Marc
M
Mercken
D000818:Animals; D015220:Calcium Channels; D006801:Humans; D015394:Molecular Structure; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors*; D011743:Pyrimidines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D000074025:TRPA1 Cation Channel; D050052:TRPC Cation Channels / Q000037:antagonists & inhibitors*; D013871:Thiones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D050051:Transient Receptor Potential Channels / Q000037:antagonists & inhibitors*
C574445:4-phenyl-2-thioxo-1,2,3,4-tetrahydroindeno(1,2-d)pyrimidin-5-one; D015220:Calcium Channels; D009419:Nerve Tissue Proteins; D011743:Pyrimidines; D000074025:TRPA1 Cation Channel; C473350:TRPA1 protein, human; D050052:TRPC Cation Channels; D013871:Thiones; D050051:Transient Receptor Potential Channels; C480976:Trpa1 protein, rat