1. Academic Validation
  2. Tricyclic 3,4-dihydropyrimidine-2-thione derivatives as potent TRPA1 antagonists

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

  • Bioorg Med Chem Lett. 2012 Jan 15;22(2):797-800. doi: 10.1016/j.bmcl.2011.12.068.
Harrie J M Gijsen 1 Didier Berthelot Michel A J De Cleyn Ivo Geuens Bert Brône Marc Mercken
Affiliations

Affiliation

  • 1 Neuroscience, Janssen Research & Development, Janssen Pharmaceutica N.V., Turnhoutseweg 30, B-2340 Beerse, Belgium. hgijsen@its.jnj.com
Abstract

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.

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