A series of potent and selective carboxamide TRPA1 antagonists were identified by a high throughput screen. Structure-activity relationship studies around this series are described, resulting in a highly potent example of the series. Pharmacokinetic and skin flux data are presented for this compound. Efficacy was observed in a topical cinnamaldehyde flare study, providing a topical proof of pharmacology for this mechanism. These data suggest TRPA1 antagonism could be a viable mechanism to treat topical conditions such as atopic dermatitis.
The discovery of a potent series of carboxamide TRPA1 antagonists
Pryde, D. C., Marron, B., West, C. G., Reister, S., Amato, G., Yoger, K., Padilla, K., Turner, J., Swain, N. A., Cox, P. J., Skerratt, S. E., Ryckmans, T., Blakemore, D. C., Warmus, J., & Gerlach, A. C. (2016). The discovery of a potent series of carboxamide TRPA1 antagonists. MedChemComm, 7(11), 2145-2158. https://doi.org/10.1039/c6md00387g