Discovery and optimization of imidazole carboxamides, a new class of NLRP3 inflammasome inhibitors
The NLRP3 inflammasome is a key component of the innate immune system. It is activated by danger signals which leads to the production of pro-inflammatory cytokines IL-1β and IL-18 as well as causes a type of pro-inflammatory cell death termed pyroptosis. Dysregulation of the NLRP3 inflammasome is associated with multiple inflammatory diseases including atherosclerosis1 and Alzheimer’s disease2 making its inhibition an attractive therapeutic strategy. NLRP3 inhibitors that are currently subject of clinical investigation are largely limited to sulfonylurea-, and pyridazine-based scaffolds3. In a high-throughput screening campaign we identified novel naphthyl-substituted heteroaromatic amides which complement the toolbox of NLRP3 inhibitors. In our presentation, we will describe the binding mode of this new class of inhibitors, discuss its SAR and our multiparametric optimization strategy, which led to the identification of an advanced candidate for in vivo investigation.
[1] P. Duewell, H. Kono, K. J. Rayner, C. M. Sirois, G. Vladimer, F. G. Bauernfeind, G. S. Abela, L. Franchi, G. Nuñez, M. Schnurr, T. Espevik, E. Lien, K. A. Fitzgerald, K. L. Rock, K. J. Moore, S. D. Wright, V. Hornung, E. Latz, Nature, 2010, 464, 1357–1361.
[2] M. T. Heneka, M. P. Kummer, A. Stutz, A. Delekate, S. Schwartz, A. Vieira-Saecker, A. Griep, D. Axt, A. Remus, T. C. Tzeng, E. Gelpi, A. Halle, M. Korte, E. Latz, D. T. Golenbock, Nature, 2013, 493, 674–678.
[3] A. Mackay, J. Velcicky, N. Gommermann, H. Mattes, P. Janser, M. Wright, C. Dubois, S. Brenneisen, S. Ilic, E. Vangrevelinghe, N. Stiefl, A. Boettcher, M. Schoenboerner, M. Vogelsanger, S. Muller-Bentz, M. Kamke, J. Rubert, M. Kauffmann, S. Desrayaud, M. Trunzer, H. Srinivas, A. Hinniger, N. von Burg, K. Beltz, C. Dekker, C. J. Farady, J. Med. Chem., 2024, 67, 20780-20798.