Mackay, Angela, Farady, Christopher, Dekker, Carien, Gommermann, Nina, Velcicky, Juraj, Wright, Michael, Ilic, Slavica, Brenneisen, Silke, Hinniger, Alexandra, Srinivas, Honnappa, Vangrevelinghe, Eric, von Burg, Nicole, Beltz, Karen, Desrayaud, Sandrine, Trunzer, Markus, Mattes, Henri, Janser, Philipp, Schoenboerner, Michel, Vogelsanger, Melanie, MULLER-BENTZ, Sophie, Kamke, Marion, Rubert, Joelle, Kauffmann, Muriel, Dubois, Celine, Boettcher, Andreas and Stiefl, Nikolaus (2024) Discovery of NP3-253, a potent brain penetrant inhibitor of the NLRP3 Inflammasome. Journal of Medicinal Chemistry, 67 (23). ISSN 0022-26231520-4804

Abstract

Activation of the NLRP3 inflammasome in response to danger signals is a key innate immune mechanism, and results in the production of the pro-inflammatory cytokines interleukin 1-beta (IL-1β) and interleukin-18 (IL-18), as well as pyroptotic cell death. Aberrant NLRP3 activation has been linked to many acute and chronic conditions ranging from atherosclerosis to Alzheimer’s disease, and cancer, and based on the clinical success of IL-1-targeting therapies, NLRP3 has emerged as an attractive therapeutic target, with the first wave of NLRP3 inhibitors entering clinical trials. Herein, we describe our discovery, characterization, and structure-based optimization of a pyridazine based series of NLRP3 inhibitors initiating from an HTS campaign. The scaffold, exemplified by lead molecule NP3-253 has excellent potency, physicochemical, and PK properties including significant brain penetration. The establishment of PK/PD relationships in the periphery and CNS in mechanistic models facilitate the use of NP3-253 as a tool to further interrogate the biology of NLRP3 in peripheral and neuroinflammatory models.

Item Type:	Article
Date Deposited:	27 Feb 2025 00:45
Last Modified:	27 Feb 2025 00:45
URI:	https://oak.novartis.com/id/eprint/55206