Design, synthesis, and pharmacological characterization of sulfonylurea-based NLRP3 inhibitors: Towards an effective therapeutic strategy for Alzheimer's disease

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that severely diminishes the quality of life for millions. The NLRP3 inflammasome, a critical mediator of inflammation, has emerged as a promising therapeutic target for AD. In this study, we report the development and optimization of a novel series of sulfonylurea-based NLRP3 inhibitors, with a focus on compound MC1 for the treatment of AD. Utilizing the co-crystal structure of MCC950 in complex with NLRP3 as a guide, we employed a hybrid approach of computer-aided drug design and traditional medicinal chemistry to perform two iterative optimization cycles. This strategy led to the synthesis and evaluation of 40 sulfonylurea derivatives, culminating in the identification of MC1 as the lead candidate. MC1 exhibited enhanced NLRP3 inhibitory activity and demonstrated high binding affinity to NLRP3, effectively blocking NLRP3 activation induced by diverse stimuli such as ATP and Nigericin, without perturbing upstream processes like reactive oxygen species (ROS) generation. In vivo experiments in AD mouse models revealed that MC1 significantly ameliorated cognitive deficits, surpassing the performance of MCC950. Importantly, MC1 showed no signs of hepatotoxicity or adverse effects on the central nervous system. These findings suggest that MC1 holds strong potential as a lead compound for further development in AD therapy, providing a new scaffold for NLRP3 inhibition with improved safety and efficacy profiles. [Display omitted] •A novel sulfonylurea-based NLRP3 inhibitor, MC1, was developed, showing enhanced efficacy in treating Alzheimer's disease (AD) compared to MCC950.•MC1 demonstrated significant NLRP3 inhibition, improved cognitive function in AD models, and no observable toxicity, even after a 30-day treatment.•Molecular dynamics and SPR revealed strong binding interactions of MC1 with NLRP3, contributing to its potent anti-inflammatory and neuroprotective properties.