Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity

He, Chen; Liu, Junkai; Li, Junda; Wu, Hongyu; Jiao, Chenyang; Ze, Xiaotong; Xu, Shengtao; Zhu, Zheying; Guo, Wenjie; Xu, Jinyi; Yao, Hong

Abstract

Targeting NLRP3 inflammasome with inhibitors is a novel strategy for NLRP3-driven diseases. Herein, hit compound 5 possessing an attractive skeleton was identified from our in-house database of oridonin, and then a potential lead compound 32 was obtained by optimization of 5, displaying two-digit nanomolar inhibition on NLRP3. Moreover, compound 32 showed enhanced safety index (SI) relative to oridonin (IC50 = 77.2 vs 780.4 nM, SI = 40.5 vs 8.5) and functioned through blocking ASC oligomerization and interaction of NLRP3-ASC/NEK7, thereby suppressing NLRP3 inflammasome assembly and activation. Furthermore, diverse agonists-induced activations of NLRP3 could be impeded by compound 32 without altering NLRC4 or AIM2 inflammasome. Crucially, compound 32 possessed tolerable pharmaceutical properties and significant anti-inflammatory activity in MSU-induced gouty arthritis model. Therefore, this work enriched the SAR of NLRP3 inflammasome inhibitors and provided a potential candidate for the treatment of NLRP3-associated diseases.

Citation

He, C., Liu, J., Li, J., Wu, H., Jiao, C., Ze, X., Xu, S., Zhu, Z., Guo, W., Xu, J., & Yao, H. (2024). Hit-to-Lead Optimization of the Natural Product Oridonin as Novel NLRP3 Inflammasome Inhibitors with Potent Anti-Inflammation Activity. Journal of Medicinal Chemistry, https://doi.org/10.1021/acs.jmedchem.4c00504

• Journal Article Type: Article
• Acceptance Date: May 7, 2024
• Online Publication Date: May 15, 2024
• Publication Date: May 15, 2024
• Deposit Date: Jun 2, 2024
• Publicly Available Date: May 16, 2025
• Journal: Journal of Medicinal Chemistry
• Print ISSN: 0022-2623
• Electronic ISSN: 1520-4804
• Publisher: American Chemical Society
• Peer Reviewed: Peer Reviewed
• DOI: https://doi.org/10.1021/acs.jmedchem.4c00504
• Public URL: https://nottingham-repository.worktribe.com/output/35425918
• Publisher URL: https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00504
• Additional Information: This document is the Accepted Manuscript version of a Published Work that appeared in final form in Journal of Medical Chemistry, copyright © 2024 American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see https://pubs.acs.org/doi/10.1021/acs.jmedchem.4c00504