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

  • J Med Chem. 2024 Jun 13;67(11):9406-9430. doi: 10.1021/acs.jmedchem.4c00504.
Chen He  1 ,  Junkai Liu  1 ,  Junda Li  1 ,  Hongyu Wu  1 ,  Chenyang Jiao  2 ,  Xiaotong Ze  1 ,  Shengtao Xu  1 ,  Zheying Zhu  3 ,  Wenjie Guo  2 ,  Jinyi Xu  1 ,  Hong Yao  1
Affiliations
  • 1. State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu 211198, P. R. China.
  • 2. State Key Laboratory of Pharmaceutical Biotechnology, School of Life Sciences, Nanjing University, Nanjing 210093, P. R. China.
  • 3. Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, Nottingham NG7 2RD, U.K.
PMID: 38751194 DOI: 10.1021/acs.jmedchem.4c00504
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.

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