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Structural insights of sulfonamide-based NLRP3 inflammasome inhibitors: design, synthesis, and biological characterization

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Abstract

NLRP3 inflammasome has recently attracted much attention as a potentially druggable target to develop potential therapeutics for inflammatory and neurodegenerative disorders. In our continuing studies, structure–activity relationship studies were conducted based on a newly identified NLRP3 inhibitor, YQ-II-128, from our laboratory to understand the structural features and improve aqueous solubility. The results revealed that steric interactions at the propoxyl and amide domain of YQ-II-128 are important for the observed inhibitory potency on the NLRP3 inflammasome. The results also identified the amide domain to incorporate polar moieties to improve solubility and potentially pharmacokinetic properties. As a result, analog 10 was identified as a selective NLRP3 inhibitor with comparable potency while significantly improved aqueous solubility. Collectively, these findings strongly encourage further optmization of 10 to develop analogs with improved pharmacokinetic properties as potential NLRP3-targted therapeutics.

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Acknowledgements

The work was supported in part by the NIA of the NIH under award number R01AG058673 (SZ), Alzheimer’s Drug Discovery Foundation 20150601 (SZ).

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Authors and Affiliations

  1. Department of Medicinal Chemistry, Virginia Commonwealth University, Richmond, VA, 23298, USA

    Yiming Xu, Matteo Scipioni, Hallie Blevins & Shijun Zhang

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  1. Yiming Xu
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  2. Matteo Scipioni
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Contributions

YX and MS performed organic synthesis and biological characterization. HB tested the solubility. SZ designed the research. SZ and YX wrote the manuscript.

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Correspondence to Shijun Zhang.

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Xu, Y., Scipioni, M., Blevins, H. et al. Structural insights of sulfonamide-based NLRP3 inflammasome inhibitors: design, synthesis, and biological characterization. Med Chem Res 30, 473–482 (2021). https://doi.org/10.1007/s00044-020-02692-4

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  • DOI: https://doi.org/10.1007/s00044-020-02692-4

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