Discovery and optimization of 4-oxo-2-thioxo-thiazolidinones as NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inhibitors

Yun Chen; Hongbin He; Hua Jiang; Li Li; Zhiyu Hu; Huiying Huang; Qingyan Xu; Rongbin Zhou; Xianming Deng

doi:10.1016/j.bmcl.2020.127021

Discovery and optimization of 4-oxo-2-thioxo-thiazolidinones as NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inhibitors

Bioorg Med Chem Lett. 2020 Apr 1;30(7):127021. doi: 10.1016/j.bmcl.2020.127021. Epub 2020 Feb 6.

Authors

Yun Chen¹, Hongbin He², Hua Jiang², Li Li¹, Zhiyu Hu¹, Huiying Huang¹, Qingyan Xu¹, Rongbin Zhou³, Xianming Deng⁴

Affiliations

¹ State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China.
² Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, China.
³ Institute of Immunology and the CAS Key Laboratory of Innate Immunity and Chronic Disease, CAS Center for Excellence in Molecular Cell Sciences, School of Life Sciences and Medical Center, China. Electronic address: zrb1980@ustc.edu.cn.
⁴ State-Province Joint Engineering Laboratory of Targeted Drugs from Natural Products, School of Life Sciences, Xiamen University, Xiamen, Fujian 361102, China. Electronic address: xmdeng@xmu.edu.cn.

PMID: 32057583
DOI: 10.1016/j.bmcl.2020.127021

Abstract

Aberrant activation of NLRP3 inflammasome is present in a subset of acute and chronic inflammatory diseases. The NLRP3 inflammasome has been recognized as an attractive therapeutic target for developing novel and specific anti-inflammatory inhibitors. Cellular structure-activity relationship-guided optimization resulted in the identification of 4-oxo-2-thioxo-thiazolidinone derivative 9 as a selective and direct small-molecule inhibitor of NLRP3 with IC₅₀ of 2.4 μM, possessing favorable ex vivo and in vivo pharmacokinetic properties. Compound 9 may represent a lead for the development of anti-inflammatory therapeutics for treating NLRP3-driven diseases.

Keywords: NLRP3; Structure-activity relationship (SAR); Thiazolidinones.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Drug Discovery
HT29 Cells
Humans
Inflammasomes / drug effects
Molecular Structure
NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors*
Rats, Sprague-Dawley
Structure-Activity Relationship
Thiazolidines / chemical synthesis
Thiazolidines / pharmacokinetics
Thiazolidines / pharmacology*

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein
NLRP3 protein, human
Nlrp3 protein, rat
Thiazolidines