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

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Discovery and optimization of 4-oxo-2-thioxo-thiazolidinones as NOD-like receptor (NLR) family, pyrin domain-containing protein 3 (NLRP3) inhibitors.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-02-06 , DOI: 10.1016/j.bmcl.2020.127021
Yun Chen ₁ , Hongbin He ₂ , Hua Jiang ₂ , Li Li ₁ , Zhiyu Hu ₁ , Huiying Huang ₁ , Qingyan Xu ₁ , Rongbin Zhou ₂ , Xianming Deng ₁

Affiliation

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.

中文翻译：

发现和优化的4-氧代-2-硫代-噻唑烷酮类作为NOD样受体（NLR）家族，含吡啶域的蛋白3（NLRP3）抑制剂。

NLRP3炎性小体的异常激活存在于急性和慢性炎性疾病的子集中。NLRP3炎性小体已被公认为是开发新型和特异性抗炎抑制剂的有吸引力的治疗靶标。细胞结构-活性关系指导的优化导致鉴定出4-氧代-2-硫代氧杂-噻唑烷酮衍生物9作为NLRP3的选择性和直接小分子抑制剂，IC50为2.4μM，具有良好的离体和体内药代动力学特性。化合物9可以代表开发用于治疗NLRP3驱动的疾病的抗炎疗法的先导。

更新日期：2020-02-06

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