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Discovery of a Series of Ester-substituted NLRP3 Inflammasome Inhibitors.
Bioorganic & Medicinal Chemistry Letters ( IF 2.5 ) Pub Date : 2020-09-18 , DOI: 10.1016/j.bmcl.2020.127560
David Harrison 1 , Nicolas Boutard 2 , Krzysztof Brzozka 2 , Marta Bugaj 2 , Stefan Chmielewski 2 , Anna Cierpich 2 , John R Doedens 3 , Charles-Henry R Y Fabritius 2 , Christopher A Gabel 3 , Michal Galezowski 2 , Piotr Kowalczyk 2 , Oleksandr Levenets 2 , Magdalena Mroczkowska 2 , Katarzyna Palica 2 , Roderick A Porter 4 , David Schultz 2 , Marta Sowinska 2 , Grzegorz Topolnicki 2 , Piotr Urbanski 2 , Jakub Woyciechowski 2 , Alan P Watt 1
Affiliation  

The NLRP3 inflammasome is a component of the innate immune system involved in the production of proinflammatory cytokines. Aberrant activation by a wide range of exogenous and endogenous signals can lead to chronic, low-grade inflammation. It has attracted a great deal of interest as a drug target due to the association with diseases of large unmet medical need such as Alzheimer’s disease, Parkinson’s disease, arthritis, and cancer. To date, no drugs specifically targeting inhibition of the NLRP3 inflammasome have been approved. In this work, we used the known NLRP3 inflammasome inhibitor CP-456,773 (aka CRID3 or MCC 950) as our starting point and undertook a Structure-Activity Relationship (SAR) analysis and subsequent scaffold-hopping exercise. This resulted in the rational design of a series of novel ester-substituted urea compounds that are highly potent and selective NLRP3 inflammasome inhibitors, as exemplified by compounds 44 and 45. It is hypothesized that the ester moiety acts as a highly permeable delivery vehicle and is subsequently hydrolyzed to the carboxylic acid active species by carboxylesterase enzymes. These molecules are greatly differentiated from the state-of-the-art and offer potential in the treatment of NLRP3-driven diseases, particularly where tissue penetration is required.



中文翻译:

一系列酯取代的 NLRP3 炎症小体抑制剂的发现。

NLRP3 炎症小体是先天免疫系统的一个组成部分,参与促炎细胞因子的产生。各种外源性和内源性信号的异常激活可导致慢性、低度炎症。由于与大量未满足医疗需求的疾病有关,如阿尔茨海默病、帕金森病、关节炎和癌症,它作为药物靶点引起了极大的兴趣。迄今为止,尚未批准专门针对抑制 NLRP3 炎症小体的药物。在这项工作中,我们使用已知的 NLRP3 炎症小体抑制剂 CP-456,773(又名 CRID3 或 MCC 950)作为我们的起点,并进行了结构-活性关系 (SAR) 分析和随后的支架跳跃练习。4445。据推测,酯部分充当高渗透性的递送载体,随后被羧酸酯酶水解为羧酸活性物质。这些分子与最先进的技术有很大不同,并在治疗 NLRP3 驱动的疾病方面提供了潜力,特别是在需要组织穿透的情况下。

更新日期:2020-09-24
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