Discovery of a series of ester-substituted NLRP3 inflammasome inhibitors
Discovery of a series of ester-substituted NLRP3 inflammasome inhibitors
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DOI：
10.1016/j.bmcl.2020.127560
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发表时间：
2020-12-01
影响因子：
2.7
通讯作者：
Watt, Alan P.
中科院分区：
文献类型：
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作者：
Harrison, David;Boutard, Nicolas;Watt, Alan P.
NLRP3炎性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。广泛的外源性和内源性信号的异常激活可导致慢性、低度炎症。由于与阿尔茨海默病、帕金森氏病、关节炎和癌症等大量未满足医疗需求的疾病有关，它作为一种药物靶点引起了极大的兴趣。迄今为止，还没有专门针对NLRP3炎症小体抑制的药物被批准。在这项工作中，我们使用已知的NLRP3炎性体抑制剂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。这导致了一系列新型酯取代尿素化合物的合理设计，这些化合物是高效和选择性的NLRP3炎性体抑制剂，如化合物44和45。据推测，酯部分作为一种高渗透性的递送载体，随后被羧酸酯酶水解成羧酸活性物质。这些分子与最先进的分子有很大的区别，在nlrp3驱动的疾病的治疗中具有潜力，特别是在需要穿透组织的情况下。
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.