Harrison David, Bock Mark G, Doedens John R, Gabel Christopher A, Holloway M Katharine, Lewis Arwel, Scanlon Jane, Sharpe Andrew, Simpson Iain D, Smolak Pamela, Wishart Grant, Watt Alan P
NodThera Ltd., Suite 8, The Mansion, Chesterford Research Park, Little Chesterford, Saffron Walden, EssexCB10 1XL, United Kingdom.
NodThera Inc., 430 Bedford Street, Lexington, Massachusetts02420, United States.
ACS Med Chem Lett. 2022 Aug 1;13(8):1321-1328. doi: 10.1021/acsmedchemlett.2c00242. eCollection 2022 Aug 11.
The NLRP3 inflammasome is a multiprotein complex that facilitates activation and release of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18 in response to infection or endogenous stimuli. It can be inappropriately activated by a range of danger signals resulting in chronic, low-grade inflammation underlying a multitude of diseases, such as Alzheimer's disease, Parkinson's disease, osteoarthritis, and gout. The discovery of potent and specific NLRP3 inhibitors could reduce the burden of several common morbidities. In this study, we identified a weakly potent triazolopyrimidone hit () following an modeling exercise. This was optimized to furnish potent and selective small molecule NLRP3 inflammasome inhibitors. Compounds such as could be useful tool molecules for a scaffold-hopping or pharmacophore generation project or used as leads toward the development of clinical candidates.
NLRP3炎性小体是一种多蛋白复合物，可促进促炎细胞因子白细胞介素-1β（IL-1β）和IL-18在受到感染或内源性刺激时的激活和释放。它可被一系列危险信号异常激活，导致多种疾病（如阿尔茨海默病、帕金森病、骨关节炎和痛风）背后的慢性低度炎症。强效和特异性NLRP3抑制剂的发现可能会减轻几种常见疾病的负担。在本研究中，我们通过建模实验确定了一种低效的三唑并嘧啶命中化合物（）。对其进行优化以提供强效和选择性的小分子NLRP3炎性小体抑制剂。诸如之类的化合物可能是用于骨架跳跃或药效团生成项目的有用工具分子，或用作开发临床候选药物的先导物。
