Zhang Xinqi, Han Qianyu, Hou Ruilin, Xu Lijuan, Zhang Wannian, Xing Chengguo, Xue Lei, Zhuang Chunlin
School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
J Med Chem. 2023 Apr 13;66(7):5261-5278. doi: 10.1021/acs.jmedchem.3c00197. Epub 2023 Mar 12.
Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) are serious and devastating pulmonary manifestations of acute systemic inflammation with high morbidity and mortality worldwide. Currently, there are no specific effective treatments for ALI/ARDS. RIPK1, which contributes to necroptosis and inflammation, is confirmed to be a promising strategy for the treatment of ALI. Herein, 23 benzothiazole derivatives were designed to specifically target RIPK1, and showed high anti-necroptotic activity (EC = 22.4 nM) and kinase selectivity on RIPK1 over RIPK3 ( = 85 nM, > 10,000 nM). In a mTNF-α-induced systemic inflammatory response syndrome (SIRS) model, could completely reverse mouse deaths with significant anti-inflammatory effects. Furthermore, in a NNK short-term intratracheal exposure-induced ALI model, significantly alleviated ALI by reducing pulmonary edema and pathological damage. Collectively, activities of against RIPK1, necroptosis, SIRS, and ALI warranted further investigation of optimized benzothiazoles as promising lead structures against ALI-related diseases.
急性肺损伤/急性呼吸窘迫综合征（ALI/ARDS）是急性全身炎症严重且具有破坏性的肺部表现，在全球范围内发病率和死亡率都很高。目前，对于ALI/ARDS尚无特异性有效治疗方法。已证实，参与坏死性凋亡和炎症反应的受体相互作用蛋白激酶1（RIPK1）是治疗ALI的一种有前景的策略。在此，设计了23种苯并噻唑衍生物特异性靶向RIPK1，其对RIPK1显示出高抗坏死性凋亡活性（半数有效浓度[EC50] = 22.4 nM）以及对RIPK1相对于RIPK3的激酶选择性（对RIPK3的EC50 = 85 nM，选择性大于10,000 nM）。在一种小鼠肿瘤坏死因子-α（mTNF-α）诱导的全身炎症反应综合征（SIRS）模型中，该化合物能够完全逆转小鼠死亡，并具有显著的抗炎作用。此外，在一种尼古丁亚硝胺酮（NNK）短期气管内暴露诱导的ALI模型中，该化合物通过减轻肺水肿和病理损伤显著缓解了ALI。总体而言，该化合物针对RIPK1、坏死性凋亡、SIRS和ALI的活性，使得进一步研究优化的苯并噻唑作为针对ALI相关疾病有前景的先导结构成为必要。
