Discovery of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor as a pharmacological agent to mitigate cardiac and metabolic complications in an experimental model of diet-induced metaflammation,European Journal of Medicinal Chemistry

当前位置： X-MOL 学术 › Eur. J. Med. Chem. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Discovery of a novel 1,3,4-oxadiazol-2-one-based NLRP3 inhibitor as a pharmacological agent to mitigate cardiac and metabolic complications in an experimental model of diet-induced metaflammation
European Journal of Medicinal Chemistry ( IF 6.0 ) Pub Date : 2023-06-02 , DOI: 10.1016/j.ejmech.2023.115542
Simone Gastaldi ₁ , Carmine Rocca ₂ , Eleonora Gianquinto ₁ , Maria Concetta Granieri ₂ , Valentina Boscaro ₁ , Federica Blua ₁ , Barbara Rolando ₁ , Elisabetta Marini ₁ , Margherita Gallicchio ₁ , Anna De Bartolo ₂ , Naomi Romeo ₂ , Rosa Mazza ₂ , Francesco Fedele ₃ , Pasquale Pagliaro ₄ , Claudia Penna ₄ , Francesca Spyrakis ₁ , Massimo Bertinaria ₁ , Tommaso Angelone ₅

Affiliation

Inspired by the recent advancements in understanding the binding mode of sulfonylurea-based NLRP3 inhibitors to the NLRP3 sensor protein, we developed new NLRP3 inhibitors by replacing the central sulfonylurea moiety with different heterocycles. Computational studies evidenced that some of the designed compounds were able to maintain important interaction within the NACHT domain of the target protein similarly to the most active sulfonylurea-based NLRP3 inhibitors. Among the studied compounds, the 1,3,4-oxadiazol-2-one derivative (INF200) showed the most promising results being able to prevent NLRP3-dependent pyroptosis triggered by LPS/ATP and LPS/MSU by 66.3 ± 6.6% and 61.6 ± 11.5% and to reduce IL-1β release (35.5 ± 8.8% μM) at 10 μM in human macrophages. The selected compound INF200 (20 mg/kg/day) was then tested in an rat model of high-fat diet (HFD)-induced metaflammation to evaluate its beneficial cardiometabolic effects. INF200 significantly counteracted HFD-dependent “anthropometric” changes, improved glucose and lipid profiles, and attenuated systemic inflammation and biomarkers of cardiac dysfunction (particularly BNP). Hemodynamic evaluation on Langendorff model indicate that INF200 limited myocardial damage-dependent ischemia/reperfusion injury (IRI) by improving post-ischemic systolic recovery and attenuating cardiac contracture, infarct size, and LDH release, thus reversing the exacerbation of obesity-associated damage. Mechanistically, in post-ischemic hearts, IFN200 reduced IRI-dependent NLRP3 activation, inflammation, and oxidative stress. These results highlight the potential of the novel NLRP3 inhibitor, INF200, and its ability to reverse the unfavorable cardio-metabolic dysfunction associated with obesity.

中文翻译：

发现一种新型 1,3,4-恶二唑-2-one NLRP3 抑制剂作为药物，在饮食诱导的代谢炎症实验模型中减轻心脏和代谢并发症

受最近对基于磺酰脲类的 NLRP3 抑制剂与 NLRP3 传感器蛋白的结合模式的了解取得的进展的启发，我们通过用不同的杂环取代中心磺酰脲部分开发了新的 NLRP3 抑制剂。计算研究证明，一些设计的化合物能够在目标蛋白的 NACHT 结构域内维持重要的相互作用，类似于最活跃的基于磺酰脲类的 NLRP3 抑制剂。在所研究的化合物中，1,3,4-恶二唑-2-酮衍生物 (INF200) 显示出最有希望的结果，能够预防由 LPS/ATP 和 LPS/MSU 引发的 NLRP3 依赖性细胞焦亡，分别分别达到 66.3 ± 6.6% 和 61.6% ± 11.5% 并减少人巨噬细胞中 10 μM 的 IL-1β 释放 (35.5 ± 8.8% μM)。然后在高脂饮食 (HFD) 诱导的代谢炎症大鼠模型中测试所选化合物 INF200（20 毫克/公斤/天），以评估其有益的心脏代谢作用。 INF200 显着抵消了 HFD 依赖性“人体测量”变化，改善了血糖和血脂状况，并减轻了全身炎症和心脏功能障碍的生物标志物（特别是 BNP）。 Langendorff 模型的血流动力学评估表明，INF200 通过改善缺血后收缩恢复并减轻心肌挛缩、梗死面积和 LDH 释放来限制心肌损伤依赖性缺血/再灌注损伤 (IRI)，从而逆转肥胖相关损伤的加剧。从机制上讲，在缺血后的心脏中，IFN200 减少了 IRI 依赖性 NLRP3 激活、炎症和氧化应激。这些结果凸显了新型 NLRP3 抑制剂 INF200 的潜力，及其逆转与肥胖相关的不利心脏代谢功能障碍的能力。

更新日期：2023-06-02

点击分享查看原文

点击收藏

阅读更多本刊新发论文本刊介绍/投稿指南