Myeloid differentiation primary response 88 (MyD88) plays a central role in inflammatory responses and diseases. However, only a few inhibitors of MyD88 with some limits have been reported currently. Herein, we identified a lead compound (L7) through virtual screening and synthesized twenty-seven L7 derivatives. An optimal compound (A5) was determined through enzyme-linked immunosorbent assay (ELISA), 2,5-diphenyl-2H-tetrazolium bromide (MTT), and biolayer interferometry (BLI) assay. The potent isomer A5S showed a high MyD88 binding ability and exerted an anti-inflammatory effect through the NF-κB/MAPK pathway. A5S had good stability and safety, showed the highest distribution concentration in the lungs, and exhibited good therapeutic effects on LPS-induced and sepsis-induced ALI mouse models. Most importantly, A5S showed advantages in PK properties, and was identified as a promising MyD88 inhibitor with favorable drug-like properties, compared to the only approved MyD88 inhibitor, TJ-M2010-5, which is currently undergoing a Phase I study, and our previously reported MyD88 inhibitors LM8.

中文翻译：

---

发现新型 MyD88 抑制剂 A5S 减轻急性肺损伤，具有良好的类药特性


髓系分化主要反应 88 （MyD88） 在炎症反应和疾病中起着核心作用。然而，目前只有少数具有一定限制的 MyD88 抑制剂被报道。在此，我们通过虚拟筛选鉴定了一种先导化合物 （L7） 并合成了 27 种 L7 衍生物。通过酶联免疫吸附测定 （ELISA） 、 2,5-二苯基-2H-四唑溴化物 （MTT） 和生物膜干涉测定法 （BLI） 确定最佳化合物 （A5）。有效的异构体 A5S 显示出较高的 MyD88 结合能力，并通过 NF-κB/MAPK 通路发挥抗炎作用。A5S 具有良好的稳定性和安全性，在肺部分布浓度最高，对 LPS 诱导和脓毒症诱导的 ALI 小鼠模型表现出良好的治疗效果。最重要的是，A5S 在 PK 特性方面显示出优势，与目前唯一获批的 MyD88 抑制剂 TJ-M2010-5 和我们之前报道的 MyD88 抑制剂 LM8 相比，A5S 被确定为一种有前途的 MyD88 抑制剂，具有良好的药物样特性。