Discovery of Novel MyD88 Inhibitor A5S to Alleviate Acute Lung Injury with Favorable Drug-like Properties

  • J Med Chem. 2024 Dec 26;67(24):22263-22281. doi: 10.1021/acs.jmedchem.4c02401.
Pan Chen  1  2  3 ,  Yu Zou  1  2 ,  Xiemin Wang  1 ,  Zhichao Chen  1 ,  Ke Dong  1 ,  Jun Yang  1  2 ,  Yaqian Cui  1 ,  Jing Gu  4 ,  Xinyi Wu  1 ,  Xiaobo Li  1 ,  Ying Zhou  1 ,  Mi Guo  1 ,  Zhiwei Zheng  1  3 ,  Qi Chen  1 ,  Weiwei Zhu  1 ,  Di Wu  1 ,  Lina Yin  5 ,  Lingfeng Chen  5 ,  Qin Ouyang  4 ,  Guang Liang  1  2  3  5 ,  Qidong Tang  1  2  3
Affiliations
  • 1. Chemical Biology Research Center, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou 325035, China.
  • 2. Wenzhou Institute, University of Chinese Academy of Sciences, Wenzhou 325001, China.
  • 3. Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China.
  • 4. Department of Medicinal Chemistry, College of Pharmacy, Third Military Medical University, Chongqing 400038, China.
  • 5. School of Pharmaceutical Sciences, Hangzhou Medical College, Hangzhou 310053, China.
PMID: 39644263 DOI: 10.1021/acs.jmedchem.4c02401
Abstract

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.

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