Work

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

Year: 2024

Type: article

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-2 H -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 .

Source: Journal of Medicinal Chemistry

DOI: 10.1021/acs.jmedchem.4c02401