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

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.