Discovery of Chromone Derivatives as Selective BLT1 Inhibitors for Alleviating Acute Lung Injury and Sepsis

The overactivated BLT1 receptor is a key pathogenic driver
and
therapeutic target for acute lung injury and sepsis, yet no selective
BLT1 inhibitors are available in the clinic. Using virtual screening,
we identified the natural product hit compound BF-2 (IC50 = 255 nM), featuring a phloroglucinol-chromone scaffold,
as a BLT1 inhibitor. Structural simplification and optimization of
this scaffold led to a series of novel chromone derivatives. Among
the derivatives, VI-8 showed potent BLT1 inhibition (IC50 = 8.7 nM), high selectivity over BLT2 (SI > 20), and
strong
binding affinity (Kd =
121 nM). Furthermore, in vivo evaluation showed that VI-8 (20 mg/kg, p.o.) conferred significant protection against acute
lung injury and sepsis, with favorable oral bioavailability (F% =
85.3) and a good safety profile. This work provides a structural basis
for developing novel selective BLT1 inhibitors and offers new insights
for anti-inflammatory drug discovery.