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 (K_d = 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.