Fragment-Based Discovery of Azocyclic Alkyl Naphthalenesulfonamides as Keap1-Nrf2 Inhibitors for Acute Lung Injury Treatment

Blocking the Kelch-like epichlorohydrin-related protein
1 (Keap1)-nuclear
factor-erythroid 2 related factor 2 (Nrf2) pathway is a promising
strategy to alleviate acute lung injury (ALI). A naphthalensulfonamide
NXPZ-2, targeting Keap1-Nrf2 interaction to release Nrf2, was confirmed
to exhibit significant anti-inflammatory activities, however, accompanying
nonideal solubility and PK profiles. To further improve the properties,
twenty-nine novel naphthalenesulfonamide derivatives were designed
by a fragment-based strategy. Among them, compound 10u with a (R)-azetidine group displayed the highest
PPI inhibitory activity (KD2 = 0.22 μM).
The hydrochloric acid form of 10u exhibited a 9-fold
improvement on water solubility (S = 484 μg/mL,
pH = 7.0) compared to NXPZ-2 (S = 55 μg/mL,
pH = 7.0). It could significantly reduce LPS-induced lung oxidative
damages and inflammations in vitro and in vivo. Furthermore, a satisfactory
pharmacokinetic property was revealed. In conclusion, the novel azetidine-containing
naphthalenesulfonamide represents a promising drug candidate for Keap1-targeting
ALI treatment.