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

  • J Med Chem. 2023 Jun 22;66(12):8267-8280. doi: 10.1021/acs.jmedchem.3c00686.
Jianyu Yan  1 ,  Yue Li  2 ,  Li Ding  1 ,  Ruilin Hou  1  3 ,  Chengguo Xing  4 ,  Chengshi Jiang  2 ,  Zhenyuan Miao  1 ,  Chunlin Zhuang  1  3
Affiliations
  • 1. School of Pharmacy, Second Military Medical University, Shanghai 200433, China.
  • 2. School of Biological Science and Technology, University of Jinan, Jinan 250022, China.
  • 3. School of Pharmacy, Ningxia Medical University, Yinchuan 750004, China.
  • 4. Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, Florida 32610, United States.
PMID: 37257073 DOI: 10.1021/acs.jmedchem.3c00686
Abstract

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.