2. Academic Validation
  3. Discovery of novel 5-phenyl-1H-pyrrole-2-carboxylic acids as Keap1-Nrf2 inhibitors for acute lung injury treatment

Discovery of novel 5-phenyl-1H-pyrrole-2-carboxylic acids as Keap1-Nrf2 inhibitors for acute lung injury treatment

  • Bioorg Chem. 2024 Aug 31:153:107741. doi: 10.1016/j.bioorg.2024.107741.
Jiaqin Tang 1,  Xin Tie 1,  Shumeng Zhi 1,  Zhizhong Wang 1,  Qipeng Zhao 1,  Zhuo Qu 2,  Guangyuan Lu 3,  Qin Li 4,  Yanran Wu 5,  Ying Shi 6
Affiliations

Affiliations

  • 1 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China.
  • 2 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China. Electronic address: quzhuo2008@163.com.
  • 3 Ningxia Key Laboratory of Craniocerebral Diseases, Incubation Base of National Key Laboratory, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China. Electronic address: lugy@nxmu.edu.cn.
  • 4 Department of Clinical Laboratory, People's Hospital of Ningxia Hui Autonomous Region (Ningxia Medical University), No.301, Zhengyuan North Street, Jinfeng District, Yinchuan City 750001, China. Electronic address: wlrxlq@163.com.
  • 5 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China. Electronic address: 15900975732@163.com.
  • 6 Key Laboratory of Protection, Development and Utilization of Medicinal Resources in Liupanshan Area (Ningxia Medical University), Ministry of Education, School of Pharmacy, Ningxia Medical University, 1160 Shengli Street, Yinchuan 750004, China. Electronic address: nxshiying@163.com.
PMID: 39232343 DOI: 10.1016/j.bioorg.2024.107741
Abstract

Oxidative stress is intricately linked to acute lung injury (ALI) and cerebral ischemic/reperfusion (I/R) injury. The Keap1 (Kelch-like ECH-Associating protein 1)-Nrf2 (nuclear factor erythroid 2-related factor 2)-ARE (antioxidant response element) signaling pathway, recognized as a crucial regulatory mechanism in oxidative stress, holds immense potential for the treatment of both diseases. In our laboratory, we initially screened a compound library and identified compound 3, which exhibited a dissociation constant of 5090 nM for Keap1. To enhance its binding affinity, we developed a novel 5-phenyl-1H-pyrrole-2-carboxylic acid Keap1-Nrf2 inhibitor through scaffold hopping from compound 3. Structure-activity relationship studies identified compound 19 as the most potent, with a KD2 of 42.2 nM against Keap1. Furthermore, compound 19 showed significant protection against LPS-induced injury in BEAS-2B cells and promoted Nrf2 nuclear translocation. Subsequently, we investigated its therapeutic effects in mouse models of ALI injury. Compound 19 effectively alleviated symptoms at doses of 15 mg/kg for ALI injury. Additionally, it facilitated Nrf2 translocation to the nucleus, increased Nrf2 levels, and upregulated the expression of HO-1 and NQO1 in affected tissues.

Figures
Products