2. Academic Validation
  3. Design, Synthesis, and Evaluation of Indolizine Derivatives as Nonclassical Ferroptosis Inhibitors with Efficacy in Acute Liver Injury and Ischemic Stroke Models

Design, Synthesis, and Evaluation of Indolizine Derivatives as Nonclassical Ferroptosis Inhibitors with Efficacy in Acute Liver Injury and Ischemic Stroke Models

  • J Med Chem. 2026 Apr 9;69(7):8051-8074. doi: 10.1021/acs.jmedchem.5c03439.
Yijing Shu 1,  Yuheng Jiang 1,  Ying Xiong 1,  Sheng Huang 1,  Chen Lunjie 1,  Wen Ye 1,  Yao Jian 1,  Yimou Gong 1,  Bowen Lei 1,  Dong Yi 1,  Dan Zhang 2,  An Guo Wu 3,  Siping Wei 1 4,  Qiang Fu 1 4,  Xia Zhou 1 4
Affiliations

Affiliations

  • 1 Green Pharmaceutical Technology Key Laboratory of Luzhou City, School of Pharmacy, Southwest Medical University, Luzhou 646000, P.R. China.
  • 2 School of Pharmacy, Department of Pharmacy of Traditional Chinese Medicine, Southwest Medical University, Luzhou 646000, P.R. China.
  • 3 Sichuan Key Medical Laboratory of New Drug Discovery and Drugability Evaluation, Luzhou Key Laboratory of Activity Screening and Druggability Evaluation for Chinese Materia Medica, Key Laboratory of Medical Electrophysiology of Ministry of Education, School of Pharmacy, Southwest Medical University, Luzhou 646000, P.R. China.
  • 4 Central Nervous System Product Research and Development Key Laboratory of Sichuan Province, Southwest Medical University, Luzhou 646000, P.R. China.
PMID: 41854030 DOI: 10.1021/acs.jmedchem.5c03439
Abstract

Ferroptosis is a regulated form of cell death driven by iron-dependent lipid peroxidation. Inhibiting Ferroptosis has emerged as a promising therapeutic strategy, but existing inhibitors suffer from limited chemical diversity and suboptimal drug-likeness. Here, we report 1,3-disubstituted indolizine derivatives as novel noncanonical Ferroptosis inhibitors. Through phenotypic screening and SAR optimization, we identified D12 (3-(2-methylbenzoyl)indolizine-1-yl acetate). D12 exhibits nanomolar potency (EC50 = 39.7 nM) in RSL3/erastin-induced PC12 cells, outperforming Fer-1. Mechanistically, D12 acts independently of iron chelation, radical trapping, or direct Nrf2 activation; instead, it alleviates oxidative stress and lipid peroxidation upstream. Compared to Fer-1, D12 displays improved metabolic stability, markedly higher systemic exposure, and robust brain penetration (brain/plasma ratio = 6.31). In vivo, D12 attenuates acetaminophen-induced liver injury and cerebral ischemia-reperfusion injury. These findings establish D12 as a mechanistically distinct, drug-like preclinical candidate and. highlight the indolizine scaffold as a promising new chemotype for ferroptosis-targeted drug discovery.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z