Design and synthesis of pyridazin-4-one derivatives as necroptosis inhibitors

Yuxiang An; Xia Peng; Tianchen Wang; Kaiyuan Liu; Dazhi Feng; Chen Fang; Xuan Zhou; Meiyu Geng; Wenhu Duan; Jing Ai; Hefeng Zhang

doi:10.1002/ardp.202400594

Design and synthesis of pyridazin-4-one derivatives as necroptosis inhibitors

Arch Pharm (Weinheim). 2024 Nov 21:e2400594. doi: 10.1002/ardp.202400594. Online ahead of print.

Authors

Yuxiang An^{1

2}, Xia Peng³, Tianchen Wang^{1

2}, Kaiyuan Liu^{2

3

4}, Dazhi Feng^{1

5}, Chen Fang^{1

6}, Xuan Zhou^{2

3

7}, Meiyu Geng^{2

3

4

8}, Wenhu Duan^{1

2

8}, Jing Ai^{2

3}, Hefeng Zhang¹

Affiliations

¹ Small-Molecule Drug Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
² School of Pharmacy, University of Chinese Academy of Sciences, Beijing, China.
³ Cancer Research Center, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, Shanghai, China.
⁴ School of Life Sciences and Technology, ShanghaiTech University, Shanghai, China.
⁵ State Key Laboratory of Natural Medicines, Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing, People's Republic of China.
⁶ School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.
⁷ School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China.
⁸ Shandong Laboratory of Yantai Drug Discovery, Bohai Rim Advanced Research Institute for Drug Discovery, Yantai, Shandong, China.

PMID: 39573835
DOI: 10.1002/ardp.202400594

Abstract

Necroptosis is a regulated inflammatory cell death process that is closely associated with autoimmune diseases, acute ischemic injuries, neurodegenerative disorders, and so on. Due to the crucial role of receptor-interacting protein kinase 1 (RIPK1) in the necroptosis pathway, RIPK1 inhibitors are believed to have great potential in the treatment of necroptosis-related diseases. In this article, we reported a series of pyridazin-4-one derivatives as potent necroptosis inhibitors for both human and mouse cells. The representative compound 13 exhibited favorable RIPK1 selectivity and dose-dependently inhibited RIPK1 phosphorylation. The in vivo pharmacokinetic study indicated that compound 13 was an orally available candidate. Finally, molecular docking and molecular dynamics simulations were performed to elucidate the binding pattern of compound 13 with RIPK1. Collectively, compound 13 represents a promising lead compound for the future development of RIPK1-targeted necroptosis inhibitors.

Keywords: inhibitor; pharmacokinetic study; pyridazin‐4‐one; receptor‐interacting protein kinase 1; selectivity.

Abstract

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