Discovery of N-Phenyl-5-propyl-1 H-pyrazole-3-carboxamide, with Selective Inhibition and Degradation of HDAC6 for the Treatment of Acute Liver Injury

  • J Med Chem. 2025 Jan 9;68(1):531-554. doi: 10.1021/acs.jmedchem.4c02341.
Hao Cui  1  2 ,  Guodong Zhang  1 ,  Liyuan Zhang  2 ,  Shilong Sun  2 ,  Kang Yang  2 ,  Aixin Gen  2 ,  Penfeng Wang  2 ,  Hui Wang  2 ,  Qing-Qing Zhou  3 ,  Hongmei Li  2 ,  Yadong Chen  2 ,  Yuqin Yao  4  5 ,  Tao Lu  2  6 ,  Lei Zhang  1 ,  Yong Zhu  2
Affiliations
  • 1. School of Pharmacy, Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei 230032, China.
  • 2. School of Science, China Pharmaceutical University, 639 Longmian Avenue, Nanjing 211198, PR China.
  • 3. Department of Radiology, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing 211100, PR China.
  • 4. Molecular Toxicology Laboratory of Sichuan Provincial Education Office, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu 610041, PR China.
  • 5. State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China.
  • 6. State Key Laboratory of Natural Medicines, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, PR China.
PMID: 39680630 DOI: 10.1021/acs.jmedchem.4c02341
Abstract

Acute liver injury is a severe and potentially life-threatening condition. Currently, there are no specific effective treatments available. HDAC6 has been identified as a promising strategy for treating ALI by inhibiting necrosis and inflammation. In this study, a series of pyrazole derivatives were designed to specifically target HDAC6, among which compound 6 demonstrated high antinecroptotic activity (IC50 = 0.5 nM) and excellent selective HDAC6 inhibition (IC50 = 4.95 nM, HDAC1/HDAC6 = 251). Surprisingly, compound 6 also exhibited excellent HDAC6 degradation activity (DC50 = 0.96 nM) through mechanistic studies. Additionally, it demonstrated strong inhibitory effects on inflammatory proteins TNF-α, IL-1β, and IL-6, indicating significant anti-inflammatory activity. Moreover, in a mouse model of acetaminophen (APAP)-induced acute liver injury, compound 6 exhibited significant therapeutic and protective efficacy at a dose of 40 mg/kg. These findings confirm that compound 6 is a promising lead structure for combating ALI-related diseases and warrants further investigation.

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