2. Academic Validation
  3. 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

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

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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