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

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.