Design, synthesis, and biological evaluation of carbonyl-hydrazine-1-carboxamide derivatives as anti-hepatic fibrosis agents targeting Nur77

[Display omitted] •New carbonyl-hydrazine-1-carboxamide derivatives are synthesized and performed SAR study.•16f binds well to Nur77 (KDSPR = 288 nM) and upregulates Nur77 expression.•16f significantly inhibits HSCs activation and reduces ECM deposition.•16f enhances Nur77-mediated autophagic flux and lysosomal biogenesis against HSC activation.•16f displays strong anti-hepatic fibrosis and improved liver function in CCl4-stimulated mice. Hepatic fibrosis remains a great challenge clinically. The orphan nuclear receptor Nur77 is recently suggested as the critical regulator of transforming growth factor-β (TGF-β) signaling, which plays a central role in multi-organic fibrosis. Herein, we optimized our previously reported Nur77-targeted compound 9 h for attempting to develop effective and safe anti-hepatic fibrosis agents. The critical pharmacophore scaffold of pyridine-carbonyl-hydrazine-1-carboxamide was retained, while the naphthalene ring was replaced with an aromatic ring containing pyridyl or indole groups. Four series of derivatives were thus generated, among which the compound 16f had excellent binding activity toward Nur77-LBD (KD = 470 nM) with the best inhibitory activity against the TGF- β 1 activation of hepatic stellate cells (HSCs) and low cytotoxicity to normal mice liver AML-12 cells (IC50 > 80 μM). In mice, 16f displayed potent activity against CCl4-induced liver fibrosis with improved liver function. Mechanistically, 16f-mediated inactivation of HSC and suppression of liver fibrosis were associated with its enhancement of autophagic flux in a Nur77-dependent manner. Together, 16f was identified as a potential anti-liver fibrosis agent. Our study suggests that Nur77 may serve as a critical anti-hepatic fibrosis target.