Design and synthesis of genipine derivatives for the treatment of liver fibrosis by modulating TGF-β1/Smad signaling pathway.

The key event in the development of liver fibrosis is that hepatic stellate cells (HSCs) actives and transforms into myofibroblasts, so inhibiting HSCs activation is an important strategy in the search for therapeutic agents for liver fibrosis. In this study, we designed and synthesized a series of novel genipin derivatives that could effectively inhibit the activation of hepatic stellate cell (HSC) line LX-2 induced by TGF-β1. Among them, compound C9 can dose-dependently inhibit the expression of fibrosis markers (α-SMA and COL1A1) induced by TGF-β1, and has excellent in vitro safety. In a mouse model of CCl4-induced hepatic fibrosis, C9 exhibited significant antifibrotic effects, which was significantly superior to that of genipin and without hepatotoxicity. Meanwhile, C9 exhibited good pharmacokinetic properties in SD rats. Overall, compound C9 is expected to be a potential candidate for the treatment of hepatic fibrosis.