ZSP1601 is a non-selective phosphodiesterase inhibitor and a clinical drug candidate for the oral treatment of metabolic dysfunction-associated steatohepatitis.

Abstract

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health challenge. Its advanced stage, metabolic dysfunction-associated steatohepatitis (MASH), involves complex processes such as metabolic dysregulation, inflammation, and fibrosis. Existing treatments mainly target steatosis but have limited success. Therefore, focusing on inflammation and fibrosis may offer more effective therapeutic options. Phosphodiesterases regulate cAMP/cGMP signaling and are key in MASH-related inflammation and fibrosis. Inhibiting specific PDE subtypes is a promising approach for drug development in MASH. This study presents a comprehensive preclinical pharmacological and pharmacokinetic profile of ZSP1601, a non-selective phosphodiesterase inhibitor currently in clinical trials for MASH. ZSP1601 was developed through structural optimization of pentoxifylline via a three-step chemical synthesis. Molecular docking and enzymatic assays confirmed its role as a non-selective PDE inhibitor. In vitro, ZSP1601 significantly lowered TNF-α levels, showed strong anti-inflammatory effects, and was more effective than pentoxifylline at the same dose. In vivo, ZSP1601 markedly reduced liver NAS scores in the STZ + HFD model and decreased fibrosis in the CDAHFD model in a dose-dependent manner. Consistent with these results, data from liver fibrosis models demonstrated that ZSP1601 significantly alleviated hepatocellular injury and reduced hepatic fibrosis. Pharmacokinetic studies indicated that ZSP1601 has favorable properties in mice, rats, and beagle dogs after single and multiple doses. In summary, ZSP1601, a non-selective PDE inhibitor, presents a promising new treatment for MASH by effectively improving disease outcomes. It is currently being evaluated in a phase II clinical trial.