Design, synthesis, and biological studies of novel sulfonamide derivatives as farnesoid X receptor agonists.

Farnesoid X receptor (FXR) is considered as a promising target for the treatment of NASH. Although many non-steroidal FXR agonists have been reported, the structure types are quite scarce and mainly limited to the isoxazole scaffold derived from GW4064. Therefore, it is crucial to expand the structure types of FXR agonist to explore wider chemical space. In this study, the structure-based scaffold hopping strategy was performed by hybrid FXR agonist 1 and T0901317, which resulted in the discovery of sulfonamide FXR agonist 19. Molecular docking study reasonably explained the SAR in this series, and compound 19 fitted well with the binding pocket in a similar mode to the co-crystal ligand. In addition, compound 19 exhibited considerable selectivity against other nuclear receptors. In NASH model, compound 19 alleviated the typical histological features of fatty liver, including steatosis, lobular inflammation, ballooning, and fibrosis. Moreover, compound 19 exhibited acceptable safety profiles with no acute toxicity to major organ. These results suggested that the novel sulfonamide FXR agonist 19 might be a promising agent for the treatment of NASH.

Working memory deficits in children with schizophrenia and its mechanism, susceptibility genes, and improvement: A literature review.

The negative influence on the cognitive ability of schizophrenia is one of the issues widely discussed in recent years. Working memory deficits are thought to be a core cognitive symptom of schizophrenia and lead to poorer social functions and worse academic performance. Previous studies have confirmed that working memory deficits tend to appear in the prodromal phase of schizophrenia. Therefore, considering that children with schizophrenia have better brain plasticity, it is critical to explore the development of their working memory. Although the research in this field developed gradually in recent years, few researchers have summarized these findings. The current study aims to review the recent studies from both behavior and neuroimaging aspects to summarize the working memory deficits of children with schizophrenia and to discuss the pathogenic factors such as genetic susceptibility. In addition, this study put forward some practicable interventions to improve cognitive symptoms of schizophrenia from psychological and neural perspectives.