Exploration of a Class of Aryl Imidazolyl Ureas As Potent Acid Ceramidase Inhibitors for the Treatment of Fibrotic Diseases.

Acid ceramidase (aCDase) is an essential enzyme in sphingolipid metabolism and has been linked to various pathological conditions, including cancer and fibrosis. In our previous studies, we observed that inhibiting aCDase with B13 (4) helped alleviate liver fibrosis in mouse models and in ex vivo human precision-cut liver slices. However, B13 (4) showed limited potency, prompting us to search for more effective aCDase inhibitors. During our exploration of well-established urea-type inhibitors, we discovered that the aryl imidazolyl urea scaffold demonstrated both high potency and chemical stability. Among the tested compounds, compound 43 stood out with its nanomolar IC(50) activity against aCDase and its ability to significantly reduce fibrosis markers, such as collagen production, in hepatic stellate cells. Kinetic studies were also performed to understand the interaction of compound 43 with aCDase. Additionally, proteomics analysis of activated hepatic stellate cells treated with compound 43 revealed a notable change in several cellular proteins, including those related to growth factors, such as platelet-derived growth factor receptor (PDGFR). These results indicate that the aryl imidazolyl urea scaffold holds strong potential for further development as a therapeutic option for fibrotic diseases.