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 IC50 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.