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

  • ACS Omega. 2025 Jul 31;10(31):34747-34761. doi: 10.1021/acsomega.5c03734.
Richard Beresis  1 ,  Vijaya Prathigudupu  2 ,  Carson Cable  2 ,  Amy Yu  2 ,  Marc Adler  3 ,  Roopa Ramamoorthi  4 ,  Seul Ki Yeon  1 ,  John D Gordan  5 ,  Sachin Sharma  2 ,  William F DeGrado  1 ,  Balyn Zaro  1 ,  Jennifer Y Chen  2  6 ,  Hyunil Jo  1
Affiliations
  • 1. Department of Pharmaceutical Chemistry, University of California, San Francisco, California 94143, United States.
  • 2. Division of Gastroenterology, Department of Medicine, University of California, San Francisco, California 94143, United States.
  • 3. ChemPartner, 280 Utah Ave, South San Francisco, California 94080, United States.
  • 4. Innovation Ventures, University of California, San Francisco, California 94143, United States.
  • 5. Division of Hematology and Oncology, University of California, San Francisco, California 94143, United States.
  • 6. Liver Center, University of California San Francisco, San Francisco, California 94143, United States.
PMID: 40821548 DOI: 10.1021/acsomega.5c03734
Abstract

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.

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