Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure-Activity Relationships

Eleonora Diamanti, Giovanni Bottegoni, Luca Goldoni, Natalia Realini, Chiara Pagliuca, Fabio Bertozzi, Daniele Piomelli*, Daniela Pizzirani

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Citations (Scopus)

Abstract

Acid ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.

Original languageEnglish
Pages (from-to)2739-2756
Number of pages18
JournalSynthesis (Germany)
Volume48
Issue number17
Early online date9 Jun 2016
DOIs
Publication statusPublished - 1 Sep 2016

Keywords

  • acid ceramidase
  • atomic property field (APF)
  • ceramides
  • melanoma
  • regioisomers
  • structure-activity relationship (SAR)

ASJC Scopus subject areas

  • Catalysis
  • Organic Chemistry

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