Pharmacophore Identification and Scaffold Exploration to Discover Novel, Potent, and Chemically Stable Inhibitors of Acid Ceramidase in Melanoma Cells

Acid
ceramidase (AC) hydrolyzes ceramides, which are central lipid
messengers for metabolism and signaling of sphingolipids. A growing
body of evidence links deregulation of sphingolipids to several diseases,
including cancer. Indeed, AC expression is abnormally high in melanoma
cells. AC inhibition may thus be key to treating malignant melanoma.
Here, we have used a systematic scaffold exploration to design a general
pharmacophore for AC inhibition. This pharmacophore comprises a 6
+ 5 fused ring heterocycle linked to an aliphatic substituent via
a urea moiety. We have thus identified the novel benzimidazole derivatives 10, 21, 27, and 30,
which are highly potent AC inhibitors. Their chemical and metabolic
stabilities are comparable or superior to those of previously reported
AC inhibitors. Moreover, they are potent against endogenous AC in
intact melanoma cells. These novel inhibitors merit further characterization
and can serve as a promising starting point for the discovery of new
antimelanoma therapeutics.