TY  - JOUR
AU  - Ortega, Jose Antonio
AU  - Arencibia, Jose M.
AU  - La Sala, Giuseppina
AU  - Borgogno, Marco
AU  - Bauer, Inga
AU  - Bono, Luca
AU  - Braccia, Clarissa
AU  - Armirotti, Andrea
AU  - Girotto, Stefania
AU  - Ganesan, Anand
AU  - De Vivo, Marco
TI  - Pharmacophore Identification and Scaffold Exploration to Discover Novel, Potent, and Chemically Stable Inhibitors of Acid Ceramidase in Melanoma Cells
JO  - Journal of medicinal chemistry
VL  - 60
IS  - 13
SN  - 1520-4804
CY  - Washington, DC
PB  - ACS
M1  - FZJ-2017-04723
SP  - 5800 - 5815
PY  - 2017
AB  - 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.
LB  - PUB:(DE-HGF)16
UR  - <Go to ISI:>//WOS:000405764900035
C6  - pmid:28603987
DO  - DOI:10.1021/acs.jmedchem.7b00472
UR  - https://juser.fz-juelich.de/record/834832
ER  -