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000834832 0247_ $$2doi$$a10.1021/acs.jmedchem.7b00472
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000834832 0247_ $$2ISSN$$a0095-9065
000834832 0247_ $$2ISSN$$a1520-4804
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000834832 1001_ $$0P:(DE-HGF)0$$aOrtega, Jose Antonio$$b0
000834832 245__ $$aPharmacophore Identification and Scaffold Exploration to Discover Novel, Potent, and Chemically Stable Inhibitors of Acid Ceramidase in Melanoma Cells
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000834832 520__ $$aAcid ceramidase (AC) hydrolyzes ceramides, which are central lipid messengers for metabolism and signaling of sphingolipids. A growing body of evidence links deregulation of sphingolipids to several diseases, including cancer. Indeed, AC expression is abnormally high in melanoma cells. AC inhibition may thus be key to treating malignant melanoma. Here, we have used a systematic scaffold exploration to design a general pharmacophore for AC inhibition. This pharmacophore comprises a 6 + 5 fused ring heterocycle linked to an aliphatic substituent via a urea moiety. We have thus identified the novel benzimidazole derivatives 10, 21, 27, and 30, which are highly potent AC inhibitors. Their chemical and metabolic stabilities are comparable or superior to those of previously reported AC inhibitors. Moreover, they are potent against endogenous AC in intact melanoma cells. These novel inhibitors merit further characterization and can serve as a promising starting point for the discovery of new antimelanoma therapeutics.
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000834832 7001_ $$0P:(DE-HGF)0$$aArencibia, Jose M.$$b1
000834832 7001_ $$0P:(DE-HGF)0$$aLa Sala, Giuseppina$$b2
000834832 7001_ $$0P:(DE-HGF)0$$aBorgogno, Marco$$b3
000834832 7001_ $$0P:(DE-HGF)0$$aBauer, Inga$$b4
000834832 7001_ $$0P:(DE-HGF)0$$aBono, Luca$$b5
000834832 7001_ $$0P:(DE-HGF)0$$aBraccia, Clarissa$$b6
000834832 7001_ $$0P:(DE-HGF)0$$aArmirotti, Andrea$$b7
000834832 7001_ $$0P:(DE-HGF)0$$aGirotto, Stefania$$b8
000834832 7001_ $$0P:(DE-HGF)0$$aGanesan, Anand$$b9
000834832 7001_ $$0P:(DE-Juel1)167585$$aDe Vivo, Marco$$b10$$eCorresponding author
000834832 773__ $$0PERI:(DE-600)1491411-6$$a10.1021/acs.jmedchem.7b00472$$gVol. 60, no. 13, p. 5800 - 5815$$n13$$p5800 - 5815$$tJournal of medicinal chemistry$$v60$$x1520-4804$$y2017
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