title: Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies.
abstract: Ceramides are lipid-derived intracellular messengers involved in the control of senescence, inflammation, and apoptosis. The cysteine amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine and fatty acid and, by doing so, regulates their signaling activity. AC inhibitors may be useful in the treatment of pathological conditions, such as cancer, in which ceramide levels are abnormally reduced. Here, we present a systematic SAR investigation of the benzoxazolone carboxamides, a recently described class of AC inhibitors that display high potency and systemic activity in mice. We examined a diverse series of substitutions on both benzoxazolone ring and carboxamide side chain. Several modifications enhanced potency and stability, and one key compound with a balanced activity-stability profile (14) was found to inhibit AC activity in mouse lungs and cerebral cortex after systemic administration. The results expand our arsenal of AC inhibitors, thereby facilitating the use of these compounds as pharmacological tools and their potential development as drug leads.
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Anders
authors.initials: A
authors.lastname: Bach
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Pizzirani
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Natalia
authors.initials: N
authors.lastname: Realini
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Vozella
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Debora
authors.initials: D
authors.lastname: Russo
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Ilaria
authors.initials: I
authors.lastname: Penna
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Laurin
authors.initials: L
authors.lastname: Melzig
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Scarpelli
authors.affiliation: Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia , Via Morego 30, I-16163 Genova, Italy.|Departments of Anatomy and Neurobiology, Biological Chemistry, and Pharmacology, University of California , Irvine, California 92697-4625, United States.
authors.forename: Daniele
authors.initials: D
authors.lastname: Piomelli
mesh_terms: D055573:Acid Ceramidase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001583:Benzoxazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008168:Lung / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D013329:Structure-Activity Relationship
chemical_list: D001583:Benzoxazoles; D004791:Enzyme Inhibitors; C017057:benzoxazolone; D055573:Acid Ceramidase