220728-25-6Relevant articles and documents
Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure-Activity Relationship (SAR) Studies
Bach, Anders,Pizzirani, Daniela,Realini, Natalia,Vozella, Valentina,Russo, Debora,Penna, Ilaria,Melzig, Laurin,Scarpelli, Rita,Piomelli, Daniele
supporting information, p. 9258 - 9272 (2015/12/23)
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.
Synthesis of potent non-imidazole histamine H3-receptor antagonists
Ganellin, C. Robin,Leurquin, Fabien,Piripitsi, Antonia,Arrang, Jean-Michel,Garbarg, Monique,Ligneau, Xavier,Schunack, Walter,Schwartz, Jean-Charles
, p. 395 - 404 (2007/10/03)
Histamine has been converted into a non-imidazole H3-receptor histamine antagonist by addition of a 4-phenylbutyl group at the N(α)-position followed by removal of the imidazole ring. The resulting compound, N-ethyl- N-(4-phenylbutyl)amine, remarkably has a Ki = 1.3 μM as an H3 antagonist. Using this as a lead compound, a novel series of homologous O and S isosteric tertiary amines was synthesised and structure-activity studies furnished N- (5-phenoxypentyl)pyrrolidine (Ki = 0.18 ± 0.10 μM, for [3H]histamine release from rat cerebral cortex synaptosomes) which, more importantly, was active in vivo. Substitution of NO2 into the para position of the phenoxy group gave N-(5-p-nitrophenoxypentyl)pyrrolidine, UCL 1972 (Ki= 39 ± 11 nM), ED50 = 1.1 ± 0.6 mg/kg per os in mice on brain tele-methylhistamine levels.
