5006-89-3Relevant academic research and scientific papers
Discovery and Mechanism of Action of Small Molecule Inhibitors of Ceramidases**
Arenz, Christoph,Basu, Shibom,Bechara, Cherine,Bossis, Guillaume,Cong, Xiaojing,Del Nero, Elise,Drapeau, Marion,Fontanel, Simon,Gabellier, Ludovic,Golebiowski, Jér?me,Granier, Sebastien,Healey, Robert D.,Hornemann, Thorsten,Jeannot, Sylvain,Karsai, Gergely,Leyrat, Cedric,Maurel, Damien,Saied, Essa M.,Saint-Paul, Julie
supporting information, (2021/12/09)
Sphingolipid metabolism is tightly controlled by enzymes to regulate essential processes in human physiology. The central metabolite is ceramide, a pro-apoptotic lipid catabolized by ceramidase enzymes to produce pro-proliferative sphingosine-1-phosphate. Alkaline ceramidases are transmembrane enzymes that recently attracted attention for drug development in fatty liver diseases. However, due to their hydrophobic nature, no specific small molecule inhibitors have been reported. We present the discovery and mechanism of action of the first drug-like inhibitors of alkaline ceramidase 3 (ACER3). In particular, we chemically engineered novel fluorescent ceramide substrates enabling screening of large compound libraries and characterized enzyme:inhibitor interactions using mass spectrometry and MD simulations. In addition to revealing a new paradigm for inhibition of lipid metabolising enzymes with non-lipidic small molecules, our data lay the ground for targeting ACER3 in drug discovery efforts.
Antischistosomal activity of N,N′-arylurea analogs against Schistosoma japonicum
Yao, Houzong,Liu, Fengyou,Chen, Jinglei,Li, Yan,Cui, Jinhao,Qiao, Chunhua
supporting information, p. 1386 - 1390 (2016/02/19)
Although the antischistosomal activities of N,N′-arylurea analogs were reported, systematic structure-activity relationships have not been conducted. In this Letter, we reported the design, synthesis and evaluation of 45 N,N′-arylurea analogs. Among these prepared compounds, 13 compounds were urea linker modified and 32 were N,N′-arylurea derivatives. The activity evaluation revealed 12 analogs exhibited IC50 values lower than 22.6 μM, and 7 of them had IC50 less than 10 μM against the juvenile Schistosoma japonicum in vitro. Their worm killing potency was even higher against adult worm. Unfortunately, low to moderate worm burden reduction of 0-33.4% was recorded after administration of a single oral dose of 200 mg/kg or 400 mg/kg to mice harboring S. japonicum.
