Use of cyclopropenylsphingosine derivatives as ceramidase modulators for diagnosis and treatment of Farber's disease and treating e.g. cancer and cardiovascular disease

摘要

Use of cyclopropenylsphingosine derivatives (I) is claimed to prepare a composition that modulates activity of ceramidase (II). Independent claims are also included for: (1) a composition (C1) containing (I), and (2) use of (C1) for diagnosing Farber's disease which comprises: (a) incubating (I) with control cells (CC) and with cells (CT) from the subject being tested; (b) extracting the cells to recover lipids and filtering through an ion exchange column; (c) measuring the fluorescence from the fraction that elutes in acidic medium, by comparison with values obtained using various concentrations of 12-(4-nitrobenzo-2-oxa-1,3-diazolo)dodecanoic acid (X), and (d) determining the amount of (X) formed from a substrate as a result of ceramide activity and if the amount of (X) formed in CT is significantly less than that formed in CC, Farber's disease is diagnosed. ACTIVITY : Cytostatic; Cardiant; Vasotropic; Antiarteriosclerotic; Antiinflammatory; Antiasthmatic; Antiarthritic; Antirheumatic. MECHANISM OF ACTION : Ceramidase modulator. In a test, (1S,2S)-N-[2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (Ia) was incubated with rat liver microsomes (containing neutral and alkaline ceramidase) in the presence of the substrate N-[12-(4-nitrobenzo-2-oxa-1,3-diazolo)dodecyl]sphingosine. After 40 minutes at 37 [deg]C, the mixture was treated with methanol, centrifuged and the amount of 12-(4-nitrobenzo-2-oxa-1,3-diazolo)dodecanoic acid (X) formed measured by high performance liquid chromatography, as described in Anal. Biochem., 274 (1999) 264. Absorbance (in units X 103) was 1800 in the absence of (Ia), but only 1400, 700 and 300 in the presence of 250, 500 and 1000 MicroM (Ia), respectively.