However, studies using cells derived from Niemann-Pick disease patients or from ASM knock-out mice revealed that the deficiency of this enzyme might also have beneficial consequences, including anti-apoptotic and cytoprotective effcts. In fact, there is increasing evidence that ASM activation and MK-4827 ceramide accumulation play a central role in the development of common human diseases. Reports have been published of aberrant activation of ASM and/or altered levels of ceramide, for instance, for several psychiatric and neurological disorders such as major depression, morphine antinociceptive tolerance, Alzheimer’s disease, spinal cord injuryand seizure disorder. Therefore, ASM inhibitors hold promise for a number of new clinical therapies and might be used to prevent apoptosis and other negative effects occurring in different disease states such as in ischemia, stroke, Alzheimer’s dementia, Parkinson’s disease, Huntington’s chorea, and of certain infections, in endotoxemia, and in atherosclerosis, and for the therapy of major depressive disorder. Currently, only few examples of inhibitors directly interacting with ASM are known. These substances include physiological inhibitors of ASM such as phosphatidyl-myoinositol-3,4,5-trisphosphate, L-a-phosphatidyl-D-myo-inositol3,5-bisphosphateand non-natural direct inhibitors of ASM, such as SMA-7and AD2765. A high throughput screening for direct ASM inhibitors was unsuccessful in finding lead structures. The rational development of compounds that block ASM by direct interaction with the enzyme is difficult, since the crystal structure of the enzyme is not yet available. On the other hand, it has been known since the 1970s that some weak organic bases have the potential to reduce the activity of ASM. Weak bases, such as desipramine 168, strongly accumulate in acidic intracellular compartments like lysosomes, a phenomenon called ‘acid trapping’ and in the case of lysosomes ‘lysosomotropism’. This accumulation of desipramine 168 results in detachment of the ASM from the inner lysosomal membraneand its subsequent inactivation, probably by proteolytic degradation. Weak bases, therefore, do not directly inhibit ASM, but result in a functional inhibition of ASM. We have thus proposed the acronym FIASMA for Functional Inhibitor of Acid SphingoMyelinAse. According to this model, functional inhibition of ASM requires high lysosomal concentrations of a weak basic drug. Previously, we have shown that functional inhibition of ASM is related to high pKa- and high logP-values and have characterized several new FIASMAs, including the antidepressant drugs doxepine 63, fluoxetine 104, maprotilin 109, nortriptyline 114, paroxetine 118 and sertraline 124. The aims of the present study wereto identify more FIASMAs,to further improve the in silico prediction of functional ASM inhibition by developing compact and easily-interpretable models with high internal Talazoparib consistency,to investigate the relationship between permeation of the blood-brain barrier and functional inhibition of ASM andto study the distribution of FIASMAs across different classes of drugs licensed for medical use in humans. Using the present knowledge about lysosomal accumulation and drug-membrane interaction as prerequisite to functional inhibition of ASM, we developed the following hypotheses: FIASMAshave shared structural and physicochemical properties allowing high lysosomal drug concentrations, compatible with partitioning into the inner surface of the lysosomal membrane and alteration of electrostatic membrane properties. We hypothesize that FIASMAswill be found in different therapeutic drug classes andbelong to diverse structural drug classes.