FIASMA

Functional inhibitors of acid sphingomyelinase, or FIASMA, is a term which characterizes a large group of pharmacological compounds inhibiting the enzyme acid sphingomyelinase (ASM, EC 3.1.4.12). This enzyme is mainly located within the lysosome, where it cleaves sphingomyelin to ceramide and sphingosine, the latter of which is then phosphorylated to sphingosine-1-phosphate. These metabolites, and subsequent inhibition of the enzyme, influence the balance between cell death (apoptosis) and cell growth (proliferation). A lack of regulation of this sensitive equilibrium can lead to serious clinical consequences.

FIASMAs inhibit the ASM via an indirect, functional mechanism. They insert into the inner leaf of the lysosomal membrane and subsequently cause membrane-associated enzymes, such as ASM, to detach. Upon detachment from the membrane, these enzymes are cleaved and degraded within lysosomes. Inhibition of ASM by certain drugs has been known about for a long time, but systematic studies which characterize the pharmacological group of FIASMAs are relatively recent. ASM is not completely inhibited by FIASMAs and a low residual activity remains, allowing sufficient metabolism for cellular survival to occur. Application of FIASMAs therefore do not result in a clinical condition like Niemann-Pick disease, where ASM-activity is completely lacking because of genetic mutations.

In contrast to FIASMAs, a screen of over 346,000 small molecules found only 20 that where direct inhibitors of acid sphingomyelinase. These 20 included amiodarone and etidronic acid.

FIASMAs are structurally diverse, but have common physicochemical properties. All hitherto identified FIASMAs share a basic nitrogen atom and lipophilic part, which characterizes them as “cationic amphiphilic drugs”. Additionally, they also violate Lipinski's Rule of Five more often than non-FIASMAs. Still they are highly bioavailable and reabsorbed by the gastrointestinal tract. In general, they also show high blood–brain barrier permeability.

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