Potent and Selective Inhibition of Acid Sphingomyelinase by Bisphosphonates

Roth, Anke G.; Drescher, Daniela; Yang, Yang; Redmer, Susanne; Uhlig, Stefan

doi:10.1002/anie.200903288

Cited by 79 publications

(83 citation statements)

References 36 publications

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“…In a cell-free drug screen of a wide range of compounds, no drug-like competitive inhibitors of S-ASM were identified (Mintzer et al, 2005). More recently, new competitive inhibitors of ASM have been identified and/or developed (Roth et al, 2009a(Roth et al, ,b, 2010Arenz, 2010) that should function against both L-ASM and S-ASM. Available compounds include substrate analogues such as L-carnitine, phosphate analogues such as phosphatidylinositol-3,5-bisphosphate and natural compounds such as α-mangostin (Arenz, 2010).…”

Section: Pharmacologymentioning

confidence: 99%

Secretory sphingomyelinase in health and disease

Kornhuber

Rhein

Müller

et al. 2015

Biological Chemistry

122

138

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Acid sphingomyelinase (ASM), a key enzyme in sphingolipid metabolism, hydrolyzes sphingomyelin to ceramide and phosphorylcholine. In mammals, the expression of a single gene, SMPD1, results in two forms of the enzyme that differ in several characteristics. Lysosomal ASM (L-ASM) is located within the lysosome, requires no additional Zn 2+ ions for activation and is glycosylated mainly with high-mannose oligosaccharides. By contrast, the secretory ASM (S-ASM) is located extracellularly, requires Zn 2+ ions for activation, has a complex glycosylation pattern and has a longer in vivo half-life. In this review, we summarize current knowledge regarding the physiology and pathophysiology of S-ASM, including its sources and distribution, molecular and cellular mechanisms of generation and regulation and relevant in vitro and in vivo studies. Polymorphisms or mutations of SMPD1 lead to decreased S-ASM activity, as detected in patients with Niemann-Pick disease B. Thus, lower serum/ plasma activities of S-ASM are trait markers. No genetic causes of increased S-ASM activity have been identified. Instead, elevated activity is the result of enhanced release (e.g., induced by lipopolysaccharide and cytokine stimulation) or increased enzyme activation (e.g., induced by oxidative stress). Increased S-ASM activity in serum or plasma is a state marker of a wide range of diseases. In particular, high S-ASM activity occurs in inflammation of the endothelium and liver. Several studies have demonstrated a correlation between S-ASM activity and mortality induced by severe inflammatory diseases. Serial measurements of S-ASM reveal prolonged activation and, therefore, the measurement of this enzyme may also provide information on past inflammatory processes. Thus, S-ASM may be both a promising clinical chemistry marker and a therapeutic target.

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Section: Pharmacologymentioning

confidence: 99%

Secretory sphingomyelinase in health and disease

Kornhuber

Rhein

Müller

et al. 2015

Biological Chemistry

122

138

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“…In contrast, a small collection of geminal bisphosphonates surprisingly showed remarkable inhibition of aSMase. A subsequent more detailed SAR study led to the development of the aSMase-inhibiting bisphosphonates 12-14 [53]. The geminal aminobisphosphonate 12 (ARC 39)is the most potent inhibitor of aSMase (IC 50 = 20 nM), so far.…”

Section: Poor Off-rates From Biomembranesmentioning

confidence: 99%

Small Molecule Inhibitors of Acid Sphingomyelinase

Arenz

2010

Cell Physiol Biochem

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Despite of the importance of the acid sphingomyelinase for sphingomyelin homeostasis and sphingolipid signalling, potent and selective inhibitors for this enzyme are rare. An increasing set of data on the inhibition of acid sphingomyelinase in different disease models using indirect inhibitors has been generated and strongly implies acid sphingomyelinase as an emerging drug target. Very recently, some new and promising inhibitors from different substance classes have been developed. In this review, previous and current developments in the field are summarized.

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“…Amides, being highly stable and easily available compounds, are substrates of choice, and the most commonly applied procedures are simple modifications of those elaborated for carboxylic acids. The most straightforward are reactions of N-acylamines and N-formylamines with phosphorus trichloride and phosphorous acid [30][31][32], phosphorus tribromide [33], or triphosgene [34], which provide a wide structural variety of 1-amino-1,1-bisphosphonic acids (compound 4, Scheme 3). They are based on modification of the first procedure elaborated by Plöger et al with formamide as a substrate [35].…”

Section: Synthesis From Amidesmentioning

confidence: 99%

Synthetic Procedures Leading towards Aminobisphosphonates

Chmielewska

Kafarski

2016

Molecules

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Abstract:Growing interest in the biological activity of aminobisphosphonates has stimulated the development of methods for their synthesis. Although several general procedures were previously elaborated to reach this goal, aminobisphosphonate chemistry is still developing quite substantially. Thus, innovative modifications of the existing commonly used reactions, as well as development of new procedures, are presented in this review, concentrating on recent achievements. Additionally, selected examples of aminobisphosphonate derivatization illustrate their usefulness for obtaining new diagnostic and therapeutic agents.

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Potent and Selective Inhibition of Acid Sphingomyelinase by Bisphosphonates

Cited by 79 publications

References 36 publications

Secretory sphingomyelinase in health and disease

Secretory sphingomyelinase in health and disease

Small Molecule Inhibitors of Acid Sphingomyelinase

Synthetic Procedures Leading towards Aminobisphosphonates

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