Scyphostatin analogues as SMase inhibitors

Details Scyphostatin analogues as SMase inhibitors Scyphostatin analogues as SMase inhibitors

2002-08-22

2004-09-14

Davis, Brian (Department: 1621)

Organic compounds -- part of the class 532-570 series

Organic compounds

Amino nitrogen containing

C548S215000

Reexamination Certificate

active

06790992

ABSTRACT:

The, present invention relates to novel scyphostatin analogues which stand out for acting as inhibitors of SMase so that they are therapeutically useful in connection with a number of diseases, such as an HIV infection, neurodegenerative diseases, inflammatory diseases, ischemia, myocardial infarction, apoplexy, or in the case of atherosclerosis.
Sphingomyelin (N-acyl-spingosyl-phosphoryl-choline, SM) is an integral constituent of both biological membranes and plasma lipoproteins and an important source of forming messenger substances (“second messenger”) such as ceramide which is released following stimulation by enzymes (“sphingoxnyetin pathway”), This signal transmission by membrane sphingolipids has been studied intensively in the last few years. SM is metabolized by isoforms of an enzyme similar to phospholipase C, which is referred as sphingomyelinase (SMase). To date, five isotypes of SMase are known. Most mammalian cells are capable of transmitting signals through the SM pathway, the signal transmission being activated by both receptors such as tumor necrosis factor (TNF) receptors or interleukin-1 receptors, and stress, such as U.V. light, oxidants or radiation. The formation of ceramide is nowadays considered co-decisive for the introduction of vital cell processes, such as cell proliferation and apoptosis. This correlation between ceramide formation and apoptosis induction comprises an activation of respectively particular SMase isoforms which display their optimum pH in an acidic (acidic SMases; acid SMases, aSMases) and/or in a neutral environment (neutral SMases; nSMases).
Apoptosis, programmed cell death, proceeds in an irreversible sequence of morphological and biochemical changes. It is the most important regulative mechanism for eliminating no longer required cells during embryonic development and growth or irreparably damaged cells. Various noxious substances, such as TNF/NGF, heat shock, cytostatic agents, ionizing radiation, infections caused by viruses or bacteria, deprivation of various growth factors and cell membrane-permeable ceramides induce apoptosis in different cell types Ceramide as a “second messenger” is involved in programmed cell death in widely differing tissues. For example, it is involved in regulating signal transduction, which eventually results in apoptosis.
The ceramide-induced cell death might play a role in widely differing diseases, such as sepsis, atherosclerosis, neurodegenerative diseases, such as Alzheimer's disease, Parkinsons' disease, and infections caused by retroviruses, such as the HIV virus, ceramide-mediated apoptosis having to be assumed in each case.
An infection with the HIV virus, type 1 (HIV-1) together with changes in the cellular metabolism results in a loss of subpopulations of T-lymphocytes, in particular the CD4
+
helper cells. There is more and more evidence for the fact that the intracellular redox system, i.e. the equilibnrium between oxidants and antioxidants, HIV infection and lymphocyte-associated ceramide are correlated via the activation of the SM pathway. The ceramide signal system is also involved in the HIV infection when either the HIV expression is regulated or apoptosis is induced. It was possible to show that ceramide initiates the signal cascade resulting in the apoptosis of lymphocytes in HIV-infected patients. This is considered one of the main causes of T-lymphocyte reduction, which ultimately leads to the fully manifested clinical picture. This takes place by induction of apoptosis' by means of the CD95/APO-1/Fas-receptor/ligand system which activates aSMase and results in the ceramide production. If this is inhibited by treatment with L-carnitine, ceramide synthesis is prevented both in vitro and in vivo. In the final analysis, it seems that the state of the redox systems and the progress of ceramic metabolism permit predictions as to the, intensity of the infection.
Apoptosis also plays a major role in neuronal cell death. It is assumed that there is a direct connection between oxidative stress and the occurrence of neurodegenerative diseases. Cell death in neurodegenerative diseases which can be caused by oxidative stress can be traced back to intracellular signals for SMase activation and the resulting ceramide production, Oxidative stress is attributed a major role in triggering Parkinson's disease and Alzheimer's disease, for example. Although the mechanisms inducing these diseases are not yet fully clear, the affected brain centers of the diseased persons have an increased apoptosis rate which is presumably due to an increased ceramide concentration.
SM/ceramide is also involved in chronic or acute inflammatory diseases. Both sepsis and the consequences of septic shock as-well as multiorgan failure have developed into the main cause of death in critical care units. Based on clinical, experimental and epidermologic data, sepsis is nowadays considered an inflammatory response to infections showing signs of severe defective organic functions herein, TNF&agr; is the central mediator for the development of septic shock. Septic patients have increased serum TNF&agr; concentrations and also cell-associated ceramide concentrations. It was possible to show that there is a direct connection between ceramide and TNF&agr; concentrations. Since TNF&agr; causes intracellular ceramide formation, the inflammatory response falsely modulated by TNF&agr; might be blocked in spite of increased TNF&agr; concentrations in the plasma by adding, SMase inhibitors, which would reduce the ceramide formation. Observations, of similar quality were also made in the case of other cellular reactions triggering sepsis. It would be possible to control the apopotosis rate and thus treat septic patients by interfering with the sphingolipid metaoblism to thus control and/or reduce the ceramide production.
Finally, SM metabolites and SMase also play are role in atherogenesis. The (phospho)lipid-protein complex “low density lipoprotein” (LDL) is important for phospolipids and neutral lipids in the plasma and very susceptible to oxidative and enzymatic modification. The oxidative or enzymatic modification of LDL comprises a number of chemical and biophysical changes of the lipoprotein. The resulting modified LDL (mLDL) is considered the biologically relevant proatherogenic lipoprotein which contains an abundance of active components. Cellular defective regulations or the injury of endothelial cells by activation of the cellular suicide mechanism resulting in apoptosis are regarded as the key steps for the development of atherosclerotic plaques. It was found that mLDL plays a double role in the case of artherosclerosis: low doses of mLDL are involved in the proliferation and synthesis of the extracellular matrix of the smooth muscle cells (SMC) during the early stage of atherosclerosis. In the advanced stage, when there is sufficient mLDL in the plaque, it may induce apoptosis in the SMC.
This results in instability and ruptures of the plaques and thus in the clinical consequences of artherosclerosis. mLDL induces the proliferation and apoptosis of SMC, Although many mechanisms are unclear, ceramide appears to act as an effector of a cellular response caused by mmLDL. mmLDL is an oxidation product of LDL (mmLDL, minimally modified LDL). Following internalization and lysosomal degradation, mmLDL containing as such a considerable SM proportion, supplies a substrate for the ceramide formation and stimulates the SM/ceramide pathway. The reduction of the aSMase activity offers a possibility of modulating the mLDL-rnediated cell death.
The modulation of endogenous ceramide generation) above all the reduction thereof, is thus a central aspect for the development of new (preventive) therapeutic approaches. This can be effected by inhibiting the membrane-bound neutral sphingomylinase (N-Smase), for example. A natural inhibitor of sphingomylinase is known. It is scyphostatin (
FIG. 1
) which could be isolated from
Trichopeziza mollissima
in 1997 for the first time
1,2
. However, this inhibitor can har

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