Compositions and methods for modulating serum cholesterol

Details Compositions and methods for modulating serum cholesterol Compositions and methods for modulating serum cholesterol

2000-02-23

2004-03-30

Criares, Theodore J. (Department: 1617)

Drug, bio-affecting and body treating compositions

Enzyme or coenzyme containing

Hydrolases

C514S013800

Reexamination Certificate

active

06713057

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compositions and methods for modulating serum cholesterol. In one aspect, the invention features novel anti-lipemic drugs that include at least one identified effector of the Low Density Lipoprotein (LDL) receptor and at least one identified serum cholesterol inhibitor. In a particular aspect, the anti-lipemic drug includes at a sphingolipid or protein modifying same linked to the serum cholesterol inhibitor. Additionally provided are methods for using the anti-lipemic drugs to significantly stabilize or reduce serum cholesterol levels in a subject mammal and particularly a human patient.
BACKGROUND OF THE INVENTION
There is nearly universal agreement that cholesterol is a key lipid constituent of cell membranes. Cholesterol is generally understood to be essential for normal growth and viability of most higher organisms. Too much serum cholesterol has been correlated with life threatening lipid related diseases including hyperlipoproteinemia, stoke, coronary heart disease, and especially atherosclerosis and related conditions. See generally Stryer, L. (1988) in
Biochemistry
, 3
rd
Ed. W. H. Freeman and Co. New York, pp. 547-574; and Brown, M. S. and Goldstein, J. L. (1993) in
The Pharmacological Basis of Therapeutics
(8
th
Ed.) Gilman, A. G. et al. eds. McGraw-Hill/New York, pp. 874-896.
The regulation of serum cholesterol in mammals and particularly primates has attracted significant attention. It is often reported that regulation of cholesterol homeostasis in humans and other mammals involves regulation of cholesterol production, bile acid biosynthesis and catabolism of specific serum cholesterol carriers. Important serum cholesterol carriers are called LDL (low density lipoprotein) particles. The LDL receptor has been reported to facilitate internalization of the LDL particle into those cells in need of cholesterol. See e.g., Brown, M. S. and Goldstein, J. L. (1986) Science 232: 34-47; and Goldstein, J. L. and Brown, (1986)
Nature,
348: 425; and references cited therein.
The LDL receptor has been disclosed as impacting serum cholesterol levels in humans. For example, there has been recognition that cells with enough cholesterol do not make sufficient LDL receptors, thereby reducing or even blocking uptake of cholesterol by the cell. In this instance, serum cholesterol levels rise substantially which can contribute to the development or severity of disease. Conversely, cells in need of cholesterol often have capacity to make more LDL receptors, thereby facilitating a decrease in serum cholesterol. Accordingly, there has been specific attention focused on regulating the LDL receptor as one therapeutic approach for stabilizing or reducing serum cholesterol levels in human patients.
In particular, it has been reported that transcription of the LDL receptor gene is suppressed when sterols accumulate and induced when sterols are depleted. Sterol sensitivity is thought to be conferred by a 10 basepair (bp) sequence upstream of the LDLr gene known as the sterol regulatory element (SRE). It has been disclosed that the mature form of the sterol regulatory element binding protein-1 (SREBP-1) binds to the SRE and promotes transcription.
There have been additional reports that the activity of SREBP-1 is influenced by sterol induced proteolysis. There is recognition that the SREBP-1 proteolysis is impacted in some settings by a cell receptor termed “cytokine tumor necrosis factor” (TNF-&agr;).
In particular, the TNF-&agr; receptor has been reported to influence a wide range of biological effects. However, the TNF-&agr; receptor remains incompletely characterized. Elucidation of TNF-&agr; pathways is sometimes complicated by presence of at least two TNF receptors. The receptors share some common downstream effectors but also signal via receptor specific pathways. See the references cited below for additional disclosure relating to the TNF-&agr; receptor.
There has been understanding that one consequence of TNF signaling is the activation of neutral sphingomyelinase (N-SMase). Neutral sphingomyelinase is a membrane bound enzyme that catalyzes the hydrolysis of sphingomyelin to ceramide and phosphocholine at a pH optima of 7.4. The role of neutral sphingomyelinase in signal transduction has primarily been related to ability to generate the lipid second messenger ceramide. In addition to TNF-&agr;, Fas receptor ligand, vitamin D
3
, interleukin-1&bgr;, nerve growth factor, anti-CD28 antibodies and &ggr;-interferon have all been shown to increase ceramide levels.
In particular, sphingomyelinases type-C (E.C. 3.1.4.12) are a group of phospholipases that catalyze the hydrolytic cleavage of sphingomyelin via the following reaction (1).
Sphingomyelin→Ceramide+Phosphocholine  (1)
See S. Chatterjee,
Adv. Lipid Res.,
26:25-48 (1993); S. Chatterjee et al.,
J. Biol. Chem.,
264:12,534-12,561 (1989); and S. Chatterjee et al.,
Methods in Enzymology, Phospholipase,
197:540-547 (1991).
In addition to the biological roles of sphingomyelin and ceramide in signal transduction pathways involving cell regulation, more recent evidence has emerged suggesting that sphingomyelinases may be involved in cholesterol homeostasis and particularly induction of LDL receptor activity. See S. Chatterjee,
Advances in Lipid Research,
26:25-48 (1993). Additional work supports a possible role of ceramide in programmed cell death and/or “apoptosis” and activation of the gene for nuclear factor (NF)-kB. See A. Alessenko and S. Chatterjee,
Mol. Cell. Biochem.,
143:169 (1995).
It has been suggested that certain enzymes involved in making cholesterol exert a significant effect on cholesterol homeostasis. Accordingly, there has been substantial interest in identifying drugs with capacity to modulate these enzymes especially to stabilize or reduce serum cholesterol to tolerable ranges. Illustrative agents include commercially available serum cholesterol inhibitors such as fluvastatin, simvastatin, lovastatin, pravastatin, and atorvastatin. See Brown, M. S. and Goldstein, J. L. (1993), supra for additional disclosure relating to these and other agents such as mevinolin (compactin).
Although some clinical benefit has been reported to follow use of these and other serum lowering agents, there have been reports of significant side-effects. See e.g., Brown, M. S. and Goldstein, J. L. (1993), supra; and
Physicians' Desk Reference
1997 (515
st
ed.) Medical Economics Co. Accordingly, there is a need to have drugs that exhibit more desirable characteristics such as enhanced potency and better patient tolerance. There is a specific need to reduce levels of administered cholesterol lowering agents for some patients.
There is also a need to identify drugs that can modulate the SREBP-1 protein and especially the LDL receptor. Moreover, methods for identifying pharmacological drugs of interest by automated, high throughput drug screening have become increasing relied upon in a variety of pharmaceutical and biotechnology drug development programs. Unfortunately, requisite drugs for such high throughput screening assays are not widespread. A significant reason for lack of progress in this area is insufficient understanding of molecules (i.e. effectors) that impact SREBP-1 and the LDL receptor.
It thus would be desirable to have anti-lipemic drugs with dual capacity to modulate the LDL receptor and serum cholesterol levels. It would be particularly desirable if such anti-lipemic drugs could be administered to subject mammal at doses near or below those presently used with many serum cholesterol inhibitors. It would be further desirable to have effective in vitro and in vivo assays for identifying drugs with potential to modulate the LDL receptor particularly involving SREBP-1 protein maturation.
SUMMARY OF THE INVENTION
The present invention generally relates to compositions and methods for modulating serum cholesterol in a subject mammal. In one aspect, the invention features novel anti-lipemic drugs that include at least one identified effector of t

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