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Nuclear sulfated oxysterol, potent regulator of cholesterol homeostasis, for therapy of hypercholesterolemia, hyperlipidemia, and atherosclerosis

a technology of sulfated oxysterol and sulfated oxysterol, which is applied in the field of lipid-lowering therapies, can solve the problems of 35% of patients with hypercholesterolemia, death or severe disability via heart attacks and/or stroke, and achieves the effects of increasing cholesterol degradation, potent cholesterol-lowering properties, and increasing cholesterol secretion and degradation

Inactive Publication Date: 2007-11-29
THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPT OF VETERANS AFFAIRS +1
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  • Summary
  • Abstract
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AI Technical Summary

Benefits of technology

[0007] The present invention provides a novel sulfated oxysterol, 5-cholesten-3β, 25-diol 3-sulphate, with potent cholesterol lowering properties. 5-Cholesten-3β, 25-diol 3-sulphate is a nuclear sterol metabolite that increases cholesterol secretion and degradation (bile acid synthesis). The increase in cholesterol degradation and decrease in cholesterol synthesis can lead to lower levels of intracellular and serum cholesterols. Thus, the sulfated oxysterol is useful for preventing or treating diseases associated with elevated cholesterol, such as hypercholesterolemia, hyperlipidemia, gallstone, cholestatic liver disease, and atherosclerosis.
[0011] It is a further object of the invention to provide a method for lowering serum cholesterol and triglyceride levels in a patient in need thereof. The method comprises the step of administering 5-cholesten-3β, 25-diol 3-sulphate to the patient in an amount sufficient to lower serum cholesterol and triglyceride levels in the patient.

Problems solved by technology

High serum cholesterol levels (hypercholesterolemia) are associated with the accumulation of cholesterol in arterial walls, and can result in atherosclerosis.
The plaques that characterize atherosclerosis inhibit blood flow and promote clot formation, and can ultimately cause death or severe disability via heart attacks and / or stroke.
Unfortunately, only about 35% of patients with hypercholesterolemia are responsive to the currently available therapies.

Method used

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  • Nuclear sulfated oxysterol, potent regulator of cholesterol homeostasis, for therapy of hypercholesterolemia, hyperlipidemia, and atherosclerosis
  • Nuclear sulfated oxysterol, potent regulator of cholesterol homeostasis, for therapy of hypercholesterolemia, hyperlipidemia, and atherosclerosis
  • Nuclear sulfated oxysterol, potent regulator of cholesterol homeostasis, for therapy of hypercholesterolemia, hyperlipidemia, and atherosclerosis

Examples

Experimental program
Comparison scheme
Effect test

example 1

REFERENCES FOR EXAMPLE 1

[0078] 1. Russell, D. W. (2003) Annu. Rev. Biochem. 72, 137-174 [0079] 2. Hylemon, P. B., Gurley, E. C., Stravitz, R. T., Litz, J. S., Pandak, W. M., Chiang, J. Y., and Vlahcevic, Z. R. (1992) J. Biol. Chem. 267, 16866-16871 [0080] 3. Chiang, J. Y., Kimmel, R., and Stroup, D. (2001) Gene 262, 257-265 [0081] 4. Saucier, S. E., Kandutsch, A. A., Taylor, F. R., Spencer, T. A., Phirwa, S., and Gayen, A. K. (1985) J. Biol. Chem. 260, 14571-14579 [0082] 5. Schroepfer, G. J., Jr. (2000) Physiol Rev. 80, 361-554 [0083] 6. Szanto, A., Benko, S., Szatmari, I., Balint, B. L., Furtos, I., Ruhl, R., Molnar, S., Csiba, L., Garuti, R., Calandra, S., Larsson, H., Diczfalusy, U., and Nagy, L. (2004) Mol. Cell Biol. 24, 8154-8166 [0084] 7. Dubrac, S., Lear, S. R., Ananthanarayanan, M., Balasubramaniyan, N., Bollineni, J., Shefer, S., Hyogo, H., Cohen, D. E., Blanche, P. J., Krauss, R. M., Batta, A. K., Salen, G., Suchy, F. J., Maeda, N., and Erickson, S. K. (2005) J. Lipid Res...

example 2

Demonstration of Up-Regulation of LXR Targeting Gene Expression

[0114] Preliminary experiments have shown that the purified nuclear oxysterol up-regulates bile acid synthesis. To further investigate the mechanism of this activity, the effect of purified 5-cholesten-3β, 25-diol 3-sulphate on gene expression of LXR-targeted cholesterol transport proteins ABCA1, ABCG1, ABCG5, ABCG8, and LDLR was investigated. Purified nuclear sulfated oxysterol was added to primary hepatocytes in culture, and mRNA levels of the transport proteins were quantitated by real time RT-PCR. The primer sets and TagMan probes for detection of mRNA levels were purchased from AB Applied Biosystem (Foster City, Calif.) and the reactions were performed on an MJ Research DNA Engine Opticon instrument. The results are presented in FIG. 12 and show that the addition of purified nuclear oxysterol to primary hepatocytes in culture increased expression of ABCA1 (2-fold) and ABCG5 (1.6-fold), and ABCG8 (3 fold). The expre...

example 3

Synthesis of 5-cholesten-3β, 25-diol 3-sulphate

[0115]FIG. 12A shows a schematic illustration of the synthesis of the novel sulfated oxysterol of the invention by addition of a sulfate group to the 3β-position of 25-hydroxycholesterol. Synthesis was carried out as follows: A mixture of 25-hydroxycholesterol (0.1 mmol) and sulfur trioxide triethyl amine complex (0.12 mmol) in dry toluene was heated to 60 degree for 24 hours under nitrogen, then cooled and the solvent was evaporated under reduced pressure. The residue was purified by flash chromatography to afford the product as a white solid using the method of described above. FIG. 12B shows the mass spectrophotometric analysis of the HPLC purified product, which suggests that the sulfate group has been successfully added to 25-hydroxycholesterol.

[0116]FIGS. 12C and 12D show NMR data for the starting material, 25-hydroxycholesterol, and product, respectively. As can be seen, the resonance of C3 in the molecule has been shifted from...

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Abstract

The sulfated oxysterol 5-cholesten-3β, 25-diol 3-sulphate, a nuclear steroid metabolite that increases cholesterol secretion and degradation, is provided as an agent to lower intracellular and serum cholesterol and / or triglycerides. Methods which involve the use of this sulfated oxysterol to treat conditions associated with high cholesterol and / or high triglycerides (e.g. hypercholesterolemia, hyperlipidemia, and atherosclerosis) are also provided.

Description

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application is a national stage CIP claiming benefits of the PCT / US2005 / 0338774 filed on Sep. 21, 2005, which in its turn claims priority to U.S. Provisional Application 60 / 621,537 filed on Oct. 25, 2004, both of which are herein incorporated by reference.BACKGROUND OF THE INVENTION [0002] 1. Field of the Invention [0003] The invention generally relates to lipid-lowering therapies. In particular, the invention provides a nuclear steroid metabolite, 5-cholesten-3β, 25-diol 3-sulphate, that increases cholesterol secretion and degradation, and is thus useful for the treatment and prevention of hypercholesterolemia, hyperlipidemia, and atherosclerosis. [0004] 2. Background of the Invention [0005] Cholesterol is used by the body for the manufacture and repair of cell membranes, and the synthesis of steroid hormones and vitamin D, and is transformed to bile acids in the liver. There are both exogenous and endogenous sources of cholestero...

Claims

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Application Information

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IPC IPC(8): A61K31/56C07J9/00
CPCC07J9/00A61K31/575C07J31/006
Inventor REN, SHUNLINPANDAK, WILLIAM M.
Owner THE GOVERNMENT OF THE UNITED STATES OF AMERICA AS REPRESENTED BY THE DEPT OF VETERANS AFFAIRS
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