Nuclear sulfated oxysterol, potent regulator of lipid homeostasis, for therapy of hypercholesterolemia, hypertriglycerides, fatty liver diseases, and atherosclerosis
Inventors
Ren, Shunlin • Pandak, William M.
Assignees
Virginia Commonwealth University • US Department of Veterans Affairs
Publication Number
US-10144759-B2
Publication Date
2018-12-04
Expiration Date
2025-09-21
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Abstract
The sulfated oxysterol 5-cholesten-3β, 25-diol 3-sulphate, a nuclear cholesterol metabolite that decreases lipid biosynthesis and increases cholesterol secretion and degradation, is provided as an agent to lower intracellular and serum cholesterol and/or triglycerides, and to prevent or treat lipid accumulation-associated inflammation and conditions associated with such inflammation. Methods which involve the use of this sulfated oxysterol to treat conditions associated with high cholesterol and/or high triglycerides and/or inflammation (e.g. hypercholesterolemia, hypertriglyceridemia, non-alcoholic fatty liver diseases, atherosclerosis, etc.) are also provided.
Core Innovation
The invention provides the nuclear cholesterol metabolite 5-cholesten-3β, 25-diol 3-sulphate (25HC3S), a novel sulfated oxysterol that decreases lipid biosynthesis while increasing cholesterol secretion and degradation. This oxysterol is a potent serum lipid-lowering agent, effective in reducing intracellular and serum cholesterol and triglyceride levels. It also prevents or treats lipid accumulation-related inflammation, offering therapeutic uses for hypercholesterolemia, hypertriglyceridemia, non-alcoholic fatty liver diseases (NAFLD), atherosclerosis, and related conditions.
The problem addressed involves the limitations of existing lipid-lowering therapies, of which only about 35% of patients respond effectively. High serum lipid levels contribute to conditions such as arterial plaque formation, NAFLD, and atherosclerosis, which can lead to severe health consequences including heart attack, stroke, liver failure, and cancer. Furthermore, the progression of NAFLD to nonalcoholic steatohepatitis (NASH) is difficult to treat, highlighting the need for novel agents that reduce intracellular and serum lipids and inhibit inflammation associated with lipid accumulation.
The invention also delineates that 5-cholesten-3β, 25-diol 3-sulphate is biosynthesized via hydroxylation and sulfation of cholesterol, presumably in mitochondria, and subsequently translocates to the nucleus to regulate gene expression related to cholesterol and triglyceride metabolism. This nuclear oxysterol acts by down-regulating lipid biosynthesis genes and up-regulating genes involved in cholesterol secretion and degradation, thereby reducing lipid accumulation and inflammatory responses. Consequently, the compound serves as a new class of medication for metabolic diseases involving lipid dysregulation and inflammation, achieving effects via antagonism of liver oxysterol receptor (LXR) pathways and activation of peroxisome proliferation activator receptor gamma (PPARγ) signaling.
Claims Coverage
The patent includes multiple claims focusing on the compound 5-cholesten-3β, 25-diol 3-sulphate and its pharmaceutically acceptable salts, as well as methods of synthesis.
Provision of pharmaceutically acceptable salts of the novel sulfated oxysterol
The claims include compounds of the formula representing 5-cholesten-3β, 25-diol 3-sulphate and their pharmaceutically acceptable salts, particularly sodium salts, provided in substantially purified forms and in powder form, free from other chemical species by at least 80%, preferably more than 90 and up to 95%.
Method of synthesis of 5-cholesten-3β, 25-diol 3-sulphate
The method involves sulfating 25-hydroxycholesterol at the 3β position by mixing it with sulfur trioxide triethyl amine complex and incubating under conditions facilitating sulfation, followed by purification by flash chromatography and/or high performance liquid chromatography (HPLC).
The claims cover both the chemical entities of the novel sulfated oxysterol and its salts in highly purified forms, as well as methods for its preparation by chemical sulfation and purification, encompassing the principal aspects of the invention related to composition and synthesis.
Stated Advantages
The sulfated oxysterol effectively decreases intracellular and serum lipid levels, including cholesterol and triglycerides.
It increases cholesterol secretion and degradation leading to improved lipid homeostasis.
The compound suppresses inflammatory responses caused by lipid accumulation by activating PPARγ and inhibiting pro-inflammatory signaling pathways.
It is a naturally occurring compound biosynthesized in vivo, therefore expected to have few or no toxic side effects.
It may serve as a novel therapy for lipid-associated diseases such as hypercholesterolemia, hypertriglyceridemia, atherosclerosis, nonalcoholic fatty liver disease, and related inflammatory conditions.
Documented Applications
Treatment and prevention of hypercholesterolemia, hypertriglyceridemia, hyperlipidemia, atherosclerosis, gallstones, and cholestatic liver disease.
Prevention and treatment of non-alcoholic fatty liver diseases including fatty liver and nonalcoholic steatohepatitis (NASH).
Treatment or prevention of inflammation caused or exacerbated by lipid accumulation, including inflammatory diseases such as atherosclerosis and type 2 adult onset diabetes.
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