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  Methods for treating atherosclerosisUSPTO Application #: 20080096900Title: Methods for treating atherosclerosis Abstract: The invention provides compounds, pharmaceutical compositions and methods for treating atherosclerosis, inflammation, thrombosis and other conditions and for decreasing or prevention of accumulation of cholesterol in a subject by modifying LCAT polypeptide. (end of abstract) Agent: Amgen Inc. - South San Francisco, CA, US Inventors: Frank Kayser, Marc LaBelle, Bei Shan, Jian Zhang, Mingyue Zhou USPTO Applicaton #: 20080096900 - Class: 514255050 (USPTO) Related Patent Categories: Drug, Bio-affecting And Body Treating Compositions, Designated Organic Active Ingredient Containing (doai), Heterocyclic Carbon Compounds Containing A Hetero Ring Having Chalcogen (i.e., O,s,se Or Te) Or Nitrogen As The Only Ring Hetero Atoms Doai, Hetero Ring Is Six-membered Consisting Of Two Nitrogens And Four Carbon Atoms (e.g., Pyridazines, Etc.), 1,4-diazine As One Of The Cyclos, Additional Hetero Ring Attached Directly Or Indirectly To The 1,4-diazine Ring By Nonionic Bonding The Patent Description & Claims data below is from USPTO Patent Application 20080096900. Brief Patent Description - Full Patent Description - Patent Application Claims
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS [0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 60/816,415, filed on Jun. 26, 2006. FIELD OF THE INVENTION [0002] This invention relates generally to the field of medicine and, more specifically, to compositions and methods for treating coronary heart disease and atherosclerosis. BACKGROUND OF THE INVENTION [0003] Over 50 million Americans have cardiovascular problems, and many other countries face high and increasing rates of cardiovascular disease. It is the number one cause of death and disability in the United States and most European countries. By the time that heart problems are detected, the underlying cause, atherosclerosis, is usually quite advanced, having progressed for decades. [0004] Atherosclerosis is a polygenic complex disease of mammals characterized by the deposits or plaques of lipids and other blood derivatives in the arterial walls (aorta, coronary arteries, carotid). These plaques can be calcified to a greater or lesser extent according to the progression of the process. They are also associated with the accumulation of fatty deposits consisting mainly of cholesterol esters in the arteries. Cholesterol accumulates in the foam cells of the arterial wall, thereby narrowing the lumen and decreasing the flow of blood. This is accompanied by a thickening of the arterial wall, with hypertrophy of the smooth muscle, the appearance of foam cells and the accumulation of the fibrous tissue. Hypercholesterolemia can therefore result in very serious cardiovascular pathologies such as infarction, peripheral vascular disease, stroke, sudden death, cardiac decompensation, cerebral vascular accidents and the like. [0005] The cholesterol is carried in the blood by various lipoproteins including the low-density lipoproteins (LDL) and the high-density lipoproteins (HDL). The LDL is synthesized in the liver and makes it possible to supply the peripheral tissues with cholesterol. In contrast, the HDL captures cholesterol molecules from the peripheral tissues and transports them to the liver where they are converted to bile acids and excreted. The development of atherosclerosis and the risk of coronary heart disease (CHD) inversely correlate to the levels of HDL in the serum. Gordon et al. (1989) N. Engl. J. Med. 321: 1311; Goldbourt et al. (1997) Thromb Vasc. Biol. 17: 107. Low HDL cholesterols often occur in the context of central obesity, diabetes and other features of the metabolic syndrome. Goldbourt et al., supra. It has been suggested that low HDL cholesterol levels are associated with an increased risk of CHD, while high concentrations of HDL have a protective effect against the development of premature atherosclerosis. Gordon et al. (1986) Circulation 74: 1217. Studies demonstrated that the risk for developing clinical atherosclerosis in men drops 3% with a 1% increase in the concentration of HDL in plasma. Gordon et al. (1989) N. Engl. J. Med. 321: 1311. It has been established that concentrations of LDL cholesterol can be reduced by treatment with statins, inhibitors of the cholesterols biosynthesis enzyme 3-hydroxyl-3-methylglutary Coenzyme A reductase and thereby this treatment has been used as a successful approach for reducing the risk for atherosclerosis where the primary indication is high LDL level. However, it remains unclear whether statins are beneficial for patients whose primary lipid abnormality is low HDL cholesterol. [0006] Lecithin-cholesterol acyltransferase (LCAT) is an enzyme which catalyzes the esterification of free cholesterol by the transfer of an acyl group from phosphatidylcholine onto 3-hydroxyl group of the cholesterol, forming cholesteryl ester and lysophosphatidylcholine. McLean et al. (1986) Proc. Natl. Acad. Sci. 83: 2335 and McLean et al. (1986) Nucleic Acids Res. 14(23): 9397. LCAT is synthesized in the liver and released into the plasma, where it is combined with HDL, called anti-atherogenic lipoproteins. These HDL particles have the capacity to accept the excess cholesterol, which is then esterified by LCAT. The cholesteryl ester molecules in the HDL particles are either transported to the liver directly through SR-BI receptor, or transferred to apoB-containing lipoproteins, including very low density lipoproteins (VLDL) and LDL, mediated by CETP, and then transported to the liver through LDL-receptor pathway. This mechanism, called reverse cholesterol transport (Glomset (1968) J. Lipid Res. 9:155), allows the removal of excess cholesterol from the body, and therefore is involved in the prevention of atherogenesis. LCAT plays a significant role in this process by creating a gradient of free cholesterol between the plasma membranes and the circulating lipoproteins. [0007] This invention provides compositions comprising LCAT modified to increase enzymatic activity and/or stability and methods for treatment and prevention of atherosclerosis, CHD, and other conditions, including inflammation, thrombosis, and disorders associated with these conditions using the compounds and compositions of the invention. SUMMARY OF THE INVENTION [0008] The present invention provides methods for treating atherosclerosis in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a compound of Formula I wherein all substituents are as indicated in Detailed Description below, or a pharmaceutically acceptable salts thereof. In one aspect, the invention provides methods for treating atherosclerosis in a subject wherein X and Y are each --N.dbd.. In another aspect, Z can be --S--. In a further aspect, L can be --S--. In one aspect, R.sup.1 can be CN. In another aspect, R.sup.2 can be SR.sup.3. In one aspect, R.sup.3 can be C.sub.1-C.sub.4 alkyl, for example, methyl. [0009] In one aspect, the invention provides methods for treating atherosclerosis, inflammation, thrombosis, and conditions associated with these disorders in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a compound selected from the group consisting of 3-(5-(methylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(ethylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(allylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(propylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(butylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(isobutylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(pentylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(dodecylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(benzylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-mercapto-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-(isopropylthio)-4-methyl-4H-1,2,4-triazol-3-ylthio)pyrazine-2-carbon- itrile, 3-(5-(methylthio)-1,2,4-thiadiazol-3-ylthio)pyrazine-2-carbonitril- e, 3-(5-methyl-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(5-butyl-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile, 3-(4-methyl-4H-1,2,4-triazol-3-ylthio)pyrazine-2-carbonitrile, 3-(1-methyl-1H-imidazol-2-ylthio)pyrazine-2-carbonitrile, and 2-chloro-3-(5-(methylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine or a pharmaceutically acceptable salt thereof. [0010] The invention further provides methods for treating atherosclerosis, inflammation, thrombosis, and conditions associated with these disorders in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile. [0011] In one aspect, the modified LCAT can be administered intravenously, for example, by bolus. [0012] The invention provides methods for treating an LCAT-mediated disease comprising administering to a subject in need thereof an effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile. In one aspect, the LCAT-mediated disease can be atherosclerosis, thrombosis, coronary heart disease, high blood pressure, LCAT deficiency syndrome, Alzheimer's disease, corneal opacity, metabolic syndrome, dyslipidemia, myocardial infarction, stroke, critical limb ischemia or angina, inflammation, and conditions associated with these disorders. [0013] The invention further provides methods for increasing HDL cholesterol in a subject comprising administering to the subject in need thereof a therapeutically effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile. In one aspect, the invention provides methods for preventing accumulation of cholesterol in a subject comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile, and a pharmaceutically acceptable carrier or excipient. [0014] The invention provides a pharmaceutical composition comprising a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile, and a pharmaceutically acceptable carrier. [0015] In one aspect, the subject can be mammalian. In another aspect, the subject can be human. BRIEF DESCRIPTION OF THE DRAWINGS [0016] FIG. 1 schematically represents sequences of human (A, SEQ ID NO:1), mouse (B, SEQ ID NO:2), rat (C, SEQ ID NO:3), and consensus LCAT polypeptide (D, SEQ ID NO:4). [0017] FIG. 2(A) demonstrates activity and specificity of the compounds of the invention on LCAT enzyme. [0018] FIG. 2(B) illustrates the mechanism of action of compounds of the invention on LCAT enzyme. [0019] FIG. 3 summarizes data showing that compounds of the invention increase LCAT enzyme activity in a dose dependent manner in BALB/c mice. Continue reading... Full patent description for Methods for treating atherosclerosis Brief Patent Description - Full Patent Description - Patent Application Claims Click on the above for other options relating to this Methods for treating atherosclerosis patent application. ###  How KEYWORD MONITOR works... a FREE service from FreshPatents1. Sign up (takes 30 seconds). 2. Fill in the keywords to be monitored. 3. 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