Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Heterocyclic carbon compounds containing a hetero ring...
Patent
1997-11-24
2000-01-11
Jordan, Kimberly
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Heterocyclic carbon compounds containing a hetero ring...
514824, A61K 3155
Patent
active
060136456
DESCRIPTION:
BRIEF SUMMARY
BACKGROUND OF THE INVENTION
Coronary heart disease (CHD) remains the leading cause of death in the industrialized countries. Despite recent declines in CHD mortality, CHD is still responsible for more than 500,000 deaths in the U.S. annually. It is estimated that CHD, directly and indirectly, costs the U.S. more than $100 billion a year. The primary cause of CHD is atherosclerosis, a disease characterized by the deposition of lipid (cholesterol and triglycerides) in the arterial vessel wall, resulting in a narrowing of the arterial lumen and ultimately hardening of the arteries.
Atherosclerosis as manifested in its major clinical complication, coronary heart disease (CHD) or ischaemic heart disease, continues to be a major cause of death in industrialized countries. It is now well accepted that atherosclerosis can begin with local injury to the arterial endothelium followed by the penetration of circulatory monocytes into the intima of the arterial wall where they become loaded with lipoprotein derived lipids. At about the same time there seems to be a migration of arterial smooth muscle cells from the medial layer to the intimal layer and their proliferation there along with the deposition of lipid and accumulation of foam cells in the lesion. As the atherosclerotic plaque develops it progressively occludes more and more of the affected blood vessel and can eventually lead to ischaemia, thrombosis or infarction. Therefore, it is desirable to provide methods of inhibiting the progression of atherosclerosis in patients in need thereof.
National Institutes of Health Consensus Development Conference Panel concluded that lowering plasma cholesterol levels (specifically blood levels of low-density lipoprotein cholesterol) will definitely reduce the risk of heart attacks due to CHD. Serum lipoproteins are the carriers for lipids in the circulation. They are classified according to their density; i.e., chylomicrons, very low-density lipoproteins (VLDL), intermediate density lipoproteins (IDL), low density lipoproteins (LDL) and high-density lipoproteins (HDL). About 50% to 70% of the cholesterol circulating in the blood is carried as LDL. In contrast, about 25% of total cholesterol is found in HDL, while VLDL carries most of the plasma triglycerides and only about 10% to 15% of the total cholesterol.
Chylomicrons are assembled in the intestinal wall from products of lipid digestion and are then transported into the peripheral circulation via the thoracicolymphatic system. In the circulation, they are broken down by lipoprotein lipase (LPL) into free fatty acids and triglycerides which are primarily used by muscles for energy or stored in adipose tissue. The other serum lipoproteins are involved in the transport of endogenously synthesized lipid. Endogenous lipid transport begins when the liver secretes triglycerides and cholesterol into the plasma as VLDL. The triglycerides of VLDL are cleaved in the capillaries by LPL to IDL and finally LDL. Some of these particles are cleared rapidly by the liver by receptor-mediated endocytosis. The remainder circulate mainly as LDL.
As cells die and cell membranes turn over, cholesterol is continously released into the plasma and becomes HDL. HDL promotes the removal of cholesterol from peripheral cells and facilitates its transport back to the liver.
Arterial wall cholesterol is derived almost exclusively from LDL [Brown and Goldstein, Ann. Rev. Biochem. 52, 223 (1983); Miller, Ann. Rev. Med. 31, 97 (1980)]. Framingham investigators found the higher the levels of LDL, the higher the risk of devloping CHD [Am. J. Med. 80 (Suppl. 2A) 23-32, 1986]. In patients with low levels of LDL, the development of atheroschlerosis is rare [Patton et. al, Clin. Chem. 29, 1890 (1983)]. Accordingly, it is desirable to provide a method for reducing plasma cholesterol in patients with hypercholesterolemia or at risk of developing hypercholesterolemia.
Elevated cholesterol levels are also associated with a number of disease states, including coronary artery disease, angina pectoris, carotid art
REFERENCES:
patent: 3334091 (1967-08-01), Houlihan
patent: 3334095 (1967-08-01), Houluhan
patent: 4080449 (1978-03-01), Croisier et al.
patent: 4320057 (1982-03-01), Freed et al.
patent: 4391752 (1983-07-01), Crossley
patent: 4399136 (1983-08-01), Hassall et al.
patent: 4415496 (1983-11-01), Harris et al.
patent: 4487929 (1984-12-01), Hassall et al.
patent: 4512924 (1985-04-01), Attwood et al.
patent: 4584294 (1986-04-01), Ruyle
patent: 4658024 (1987-04-01), Attwood et al.
patent: 4692438 (1987-09-01), Hassall et al.
patent: 4716232 (1987-12-01), Ternansky
patent: 4734504 (1988-03-01), Holmes
patent: 4734505 (1988-03-01), Holmes
patent: 4762924 (1988-08-01), Hassall et al.
patent: 4772701 (1988-09-01), Attwood et al.
patent: 4782149 (1988-11-01), Lawton et al.
patent: 4785093 (1988-11-01), Hassall et al.
patent: 4808713 (1989-02-01), Attwood et al.
patent: 4824832 (1989-04-01), Flynn et al.
patent: 4826980 (1989-05-01), Hassall et al.
patent: 4902684 (1990-02-01), Floyd et al.
patent: 4973585 (1990-11-01), Flynn et al.
patent: 5208230 (1993-05-01), Flynn et al.
patent: 5238932 (1993-08-01), Flynn et al.
Flynn, et al., J. Am. Chem. Soc. 109, 7914 (1987).
Flynn, et al., Peptide Chemistry (1987); T. Shiba & Sakakibara (ed.), Protein Research Foundation, Osaka (1988).
Flynn, et al., Tetrahedron Letters, vol. 31 (6), 815-88 (1990).
Attwood, et al., J. Chem. Soc. Perkin Trans. I, p. 1011-1019 (1986).
Natoff, et al., Drugs of the Future, vol. 12 (5) : 475-483 (1987).
J. Med. Chem. 1992, 35, 823-832, Timothy D. Ocain et al.
Bioorganic and Medical Chem. Letters Vo. 1, 309, 1991.
Fournie-Zaluski, Marie-Claude et al., J. Med. Chem., 1992 vol. 35, pp. 2473-2481.
Fournie-Zaluski, Marie-Claude et al., J. Med. Chem., 1992 vol. 35, pp. 1259-1266.
French, John F., Jour. of Pharm and Exper. Therapeutics, vol. 268, No. 1, pp. 180-186.
W.H. Parsons et al., Biochemical and Biophysical Research Communications vol. 117, No. 1, 1993 (Nov. 30, 1983).
Kuglyama et al., Circulation "Abstract from the 66th Scientific Sessions" 88(4), 1993, p I-521.
Burkholder, et al. Bioorganic and Medical Chem. Letters, vol. 3, No. 2, pp. 231-234, 1993.
Flynn et al., J. Med. Chem. 1993, 36 2420-2423.
Dage Richard C.
Flynn Gary A.
French John F.
Hoechst Marion Roussel Inc.
Jordan Kimberly
Voelk Eric K.
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