MX2007000571A - Apolipoprotein a1 mimetics and uses thereof - Google Patents

Abstract

The present invention provides peptidomimetics derived from Apolipoprotein A-I, which is useful for beneficially influencing lipid parameters and/or plasma cholesterol levels. The invention also provides pharmaceutical compositions and methods of treatment for elevated levels of plasma cholesterol.

Description

APOLIPOPROTEIN IMITATORS TO AND USES OF THE SAME FIELD OF THE INVENTION The present invention provides peptidomimetics derived from apolipoprotein AI, which are useful for beneficially influencing lipid parameters and / or plasma cholesterol levels. The invention also provides pharmaceutical compositions and methods of treatment for elevated plasma cholesterol levels.

BACKGROUND OF THE INVENTION Vascular diseases, such as cardiovascular, peripheral vascular and cerebro-vascular diseases, which are related to or arising from lipid disorders, are a leading cause of death and disability in developed countries, particularly afflicting older adults. These diseases are an important cause of death in developed countries, including the United States of America, in which cardiovascular diseases are the cause of almost one million fatalities each year, more than half of all deaths; almost 5 million people are hospitalized every year afflicted with cardiovascular disease. Arteriosclerosis refers to any group of diseases that are characterized by thickening and loss of elasticity in the arterial walls. Of these diseases, atherosclerosis, the most common form of vascular disease, and coronary artery diseases have the most significant impact. Normally, the inner surface of the blood vessel is relatively smooth, which allows the easy passage of blood. In atherosclerosis, a common form of vascular disease, deposits of yellowish plaques (atheromas) are formed that contain cholesterol, fatty material, calcium, and lipid-filled macrophages within the intima and inner media of large and medium-sized arteries. The plaque causes blockage of the blood vessel, which facilitates the formation of clots and leads to an insufficient supply of blood to critical bodily organs, which results in organ failure including heart attack, stroke, or kidney failure, and causes hypertension. Atherosclerosis is the underlying cause of most coronary artery diseases. The very early stage of the development of atherosclerotic lesions (the fat band) involves the entry of monocytes into sub-endothelial regions of the blood vessels. At the same time, low density lipoprotein ("LDL") cholesterol is retained in the sub-endothelial regions and is oxidized, which causes these monocytes, now differentiated as macrophages, to absorb the modified LDL in oxidative form, and fix locally Said macrophages, or foam cells, increase in size and their subsequent death and the secretion of fibrous elements from the vascular smooth muscle cells ("VSMC") contribute to plaque formation. Atherosclerosis can be considered a hyperproliferative disease, in which some of the normal VSMCs in the arterial wall become abnormally proliferative, and concurrently invade and spread into the lining of the blood vessel, blocking blood flow and causing said blood vessel is abnormally susceptible to being completely blocked by local blood clots. Said complete blockage can result in the death of the tissue supplied by said artery. Although the elevation of the LDL level is usually undesirable and is considered as harmful to one's health, it is considered that the elevation of the HDL level is protective against atherosclerosis. HDL cholesterol is often referred to as "good" cholesterol because the negative association between the concentration of HDL in serum and coronary heart disease is at least as strong as the positive association between low density lipoprotein (LDL) and coronary heart disease. Apo-lipoproteins A-I ("Apo A-I") and A2 are the main constituents of HDL apoprotein, and have been considered as anti-atherogenic because of their ability to transport cholesterol from the arteries to the liver for catabolism and expression. See Furchart, J. and Ailhaud, G. (1992) Clin. Chem. 38: 793-797. Atherosclerosis treatment includes management and reduction of LDL cholesterol using drugs that are designed to inhibit cholesterol synthesis such as HMG-CoA reductase inhibitors (statins), nicotinic acid, bile salt sequestrants, or fibric acid derivatives. However, these pharmaceutical agents are not without significant side effects. It is known that statins show varying degrees of myotoxicity (Rosenson, (2004) Am. J. Med. 116 (6): 408-16), and nicotinic acid commonly induces vasodilatory effects. Fibrates are associated with a number of adverse effects, including elevations of liver enzymes, gastrointestinal side effects and rhabdomyolysis (Muscari et al. (2002) Cardiology 97 (3): 115-21). Several amphipathic helical peptide analogues Class A Apo A-I, which are obtained from the eight repetitive tandem 22-mer sequences of Apo A-I, (mimicking peptides of Apo A-I) have been shown to be effective against atherosclerotic development. It is believed that the C-terminal portion of Apo A-I (residues 193 to 243) is actively involved in protein-lipid interactions. Apo A-I mimic peptides increase the ability of high density lipoprotein (HDL) to protect low density lipoprotein (LDL) against oxidation and to eliminate seed molecules from LDL. However, it is not clearly understood whether the Apo A-I mimic peptides protect LDL against oxidation independently or not from HDL mediated mechanisms. Such peptides are usually rapidly degraded in vivo. It has previously been shown that L-4F, a mimic peptide containing 18 L-amino acids, and its D-amino acid analog D-4F, blocks the oxidation of LDL and the monocyte chemotactic activity induced by LDL. Likewise, it has been demonstrated that D-4F is stable after oral administration, which results in almost 80% reduction of atherosclerotic lesions in mice lacking LDL receptor. Navab et al., (2002) Circulation 105: 290-292. L-4F and D-4F have a primary amino acid sequence Ac-D- -F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F-NH2, (SEQ ID N0: 1). The 18-mer has the potential to form a helical amphipathic class A structure (Segrest et al. (1974) FEBS Lett.38: 247-253). L-4F inhibits the oxidation of LDL and phospholipid through mechanisms independent of HDL-mediated processes. However, there remains a need for improved pharmaceutical agents to treat, prevent, or alter the progression of vascular disorders having a lipid-based etiology, such as atherosclerosis, and in general for dyslipidemia, high cholesterol levels or reduced levels. of HDL.

SUMMARY OF THE INVENTION The present invention provides peptidomimetics of peptides obtained from apolipoprotein A-I ("Apo A-I"), which are useful for beneficially influencing plasma cholesterol levels and vascular diseases, for example by altering lipid parameters. In some embodiments, the peptidomimetic has a three-dimensional conformation substantially similar to that of a peptide comprising a D-amino acid sequence F-A-E-K-F-K-E-A-V-K-D-Y-F-A-K-F-W-D (SEQ ID NO: 3). The compounds of the present invention can conveniently be administered prophylactically to a patient at risk of, or who presents the symptoms of vascular diseases of lipid etiology such as atherosclerosis, hypercholesterolemia, hyperlipidemia, PAD, CHD and cerebrovascular diseases. The compounds of the present invention are peptidomimetics, in particular amino acid polymers in a retro-inverso configuration. The invention includes the use of peptidomimetics described herein as research tools, such as in the determination of the anti-atherosclerotic potential of other compounds, in the investigation of lipoprotein-receptor interactions in animals and animal models, and to clarify the mechanisms of the lipid metabolism, including identifying animal models for studies of lipid metabolism. The invention also includes the use of peptidomimetics described in medicine. In addition, the invention includes the use of the peptidomimetics described therein in the manufacture of a medicament for treating a disease or condition described therein.

BRIEF DESCRIPTION OF THE FIGURES Figure 1 shows the peptides and peptidomimetics obtained from Apo A-I. Figures 2A-D show the elution profiles of phospholipid and protein or peptide labeled with 14C. Figures 3A and B show the ability of lipid-bound peptides and Apo A-I to promote the release of SR-BI-dependent cholesterol. Figures 4A and B show the ability of lipid-free peptides and Apo A-I to promote the discharge of ABCA1-dependent cholesterol. Figure 5 shows that the peptidomimetics L-4F, D-4F and Rev D4-F inhibit lipid peroxidation caused by endothelial cells. Figure 6 shows that the peptidomimetics L-4F, D-4F and Rev D4-F inhibit lipid peroxidation caused by copper sulfate. Figure 7 shows that the peptidomimetics L-4F, D-4F and Rev D4-F inhibit the expression of MCP-1 mRNA in endothelial cells.

DETAILED DESCRIPTION OF THE INVENTION I. Generalities There is a strong correlation between vascular conditions and abnormal lipid parameters, such as high cholesterol levels, especially LDL cholesterol in the blood and in the cardiovascular system in general and HDL decreased. It is considered that beneficially altering the lipid parameters to control the amounts of cholesterol within circulating blood as well as in local foci is effective in reducing the occurrence of atherosclerosis and the subsequent morbidity. The present invention provides apolipoprotein A-I peptidomimetics, which are useful for altering lipid parameters to beneficially influence plasma cholesterol levels. The present invention is directed in general terms to methods and compositions for the treatment of abnormally elevated cholesterol levels in the cardiovascular system.

II. Definitions The term "amino acid residue" is known in the art. In general, the abbreviations used in the present invention to designate amino acids and protecting groups are based on the recommendations of the Commission on Chemical Nomenclature of the IUPAC-IUB (see Biochemistry (1972) 11: 1726-1732). In some embodiments, the amino acids used in the application of this invention are those amino acids of natural origin found in proteins, or the anabolic or catabolics of natural origin of said amino acids which contain amino and carboxyl groups. Particularly appropriate amino acid side chains include side chains which are selected from the following amino acids: glycine, alanine, valine, cysteine, leucine, isoleucine, serine, threonine, methionine, glutamic acid, aspartic acid, glutamine, asparagine, lysine, Arginine, proline, histidine, phenylalanine, tyrosine, and tryptophan. The term "amino acid residue" also includes analogs, derivatives and congeners of any specific amino acid referred to in the present invention, as well as amino acid derivatives protected at the C-terminal or N-terminal ends (eg modified with a N-terminal or C-terminal protective group) for example, the present invention contemplates the use of amino acid analogs in which a side chain is lengthened or shortened as long as it continues to provide a carboxyl, amino or other reactive precursor functional group for cyclization, as well as amino acid analogs having variant side chains with appropriate functional groups. For example, the present compound can include an amino acid analog such as, for example, cyanoalanine, canavanine, djenkolic acid, norleucine, 3-phosphoserine, homoserine, dihydroxy, phenylalanine, 5-hydroxytryptophan, 1-methylhistidine, 3-methylhistidine, diaminopimelic acid, ornithine, or diaminobutyric acid. Other metabolites or amino acid precursors present in nature having side chains that are suitable in the present invention will be recognized by those skilled in the art and are included in the field of the present invention. As used in the present invention, the terms "agent" and "compound" include both protein and non-protein portions. An agent can be a small organic molecule, a polypeptide, a protein, a peptide complex, a peptidomimetic, a non-peptidyl type agent, or a polynucleotide. As used in the present invention, "reduce" means to alleviate, lessen, or decrease the degree of a symptom or reduce the number of occurrences of episodes of manifestation of a disease. "Apoproteins" are specialized proteins in the outer coat of lipoproteins. Although different apoproteins are found in varying amounts in lipoproteins, they all play a crucial role in lipoprotein metabolism. Some apoproteins in the lipoprotein particle interact with specific cell surface receptors, while others activate or deactivate the enzymes involved in the metabolism of lipids. Ten major apoproteins have been isolated and characterized, which are synthesized and secreted by the liver and intestine. Some lipoproteins comprise a certain kind of particle. For example, apolipoprotein ("APO") B-100 is associated with VLDL, IDL, and LDL, while Apo A is associated with HDL. Apo B-100 helps remove cholesterol from the blood and Apo A helps HDL remove cholesterol from the tissues. Apo A-I is the main HDL apoprotein and is required for the normal production of HDL. The precursor of most plasma HDL is a discoidal particle that contains Apo A-I and phospholipids called HDL pre-β. HDL pre-ß? discoidal can acquire free (non-esterified) cholesterol from the cell membranes of tissues, such as the macrophages of the arterial wall interacting with the type I class B purifying receptor, to which HDL Apo AI binds free cholesterol to or from the HDL particle. After free cholesterol is acquired by HDL pre-β ?, it is esterified, depolarized and moved to the HDL core. It is believed that "atherosclerosis" begins with an injury to the inner wall of the artery (endothelium or endothelial cells). Once the inner wall is damaged, a combination of biological processes can lead to plaque buildup. In response to the injury, the Macrophages accumulate in the site and migrate beneath the inner layer. The macrophages then begin to absorb fatty substances from the blood and become foam cells. An accumulation of foam cells and other substances, such as proliferating smooth muscle cells, contribute to the formation of plaque and over time form protuberances in the arterial wall. Over time, as the bumps continue to absorb fatty substances, the buildup of plaque narrows the lumen of the blood vessel and obstructs blood flow. In addition, the buildup of plaque can cause the walls of the blood vessel to harden and lose their elasticity, which can increase resistance to blood flow and raise blood pressure. As a result, vascular diseases are considered a progressive disease with symptoms that are often not evident until people reach a middle age or advanced age. The accumulating plaque causes blockage of the blood vessel, which facilitates the formation of clots and leads to an insufficient supply of blood to the critical bodily organs, which results in a reduced supply of oxygen and nutrients, resulting in failure of the organs including heart attack, stroke, or kidney failure, and causes hypertension.

When atherosclerosis occurs in the coronary arteries (coronary artery disease (CAD) or coronary heart disease (CHD)) the condition can result in deprivation of oxygen to the heart which leads to conditions such as cardiac ischemia, angina pectoris, myocardial infarction, arrhythmias and eventually a heart attack, an important cause of morbidity and mortality in recent years. When atherosclerosis occurs in the peripheral arteries (peripheral artery disease (PAD)), the condition can result in oxygen deprivation of the leg muscles leading to reduced motility and eventually loss of motility. The term "ED50" means the dose of a drug that produces 50% of its response or maximum effect. An "effective amount" of, for example, a peptidomimetic, with respect to the present method of treatment, refers to an amount of the peptidomimetic in a preparation which, when applied as part of a desired dosage regimen, inhibits or produces, by example, prevents or produces change in the rate or number of formation of atherosclerotic lesion in accordance with clinically acceptable standards for the disorder to be treated or the desired effect. The term "health care providers" refers to individuals or organizations that provide health care services to a person, community, etc. Examples of "health care providers" include doctors, hospitals, retirement communities for continuous care, skilled nursing facilities, sub-acute care facilities, clinics, multiple specialty clinics, independent outpatient centers, care agencies health at home, and HMO. As used in the present invention, "inhibits" means that the amount is reduced compared to the amount that would be present in a control sample. In a preferred embodiment, inhibit means that the amount is reduced by more than 50%, even more preferred by more than 75% or even 100%. As used in the present invention, "instructional material" means a document or recorded media that includes a written or audible instruction for the use of a pharmaceutical composition. An instructional material includes a tag in a bottle, a paper inserted in a box, printed on the box or cardboard, instructions provided by a web site to a given address in any of said locations, etc. The term "LD50" means the dose of a drug that is lethal in 50% of the test individuals. "Lipids" are fatty substances that are insoluble in water and include fats, oils, waxes, and related compounds. These can be elaborated in the blood (endogenous) or ingested in the diet (exogenous). Lipids are essential for normal body function and whether they are produced from an exogenous source or an endogenous source, they must be transported and then released for use by the cells. The production, transport and release of lipids to be used by cells is known as lipid metabolism. Although there are several classes of lipids, two main classes are cholesterol and triglycerides. Cholesterol can be ingested in the diet and can be manufactured by the cells of most organs and tissues in the body, mainly in the liver. Cholesterol can be found in free form, or more frequently, combined with fatty acids in what are called cholesterol esters. Because of their insolubility in water, lipids, such as cholesterol, can not be transported in the blood until they are packed in special molecules called lipoproteins. Therefore, cholesterol circulates in the bloodstream as particles associated with lipoproteins. "Lipoproteins" are spherical compounds that are structured in such a way that lipids insoluble in water are contained in a partially water soluble coating. Depending on the type of lipoprotein, the contents include variable amounts of free and esterified cholesterol, triglycerides and apoproteins or apolipoproteins. There are five main types of lipoproteins, which differ in function and in their lipid and apoprotein content and are classified according to their increasing density: (i) chylomicrons and remnants of chylomicron, (ii) very low density lipoproteins ("VLDL") "), (iii) intermediate density lipoproteins (" IDL "), (iv) low density lipoproteins (" LDL "), and (v) high density lipoproteins (" HDL "). Cholesterol circulates in the bloodstream as particles associated with lipoproteins. LDL becomes atherogenic when modified by oxidation, a step required for LDL uptake by macrophage scavenging receptors in plaque accumulation, which leads to the formation of foam cells. The Class A amphipathic domain of Apo A-I in mimic peptides is responsible for its property of association with lipids. The Apo A-I mimic peptides of the invention generally alter the LDL lipid parameter by removing the phospholipid seed molecules in LDL, which causes LDL molecules are resistant to oxidation by endothelial cells. further, it is believed that the Apo A-I mimic peptides of the invention frequently alter the lipid parameter of HDL by converting pro-inflammatory HDL into anti-inflammatory HDL by removing the oxidized cholesterol from HDL. The exogenous pathway for lipid metabolism describes the process by which triglycerides and cholesterol ingested in the diet are transported by the chylomicrons from the digestive tract into the bloodstream and, after the chylomicrons deliver the triglycerides to the adipocytes and the myocytes, remnants of chylomicron return the remaining cholesterol to the liver for recycling. Specifically, fats in the diet enter the small intestine from the stomach and are dissociated and absorbed in the lining of the small intestine where they are packed into the chylomicrons and enter the bloodstream. Once the chylomicrons enter the bloodstream, most of their triglycerides are released by lipoprotein lipase, an enzyme found in the capillary walls of adipocytes and myocytes. Adipocytes and other peripheral cells use or store most triglycerides. The remnants of chylomicron then pack residual triglycerides and most dietary cholesterol and return to the liver where they are absorbed by the hepatocytes through a specific receptor mechanism mediated by apoproteins and remnants of chylomicron are catabolized into their constituent parts. The liver uses the resulting cholesterol to form bile acids and VLDL. The endogenous pathway for lipid metabolism describes the process by which cholesterol synthesized internally is produced, transported and released. Although all cells can make cholesterol, 70% is synthesized in the liver, therefore, the discussion focuses on the cholesterol synthesized in the liver. Triglycerides synthesized in the liver combine with cholesterol (either synthesized in the liver or supplied by remnants of chylomicron and HDL particles) and lipoprotein to form VLDL, enter the bloodstream and are transported to peripheral cells such as adipocytes and myocytes . Lipoprotein lipase removes most triglycerides, which are used for fuel and storage, from VLDL. After releasing the triglycerides to be used by the cells, VLDL is transformed into IDL, which can be eliminated from the blood by the liver or converted to LDL. LDL has a high cholesterol content and supplies cholesterol to the cells or is eliminated from the blood. Yes There is an excess of cholesterol, this can be absorbed by the cells in the wall of the blood vessel, which leads to atherosclerosis. HDL, made in the liver and small intestine, accepts excess cholesterol from the cells and returns it to the liver to be eliminated from the body. HDL also returns cholesterol to the liver indirectly by transferring cholesterol to VLDL, IDL or LDL. An improvement in "lipid parameters" includes one or more of a decrease in the propensity of lipoproteins to adhere to a blood vessel, a decrease in the amount of atherosclerotic plaque (even when the plasma concentrations of LDL and / or HDL do not have changed significantly), a reduction in the oxidative potential of an HDL or LDL particle, a regression in atherosclerosis (for example, as measured by angiography or ultrasound of the carotid) and a reduction in cardiac events. A "peptidomimetic" includes any modified form of an amino acid chain, such as phosphorylation, end blocking, fatty acid modification, and includes unnatural structures in the base structure and / or side chain. As described below, a peptidomimetic comprises the structural continuity between an amino acid chain and a small molecule of type no. peptide. The peptidomimetics generally retain a recognizable peptide-like polymer structural unit. Therefore, a peptidomimetic can retain the function of binding to any target molecule to which a natural peptide binds. The term "prevent" is recognized in the art, and when used in relation to a condition, such as recurrence or onset of a disease such as hypercholesterolemia, is well understood in the art, and includes administration of a composition that reduces the frequency of, or delaying the onset of, symptoms of a medical condition in an individual in relation to an individual who does not receive the composition. An "individual" or "patient" to be treated by the present method can mean either a human animal or a non-human animal. As used in the present invention, "treating" can mean slowing down, stopping or reversing the progress of the disorder. In a preferred embodiment, "treating" means reversing the advance to the point of eliminating the disorder. As used in the present invention, the term "unwanted cholesterol" means low density lipoprotein ("LDL") cholesterol and / or a mixture of LDL cholesterol and high density lipoprotein cholesterol.

("HDL") that has an HDL / LDL ratio that is undesirable for one's health. The meaning of LDL and HDL is well known in the art. In general, high levels of LDL cholesterol are not desirable (above 180 mg / dl), and a certain amount of HDL cholesterol (above 35 mg / dl) is beneficial for cardiovascular health. In particular, high concentrations of LDL (above 180 mg / dL) and low HDL concentrations (above 35 mg / dL) have been shown to be important contributors to the development of atherosclerosis. Other diseases, such as peripheral vascular disease, stroke, and hypercholesterolemia are also adversely affected by adverse HDL / LDL ratios. It is generally defined that "hypercholesterolemia" has a high level of total cholesterol above 200 mg / dL, especially with the LDL level above 160 mg / dL. This can be an autosomal dominant genetic disease (family hypercholesterolemia). Hypercholesterolemia hinders vasodilation, which leads to hypertension and impaired circulation. Therefore, controlling the levels of each type of lipoproteins is effective and necessary to maintain cardiovascular health. The terms "amine" and "amino" are recognized in the art and refer to both unsubstituted and substituted amines, for example, a portion that can be represent by the general formula: in which Rg, Ri0 and R'io each independently represent a hydrogen, an alkyl, an alkenyl, - (CH2) m-R8, or Rg and Rio taken together with the nitrogen atom to which they are attached complete a heterocycle having 4 to 8 atoms in the ring structure; Re represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a polycycle; and m is zero or an integer in the range of 1 to 8. In preferred embodiments, only one of Rg or Rio can be a carbonyl, for example, Rg, Rio and nitrogen together do not form an imide. In even more preferred embodiments, the term "amine" does not encompass amides, for example, in cases where one of Rg and Rio represents a carbonyl. In still more preferred embodiments, R9 and Rio (and optionally R 'io) each independently represent a hydrogen, an alkyl, an alkenyl, or - (CH2) m-R8- Therefore, the term "alkylamine" "as used in the present invention means an amine group, as defined above, having a substituted or unsubstituted alkyl attached thereto, ie, at least one of R9 and Rio is an alkyl group.

The term "amido" is recognized in the art as a carbonyl substituted with amino and includes a portion that can be represented by the general formula: in which R9, Ri0 are as defined above. Preferred embodiments of the amide do not include imides that may be unstable. The phrase "protecting group" as used in the present invention means temporary substituents that protect a potentially reactive functional group against undesired chemical transformations. Examples of such protecting groups include esters of carboxylic acids, silyl ethers of alcohols, and acetals and ketals of aldehydes and ketones, respectively. The protective group chemistry field has been reviewed (Greene, T.W .; uts, P.G.M, Protective Groups in Organic Synthesis, 2nd edition, Wiley: New York, 1991).

III. Example Modes Compounds Peptidomimetics are compounds based on, or derived from, peptides and proteins. The Peptidomimetics of the present invention typically can be obtained by structural modification of one or more original amino acid residues, for example, using non-natural amino acids, configuration constraints, isothermal replacement, and the like. The present peptidomimetics constitute the continuity of the structural space between peptides and synthetic non-peptidic structures. Said peptidomimetics may have attributes such as being non-hydrolysable. { for example, increased stability against proteases or other physiological conditions that degrade the corresponding peptide copolymers), specificity and / or increased potency. For illustrative purposes, the peptide analogs of the present invention can be generated using, for example, benzodiazepines. { for example, see Freidinger et al. in "Peptides: Chemistry and Biology," G.R. Marshall ed., ESCOM Publisher: Leiden, The Netherlands, 1988), substituted gamma-lactam rings (Garvey et al., In "Peptides: Chemistry and Biology," GR Marshall ed., ESCOM Publisher: Leiden, The Netherlands, 1988, p 123), imitators of C-7 (Huffman et al., in "Peptides: Chemistry and Biology," GR Marshall ed., ESCOM Publisher: Leiden, The Netherlands, 1988, p.105), keto-methylene pseudopeptides (Ewenson et al. (1986) J. Med. Chem. 29: 295; and Ewenson et al. in "Peptides: Structure and Function (Proceedings of the 9th American Peptide Symposium), "Pierce Chemical Co. Rockland, IL, 1985), β-turn dipeptide nuclei (Nagai et al (1985) Tetrahedron Lett 26: 647; and Sato et al. (1986) J. Chem. Soc. Perkin Trans. 1: 1231), ß-aminoalcohols (Gordon et al. (1985) Biochem. Biophys. Res. Commun. 126: 419; and Dann et al. (1986) Biochem. Biophys. Res. Commun. 134: 71), diaminoketones (Natarajan et al. (1984) Biochem. Biophys. Res. Commun. 124: 141), and modified with methyleneamine (Roark et al., in "Peptides: Chemistry and Biology," G.R. Marshall ed., ESCOM Publisher: Leiden, The Netherlands, 1988, p 134). Also, see in general terms, Session III: Analytical and Synthetic Methods, in "Peptides: Chemistry and Biology," G.R. Marshall ed., ESCOM Publisher: Leiden, The Netherlands, 1988). have developed numerous substitutes for amide bonding of the peptides. The most commonly used substitutes for the amide linkage include the following groups (i) trans-olefins, (ii) fluoroalkene, (iii) methyleneamino, (iv) phosphonamides, and (v) sulfonamides.

Amide bond Examples of substitutes Trans-olefin Fluoroalkene Methyleneamino Phosphonamide Sulfonamide Additionally, peptidomimetics based on more substantial modifications of the base structure of a peptide can be used. Peptidomimetics that fall into this category include (i) retro-inverso analogs, and (ii) analogues of N-alkylglycine (so-called peptoids).

Examples of analogs Retro-inverse N-alkylglycine Also, the combination chemistry methods have been applied to the development of peptidomimetic copolymers. For example, one embodiment of a so-called "peptide transformation" strategy focuses on the random generation of a group of peptide analogues comprising a broad range of peptide link substitutes.

Dipeptide In a preferred embodiment of the present invention, the peptidomimetic is a retro-inverso analog. Retro-inverse analogs can be made according to methods known in the art in a manner similar to the synthesis of L-amino acid-based peptides. More specifically, see methods such as those described by Sisto et al. in the patent E.U.A.

No. 4,522,752. The final product, or intermediates thereof, can be purified by HPLC or any other suitable chromatographic method. In another illustrative embodiment, the peptidomimetic can be obtained as a retro-enantio analogue. Retro-enantio analogs such as these can be synthesized from commercially available D-amino acids (or analogs thereof) and standard peptide synthesis techniques in solid phase or in solution. Even in another illustrative embodiment, trans-olefin derivatives can be made. A trans-olefin analog of a peptide can be synthesized according to the method of Y.K. Shue et al. (1987) Tetrahedron Lett. 28: 3225, and also in accordance with other methods known in the art. It will be appreciated that variations in the cited process, or other available methods, may be necessary in accordance with the nature of the reagent used. It is also possible to couple the pseudo-dipeptides synthesized by the above method to other pseudo-dipeptides, to make pseudo-peptides with various olefinic functional groups instead of the amide functional groups. For example, pseudo-peptides corresponding to certain di-peptide sequences can be made and then copulated together using standard techniques to produce an analogue of the peptide having alternating olefinic bonds between the residues. Even another class of peptidomimetic derivatives includes phosphonate derivatives. The synthesis of said phosphonate derivatives can be adapted from known synthesis schemes. See, for example, Loots et al. in "Peptides: Chemistry and Biology," (Escom Science Publishers, Leiden, 1988, p.128); Petrillo et al. in "Peptides: Structure and Function (Proceedings of the 9th American Peptide Symposium)", Pierce Chemical Co. Rockland, IL, 1985). In other embodiments, the modification may be the introduction of carbohydrate or lipid portions. Such modifications also change the solubility of the peptides in various media so that they can be conveniently prepared as an appropriate pharmaceutical composition. The lipid groups that are modified include farnesyl groups and myristoylo groups. The carbohydrate groups that are modified include simple sugars or oligosaccharides of any sugar and sugar alcohols of natural and / or synthetic origin, for example glucose, galactose, rhamnose, mannose, arabinose, and other sugars, and their respective alcohols. The compounds of the present invention comprise at least 15 amino acid residues, and more preferred 18 amino acid residues. In some embodiments, the peptidomimetic of the present invention has a three-dimensional conformation substantially similar to that of a peptide comprising a D-amino acid sequence F-A-E-K-F-K-E-A-V-K-D-Y-F-A-K-F-W-D (SEQ ID NO: 3). In particular modalities, the peptide includes at least one base structure bond other than an amide-type bond in the amino to carboxy direction, such as a retro-inverso peptide relative to a peptide normally present in nature, or at least one bond of base structure that is not an amide type bond. In an exemplary embodiment, the peptidomimetic has at least 75%, at least 80%, at least 85%, at least 90% or at least 95% identity with SEQ ID NO: 3 or SEQ ID NO : 2. Non-identical amino acid residues may be of natural or non-natural origin. The term "percent identity" refers to the sequence identity between two amino acid sequences or between two nucleotide sequences. The identity of each can be determined by comparing a position in each sequence that may be aligned for comparison purposes. When an equivalent position in the compared sequence is occupied by the same base or amino acid, then the molecules are identical in that position; when the equivalent site is occupied by the same amino acid residue or a similar one (for example similar in terms of the steric and / or electronic nature), it can then be said that the molecules are homologous (similar) in said position. Expression as a percentage of homology, similarity, or identity refers to a function of the number of identical or similar amino acids in the positions shared by the sequences compared. Expression as a percentage of homology, similarity, or identity refers to a function of the number of identical or similar amino acids in the positions shared by the sequences compared. Several algorithms and / or alignment programs can be used, including FASTA, BLAST, or ENTREZ. FASTA and BLAST are available as part of the GCG sequence analysis package (University of Wisconsin, Adison, Wisconsin), and can be used with, for example, predetermined parameters. ENTREZ can be obtained through the National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, MD. In one embodiment, the percent identity of two sequences can be determined by the GCG program with a weight per 1 space, for example, each amino acid is weighted as if it were a single non-amino acid or nucleotide pair between the two sequences .

In another example embodiment, which can be overlapped with the modalities described above, the amino acids in the peptidomimetic of SEQ ID NO: 3 or SEQ ID NO: 2 are substituted with conservative amino acid residues. The term "conservative amino acid substitution" refers to the substitution (conceptually or otherwise) of an amino acid of one of said groups with a different amino acid from the same group. A functional way to define the common properties between individual amino acids is to analyze the normalized frequencies of amino acid changes between corresponding proteins of homologous organisms (Schulz, G. E. and R. H. Schirmer., Principies of Protein Structure, Springer-Verlag). According to said analyzes, groups of amino acids can be defined in which the amino acids within a group are exchanged preferentially with each other, and therefore they resemble each other mainly in their impact on the overall structure of the protein. (Schulz, GE and RH Schirmer, Principies of Protein Structure, Springer-Verlag). An example of a set of amino acid groups defined in this manner include: (i) a charged group, consisting of Glu and Asp, Lys, Arg and His, (ii) a positively charged group, consisting of Lys, Arg. and His, (iii) a negatively charged group, consisting of Glu and Asp, (iv) a group aromatic, consisting of Phe, Tyr and Trp, (v) a group with nitrogenated ring, consisting of His and Trp, (vi) a large non-polar aliphatic group, consisting of Val, Leu e lie, (vii) a slightly polar group, consisting of Met and Cys, (viii) a small residue group, consisting of Ser, Thr, Asp, Asn, Gly, Ala, Glu, Gln and Pro, (ix) an aliphatic group consisting of Val, Leu, lie, Met and Cys, and (x) a small hydroxyl group consisting of Ser and Thr. In a preferred embodiment, the peptidomimetic of the present invention is a retro-inverso peptide of the D-amino acid sequence: FAEKFKEAVKDYFAKFWD (SEQ ID NO: 3) in which each letter represents the amino acid code of a conventional letter, but D-amino acid. In a more preferred embodiment, the peptidomimetic of the present invention is a retro-inverso peptide of the D-amino acid sequence: Ac-FAEKFKEAVKDYFAKF- -D-NH2 (I) (SEQ ID NO: 2) wherein each letter represents the amino acid code of a conventional letter, but of the D-amino acid. In other embodiments, the peptidomimetics of the present invention are analogs of (I) in which one or more D-amino acid residues are substituted with other D-amino acids or other non-natural residues they retain, after replacement, the spatial and ionic or non-ionic character of the waste they replace. The peptidomimetics of the present invention, including the retro-inverso peptide of (I), can be modified such that the amino terminal and / or carboxy terminal end are protected with a protecting group such as acetyl, CH3- (CH2) n ~ C0-, amide, Fmoc, t-butoxycarbonyl (t-BOC), 9-fluoren-acetyl group, 1-fluorencarboxylic group, 9-fluoren-carboxylic group, 9-fluorenone-l-carboxyl group, benzyloxycarbonyl, xanthyl group (Xan ), trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulfonyl (tr), mesitylene-2-sulfonyl (Mts), 4, 4 -methoxybenzhydryl (Mbh), tosyl (Cough), 2, 2, 5, 7, 8-pentamethylchroman-6-sulfonyl (Pmc), 4-methylbenzyl (eBzl), 4-methoxybenzyl (MeOBzl), benzyloxy (BzlO), benzyl (Bzl), Benzoyl (Bz), 3-nitro-2-pyridinesulfenyl (Npys), 1- (4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl (Dde), 2,6-dichlorobenzyl (2,6- DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-C1-Z), 2-bromobenzyloxycarbonyl (2-Br-Z), b encyloxymethyl (Bom), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), and trifluoroacetyl (TFA). The variable n is an integer from 0 to 12, typically 0 to 6 such as 0 to 4. In some embodiments, the peptidomimetics of The invention may also comprise modifications analogous to post-translation modifications. Such modifications include, but are not limited to, acetylation, carboxylation, glycosylation, phosphorylation, lipidation, and acylation. As a result, the modified peptidomimetics may contain elements of the non-amino acid type, such as polyethylene glycols, lipids, polysaccharides or monosaccharides, and phosphates. The effects of such non-amino acid-type elements on the functionality of a peptidomimetic can be evaluated using methods such as those described in the working examples.

Therapeutic Compositions Another aspect of the present invention provides pharmaceutical compositions comprising a pharmaceutically effective amount of a peptidomimetic of the present invention and a vehicle and / or acceptable excipients. A pharmaceutically acceptable carrier includes any solvents, dispersion media, or coatings that are physiologically compatible and that preferably do not interfere with or otherwise inhibit the activity of the peptidomimetic. Preferably, the vehicle is suitable for intravenous, intramuscular, oral, intraperitoneal, transdermal, topical, or subcutaneous administration. An example of a vehicle pharmaceutically acceptable is physiological saline solution. Other pharmaceutically acceptable carriers and their formulations are well known and are described in general terms in, for example, Remington's Pharmaceutical Science (18th Ed., Gennaro Publishing House, Co., Easton, PA, 1990). Various pharmaceutically acceptable excipients are well known in the art and can be found in, for example, Handbook of Pharmaceutical Excipients (4th ed., Ed Rowe et al., Pharmaceutical Press, Washington, D.C.). The composition can be formulated as a solution, micro-emulsion, liposome, capsule, tablet, or other appropriate form. The active component can be applied as a coating on a material to protect it against inactivation by the environment before it reaches the target site of action. In some embodiments of the present invention, the pharmaceutical compositions are sustained release formulations. The peptidomimetics of the present invention can be mixed with biologically compatible polymers or matrices that control the rate of release of the copolymers into the immediate environment. Controlled or sustained release compositions include formulation in lipophilic deposits (e.g., fatty acids, waxes, oils). The invention also contemplates compositions in particles coated with polymers (for example, poloxamers or poloxamines). Other embodiments of the compositions of the invention incorporate particulate forms, protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral. Acceptable carriers include carboxymethylcellulose (CMC) and modified CMC. The pharmaceutical composition of the present invention is preferably sterile and non-pyrogenic at the time of delivery, and is preferably stable under the conditions of manufacture and storage. The compound of the present invention can be used in combination, either as separate units or fixed combinations with one or more of the following: an antibody that binds to an undesired inflammatory molecule or cytokine such as interleukin-6, interleukin-8 , granulocyte macrophage colony stimulating factor, and tumor necrosis factor oi; an enzyme inhibitor such as a protease inhibitor aprotinin or a cyclo-oxygenase inhibitor; an antibiotic such as amoxicillin, rifampicin, erythromycin; an antiviral agent such as acyclovir; a spheroidal anti-inflammatory such as a glucocorticoid; a non-steroidal anti-inflammatory such as aspirin, ibuprofen, or acetaminophen; or a non-inflammatory cytokine such as interleukin-4 or interleukin-10 Other cytokines and growth factors such as interferon-ß, tumor necrosis factors, anti-angiogenic factors, erythropoietins, thrombopoietins, interleukins, maturation factors, chemotactic protein, and their variants and derivatives that preserve activities can also be used as an additional ingredient. similar physiological The compound of the present invention can also be used in combination with drugs commonly used to treat lipid disorders in diabetic patients. Such drugs include, but are not limited to, inhibitors of HMG-CoA reductase, nicotinic acid, ezetimide, fibric acid derivatives bile acid sequestrants, MTP inhibitor, ACAT inhibitor and CETP inhibitors. Examples of HMG-CoA reductase inhibitors are lovastatin, pravastatin, simvastatin, rosuvastatin, fluvastatin, and atorvastatin. Examples of bile acid sequestrants are cholestyramine, colestipol and colesevelam. Examples of fibric acid derivatives are: gemfibrozil and fenofibrate. The peptidomimetics of the invention can also be used in combination with anti-hypertensive drugs, such as, for example, diuretics, β-blockers, cathepsin S inhibitors, methyldopa, a2-adrenergic agonists, guanadrel, reserpine, β-adrenergic receptor antagonists, β-adrenergic receptor antagonists, hydralazine, minoxidil, calcium channel blockers, ACE inhibitors, and angiotensin II receptor antagonists. Examples of β-blockers are acebutolol, bisoprolol, esmolol, propranolol, atenolol, labetalol, carvedilol, and metoprolol. Examples of ACE inhibitors are captopril, enalapril, lisinopril, benazepril, fosinopril, ramipril, quinapril, perindopril, trandolapril, and moexipril. The peptidomimetics of the invention can also be used in combination with cardiovascular drugs such as calcium channel blockers, ß-adrenergic receptor agonists and antagonists, aldosterone antagonists, ACE inhibitors, angiotensin II receptor antagonists, nitrovasodilators, and glycosides cardiac The peptidomimetics of the invention can also be used in combination with anti-inflammatory drugs such as Hl receptor antagonists, agonists and antagonists mediated by H2 receptor; COX-2 inhibitors, NSAIDs, salicylates, acetaminophen, propionic acid derivatives, enolic acids, furanones disubstituted with aryl, cyclo-oxygenase inhibitors, and bradykinin agonists and antagonists.

METHOD OF TREATMENT One aspect of the present invention provides methods of treating an individual who exhibits the symptoms of or who is at risk of developing atherosclerosis by administering one or more peptidomimetics of the present invention to the individual in a therapeutically effective amount. In general, one embodiment of the invention is to administer an appropriate dose (e.g., daily dose) of a therapeutic composition that is the lowest effective dose to produce a therapeutic effect, e.g., mitigate symptoms, but consistently provide therapeutically levels effective in vivo. Therapeutic peptidomimetics are preferably administered at a dose per person per day of at least about 2 mg, at least about 5 mg, at least about 10 mg, or at least about 20 mg as appropriate minimum starting doses. In one embodiment of the methods described in the present invention, a dose of about 0.01 to about 500 mg / kg may be administered. In general, the effective dose of the compound of the present invention is from about 50 to about 400 micrograms of the compound per kilogram of the individual per day. However, the person skilled in the art will understand that the dose of the composition of the invention may vary depending on the individual and the particular route of administration used. It is common in the art to adjust the dose to suit individual subjects. Additionally, the effective amount may be based, inter alia, on the size of the compound, the biodegradability of the compound, the bioactivity of the compound and the bioavailability of the compound. If the compound does not degrade rapidly, is bioavailable and highly active, a smaller amount will be necessary to be effective and / or a less frequent dosing may be adequate (eg, fewer times per day, less than once per day) . The person skilled in the art, for example a doctor or a veterinarian, can easily determine, as a routine practice, the actual dose appropriate for an individual, given a general starting point. The compound can be supplied per hour, per day, per week, per month, per year. { for example, in a timed release form) or as a single administration. The supply may be continuous supply for a period of time, for example, intravenous delivery. In one embodiment of the methods described in the present invention, the agent is administered at least once per day. In one embodiment, the agent is administered daily. In one modality, the agent is administered every third day. In one modality, the agent is administered every 6 to 8 days. In one embodiment, the agent is administered weekly. In one embodiment of the methods described in the present invention, the route of administration may be oral, intraperitoneal, transdermal, subcutaneous, intravenous or intramuscular injection, by inhalation, topical, within a lesion, by infusion; liposome-mediated delivery; topical, intrathecal, in the gingival, rectal, intrabronchial, nasal, trans-mucosal, intestinal, ocular or otic cavities, or any other methods known in the art that can be easily perceived by the skilled artisan. Other embodiments of the compositions of the invention incorporate particulate forms of protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral. One embodiment of the method of the present invention is to administer the peptidomimetic of the present invention in a sustained release form. Said method comprises applying a transdermal sustained release patch or implanting a capsule or an implantable medical device coated with sustained release in such a way that a dose is continuously released.

Therapeutically effective of the peptidomimetic of the present invention to an individual of said method. The compounds and / or agents of the present invention can be delivered through a capsule that allows sustained release of the agent or peptide over a period of time. Sustained or controlled release compositions include formulation in lipophilic deposits (eg, fatty acids, waxes, oils). The invention also contemplates compositions of particulate material coated with polymers (e.g., poloxamers or poloxamines). In another related embodiment, the methods also comprise administering at least one additional therapeutic agent. Said agent may be an antibody, an enzyme inhibitor, an antibacterial agent, an antiviral agent, a steroid, a non-steroidal anti-inflammatory agent, an antimetabolite, a cytokine, or a soluble cytokine receptor. The enzyme inhibitor can be a protease inhibitor or a cyclo-oxygenase inhibitor. The additional agent can be added as part of the pharmaceutical composition, or it can be administered concomitantly or within a time interval when the physiological effect of the additional agent overlaps with the physiological effect of the compound of the present invention. More specific, an additional agent can be administered concomitantly or a week, several days, 24 hours, 8 hours, or immediately before the administration of the copolymer. Alternatively, an additional agent may be administered one week, several days, 24 hours, 8 hours, or immediately after the administration of the copolymer. Another embodiment of the present invention is a method of prophylactically treating an individual at risk of developing an autoimmune disease by administering a compound of the present invention. An individual at risk is identified, for example, based on family history, or any genetic markers that correlate with atherosclerosis. Said prophylactic treatment may additionally comprise other pharmaceutical agents.

Research tools The peptidomimetics of the invention are also useful as research tools. For example, the peptidomimetics of the invention can be used to evaluate the anti-atherosclerotic potential of other compounds (including other peptidomimetics). In addition, the peptidomimetics of the invention can be used to investigate lipoprotein interactions. receptor in animal and animal models, particularly when a peptidomimetic is labeled (eg, radioactive label, fluorescent label). The peptidomimetics of the invention can also be used to identify appropriate animal models to elucidate the lipid metabolic pathways. For example, peptidomimetics can be used to identify animal models in which lipid peroxidation contributes to the advancement of atherosclerosis.

IV. Eg emplos EXAMPLE 1 Synthesis and purification of a retro-inverse peptidomimetic Re-D4F Retro-inverse peptidomimetic Rev-D4F is synthesized using a standard method of peptide synthesis and purified by high performance liquid chromatography. To evaluate the ability of purified Rev-D4F to interact with phospholipids, the purified peptidomimetic is mixed with 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), which is a component of the membrane bilayer lipid with the which cholesterol is associated, and fractionated by gel filtration chromatography. Rev-D4F, like L4F and D4F, spontaneously associates with DMPC efficiently, and all the peptidomimetic co-elutes with the phospholipid (Figures 2B-D). In contrast, only certain portions of the intact Apo A-I protein are spontaneously associated with the phospholipid (FIG. 2A).

EXAMPLE 2 Effect of Rev-D4F on the discharge of cholesterol dependent SR-BI The effect of Rev-D4F on the discharge of cholesterol in a receptor manner is examined. The Class B type I purifying receptor ("SR-BI") is a receptor for HDL normally expressed on the surface of hepatocytes. Tritium-labeled cholesterol is added to cells transfected with SR-BI, with wild type Apo A-I, peptide L4F, peptide D4F, or peptidomimetic Rev-D4F, and the percentage of cholesterol discharge is determined. When compared to Apo A-I on a weight basis, L4F, D4F, and Rev-D4F are all more efficient to promote the discharge than the Apo A-I protein. When compared on a per mole basis, all the mimic peptides are less efficient than the Apo A-I protein (see Figures 3A and B.

EXAMPLE 3 Effect of Rev-D4F on the discharge of cholesterol dependent on ABCA1 The effect of Rev-D4F on cholesterol discharge is also examined in a manner dependent on the Al protein of the ATP-binding cassette ("ABCA1") using the same methodology as for SR-BI, except that ABCA1 is transfected. Similar to the release of SR-BI-dependent cholesterol, L4F, D4F, and Rev-D4F are all more efficient in promoting the discharge of cholesterol than Apo A-I on a per-weight basis. Also in a similar way to the SR-BI dependent discharge, all three are less efficient than Apo A-I when comparing one base per mole (see Figures 4A and B).

EXAMPLE 4 Effect of peptidomimetics on the oxidation of lipids in plasma The present study measures the ability of mimic peptides Rev-D4F, D-4F, and L-4F to inhibit lipid peroxidation caused by human aortic endothelial cells and copper (II) sulfate, based on inhibition of an increase in concentrations of substances reactive to thiobarbituric acid (TBARS). As shown in Figures 5 and 6, all three mimics significantly reduce the amount of lipid peroxidation in the presence of an oxidant. Likewise, the inhibition in peroxidation of lipid associated with Rev-D4F is significantly greater than the inhibition associated with D-4F.

EXAMPLE 5 Effect of peptidomimetics on MCP-I mRNA expression This study analyzes the effects of mimic peptides Rev-D4F, D-4F, and L-4F to reduce the levels of an anti-inflammatory marker, monocyte chemotactic protein-1 (MCP-I). Based on MCP-I mRNA levels, all three peptidomimetics reduce the amount of MCP-I.

EXAMPLE 6 Effect of Rev-D4F in mice lacking ApoE In this study, the comparative effect of the mimic peptides Rev-D4F, D-4F, and L-4F on atherosclerosis in mice lacking apoE. Four groups of mice without apoE are fed (4 weeks of age, n = 15) with a laboratory diet, and they are administered water (control), mimic peptides Rev-D4F, D-4F, or L-4F (1.6 mg / day, n = 12 / group) orally in the water to drink for 6 weeks. Quantitative morphometry of cross sections of the aortic root stained with red O in oil is performed using the NIH software. The Apo-AI mimic peptides do not affect the levels of total cholesterol, HDL cholesterol, non-HDL cholesterol in plasma. L-4F has no effect on atherosclerotic lesions. Both Rev-D4F and D4F significantly reduce (p <0.02) the area of injury by 46% and 33% respectively compared to the control with water. The data indicate that Rev-D4F is at least as effective or more effective than D-4F in preventing atherosclerosis in early stages of injury formation in mice lacking apoE.

Equivalents The contemplated equivalents of the peptidomimetics, subunits thereof, and other compositions described above include materials which otherwise correspond to them, and which have the same general properties thereof ( example, biocompatible), in which one or more variations of simple substituents are made that do not adversely affect the effectiveness of said molecule to achieve its intended purpose. In general, the compounds of the present invention can be prepared using the methods illustrated in general reaction schemes such as those described, for example, below, or by modifications thereto, using readily available starting materials, reagents and methods of conventional syntheses. In these reactions, it is also possible to use variants which are known per se, but which are not mentioned in the present invention. All the references cited above are incorporated in the present invention for reference in their totalities.

Claims (32)

NOVELTY OF THE INVENTION Having described the present invention, it is considered as a novelty and therefore the content of the following is claimed as property: CLAIMS

1. - A peptidomimetic with a three-dimensional conformation substantially similar to that of a peptide comprising a D-amino acid sequence F-A-E-K-F-K-E-A-V-K-D-Y-F-A-K-F-W-D (SEQ ID NO: 3).

2. The peptidomimetic according to claim 1, characterized in that the peptidomimetic has a sequence with at least 75% identity with SEQ ID NO: 3. 3. The peptidomimetic according to claim 1, characterized in that the peptidomimetic is represented by SEQ ID NO: 3 or a compound having only conservative amino acid substitutions of SEQ ID NO:

3.

4. - The peptidomimetic according to claim 1, characterized in that the peptidomimetic improves the lipid parameters in an individual.

5. - The peptidomimetic according to the claim 1, characterized in that the peptidomimetic is a retro-inverso peptide.

6. The peptidomimetic according to claim 5, characterized in that the peptidomimetic is represented by the sequence Ac-F-A-E-K-F-K-E-A-V-K-D-Y-F-A-K-F-W-D-NH2 (SEQ ID N0: 2).

7. - A peptidomimetic for treatment of elevated plasma cholesterol levels in a mammal, characterized in that the peptidomimetic has a three-dimensional conformation substantially similar to that of a peptide comprising a D-amino acid sequence Ac-FAEKFKEAVKDYFAKFWD-NH2 (SEQ ID NO. :2).

8. The peptidomimetic according to claim 7, characterized in that the peptidomimetic comprises a D-amino acid sequence Ac-F-A-E-K-F-K-E-A-V-K-D-Y-F-A-K-F-W-D-NH2 (SEQ ID NO: 2).

9. The peptidomimetic according to claim 7, characterized in that the peptidomimetic also comprises a protective group coupled to the amino terminal or carboxy terminal of the peptidomimetic.

10. The peptidomimetic according to claim 7, characterized in that the peptidomimetic also comprises a first protective group coupled to the amino terminus of the peptidomimetic and a second protective group coupled to the carboxy terminal end of the peptidomimetic. peptidomimetic

11. - The peptidomimetic according to claim 10, characterized in that said protective group is selected from acetyl, CH3- (CH2) n-CO-, amide, Fmoc, t-butoxycarbonyl, group 9-fluoren-acetyl, group 1-fluorencarboxylic, 9-fluoren-carboxylic group, 9-fluorenone-l-carboxylic group, benzyloxycarbonyl, xanthyl, trityl, 4-methyltrityl, 4-methoxytrityl, 4-methoxy-2,3,6-trimethyl-benzenesulfonyl, mesitylene 2-sulfonyl, 4,4-dimethoxybenzhydryl, tosyl, 2, 2, 5, 7, 8-pentamethylchroman-6-sulfonyl, 4-methylbenzyl, 4-methoxybenzyl, benzyloxy, benzyl, Benzoyl, 3-nitro-2-pyridinesulfenyl, l- (4,4-dimethyl-2,6-dioxocyclohexylidene) ethyl, 2,6-dichlorobenzyl, 2-chlorobenzyloxycarbonyl, 2-bromobenzyloxycarbonyl, benzyloxymethyl, cyclohexyloxy, t-butoxymethyl, t-butoxy, t-butyl, and trifluoroacetyl and n is an integer from 0 to 12.

12. A pharmaceutical composition for the treatment of elevated plasma cholesterol levels in a mammal, comprising a therapeutically effective amount of the peptidomimetic according to claim 1 or 7.

13. The composition according to claim 12, characterized in that the composition is for sustained release the compound.

14. The composition according to claim 12, which also comprises a second active agent.

15. The composition according to claim 14, characterized in that the second active agent treat lipid disorders.

16. The composition according to claim 14, characterized in that the second active agent is an anti-hypertensive agent.

17. - The composition according to claim 14, characterized in that the second active agent is a cardiovascular agent.

18. The composition according to claim 14, characterized in that the second active agent is an -inflammatory agent.

19. A method for treating high cholesterol levels in a mammal, comprising administering to said mammal a therapeutically effective amount of the composition according to claim 12.

20. A method for prophylactically treating an individual at risk of develop high plasma cholesterol levels, which comprises administering to the individual a pharmaceutically effective amount of the composition according to claim 12.

21. A method for treating a mammal that shows symptoms of atherosclerosis, which comprises administering to said mammal a therapeutically effective amount of the composition according to claim 12.

22. A method for prophylactically treating an individual at risk of developing atherosclerosis, comprising administering to the individual a Therapeutically effective amount of the composition according to claim 12.

23. A method for improving lipid parameters in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of the composition according to claim 12.

24. The method according to claim 23, which also comprises administering a second active agent.

25. - The method according to claim 24, characterized in that the second active agent treats lipidic disorders.

26. The method according to claim 24, characterized in that the second active agent is an anti-hypertensive agent.

27. The method according to claim 24, characterized in that the second agent Active is a cardiovascular agent.

28. - The method according to claim 24, characterized in that the second active agent is an anti-inflammatory agent.

29. - A method for treating a patient suffering from a disease or condition that can be treated by altering the lipid parameters, which comprises administering to the individual a therapeutically effective amount of the composition according to claim 12.

30. - A kit comprising the compound according to claim 1 or 7 in a pharmaceutically acceptable carrier, also comprising instructions for administration of the compound for treatment of elevated plasma cholesterol levels.

31. A kit comprising the compound according to claim 1 or 7 in a pharmaceutically acceptable carrier, which also comprises instructions for administration of the compound for treatment of atherosclerosis.

32. A kit comprising the compound according to claim 1 or 7 in a pharmaceutically acceptable carrier, which also comprises instructions for administration of the compound to improve the lipid parameters.