MXPA01008865A - Modulators of beta-amyloid peptide aggregation comprising d-amino acids - Google Patents

Abstract

Compounds that modulate natural&bgr;amyloid peptide aggregation are provided. The modulators of the invention comprise a peptide, preferably based on a&bgr;amyloid peptide, that is comprised entirely of D-amino acids. Preferably, the peptide comprises 3-5 D-amino acid residues and includes at least two D-amino acid residues independently selected from the group consisting of D-leucine, D-phenylalanine and D-valine. In a particularly preferred embodiment, the peptide is a retro-inverso isomer of a&bgr;amyloid peptide, preferably a retro-inverso isomer of A&bgr;17-21. In certain embodiments, the peptide is modified at the amino-terminus, the carboxy-terminus, or both. Preferred amino-terminal modifying groups alkyl groups. Preferred carboxy-terminal modifying groups include an amide group, an acetate group, an alkyl amide group, an aryl amide group or a hydroxy group. Pharmaceutical compositions comprising the compounds of the invention, and diagnostic and treatment methods for amyloidogenic diseases using the compounds of the invention, are also disclosed.

Description

BETA-AMYLOID PEPTIDE AGGREGATION MODULATORS COMPRISING D-AMINO ACIDS BACKGROUND OF THE INVENTION Alzheimer's disease (AD), first described by the Bavarian psychiatrist Alois Alzheimer in 1907, is a progressive neurological disorder that begins with memory loss of short term and advances towards disorientation, affectation of judgment and reasoning, and finally, dementia. The course of the disease usually leads to death in an immobile state severely weakened between four and 12 years after onset. It has been estimated that AD affects between 5 and 11% of the population over 65 and up to 47% of the population over 85 years of age. The cost to the AD management society is more than $ 80 billion annually, primarily due to the extensive care required by AD patients. In addition, since adults born during the population growth of the 40s and 50s approach the age at which AD becomes more prevalent, AD control and treatment will become an even more important health care problem. Today there is no treatment that significantly retards the progression of the disease. For reviews on AD see Selkoe, D.J. Sci. Amer. , November 1991, pages 68-78; and Yankner, B.A. et al. (1991) N. Eng. J Med. 325: 1849-1857. It has recently been reported (Games et al (1995) Nature 373: 523-527) that an Alzheimer-type neuropathology has been created in transgenic mice. Transgenic mice express high levels of human mutant amyloid precursor protein and progressively develop many of the pathological conditions associated with AD. Pathologically, AD is characterized by the presence of clear lesions in the victim's brain. These brain lesions include abnormal intracellular filaments known as neurofibrillary tangles (NTFs) and extracellular deposits of amyloidogenic proteins in senile or amyloid plaques. Amyloid deposits are also present in the walls of the cerebral blood vessels of patients with AD. The main protein constituent of amyloid plaques has been identified as a 4-kilodalton peptide known as β-amyloid peptide (β-AP) (Glenner, GG and Wong, CW (1984) Biochem. Biophys, Res. Commun. 885-890; Masters, C. et al (1985) Proc. Nati, Acad. Sci. USA 82: 4245-4249). Diffuse deposits of ß-AP are frequently observed in brains of normal adults whereas brain tissue from adults with AD is characterized by denser, denser ß-amyloid plaques (see, for example, Davies, L. et al. (1988) Neurology 3_8: 1688-1693). These observations suggest that the deposition of β-AP precedes and contributes to the destruction of neurons that occurs in AD. As additional support for a direct pathogenic function for β-AP, it has been shown that β-amyloid is toxic to mature neurons, both in culture and in vivo. Yankner, B.A. et al. (1989) Science 245: 417-420; Yankner, B.A. et al. (1990) Proc. Nati Acad. Sci. USA 87: 9020-9023; Roher, A.E. et al. (1991) Biochem. Biophys. Res. Commun. 17_4: 572-579; Kowall, N.W. et al. (1991) Proc. Nat. Acad. Sci. USA 8_8: 7247-7251. In addition, patients with hereditary cerebral hemorrhage with Dutch type amyloidosis (HCHWA-D), characterized by diffuse deposits of β-amyloid within the cerebral cortex and cerebral vasculature present a point mutation leading to an amino acid substitution within ß-AP. Levy, E. et al. (1990) Science 248: 1124-1126. This observation demonstrates that a specific alteration of the ß-AP sequence can cause the deposition of β-amyloid. Natural ß-AP is derived by proteolysis of a much larger protein known as amyloid precursor protein (APP).

Kang, J. et al. (1987) Nature 325: 733; Goldgaber, D. et al. (1987) Science 235: 877; Robakis, N.K. et al. (1987) Proc. Nati Acad. Sci. USA 84: 4190; Tanzi, R.E. et al. (1987) Science 235: 880. The APP gene is located on chromosome 21, thus providing an explanation for the deposition of β-amyloid observed at an early age in individuals with Down syndrome that is caused by chromosome 21 trisomy. Mann D.M. et al. (1989) Neuropathol. Appl. Neurobiol. : 317; Rumble, B. et al. (1989) N. Eng. J Med. 320: 1446. APP contains a single domain spanning the membrane, with a long amino terminal region (approximately two thirds of the protein) extending into the extracellular environment and a shorter carboxy terminal region that projects into the cytoplasm. A differential splicing of messenger RNA from APP causes at least five forms of APP, consisting of either 563 amino acids (APP-563), 695 amino acids (APP-695), 714 amino acids (APP-714), 751 amino acids (APP -751) or 770 amino acids (APP-770). Within APP, a naturally occurring β-amyloid peptide starts at a residue of aspartic acid at a 672 amino acid position of APP-770. Naturally occurring ß-AP derived from the proteolysis of APP has a length of 39 to 43 amino acid residues, according to the terminal point of carboxy terminal, which presents homogeneity. The predominant circulating form of ß-AP in blood and brain-spinal fluid in both AD patients and normal adults is ßl-40 ("short ß"). Seubert, P. et al. (1992) Nature 359: 325; Shoji, M. et al. (1992) Science 258: 126. However, ß-41 and ßl-43 ("long ß") are also formed in ß-amyloid plaques. Masters, C. et al. (1985) Proc. Nati Acad. Sci. USA 82: 4245; Miller, D. et al. (1993) Arch. Biochem. Biophys. 301: 41; Mori, H. et al. (1992) J Biol. Chem. 267: 17082. Although the precise molecular mechanism that leads to the aggregation and deposition of APP is unknown, the process has been compared with the process of nucleation-dependent polymerizations, eg protein crystallization, Microtubule formation as well as actin polymerization. See, for example, Jarrett, J.T. and Lansbury, P.T. (1993) Cell 23: 1055-1058. In such processes, the polymerization of monomeric components does not occur until core formation. Thus, these processes are characterized by a time delay before aggregation, followed by a rapid polymerization after nucleation. Nucleation can be accelerated by the addition of a "seed" or preformed core, resulting in rapid polymerization. The long ß-AP forms act as seeds, thus accelerating the polymerization of both long and short β-AP forms. Jarrett, J.T. et al. (1993) Biochemistry 32: 693. In one study, in which amino acid substitutions were made in ß-AP, two peptides of ß mutants were reported as interfering with the polymerization of non-mutated ß-AP when the mutant and non-mutant forms of peptide were mixed. Hilbich C. et al. (1992) J Mol. Biol. 228: 460-473. Equimolar amounts of the mutant and non-mutant (ie, natural) β-amyloid peptides were used to observe this effect and it was reported that the mutant peptides were unsuitable for in vivo use.

Hilbich, C. et al. (1992), supra. SUMMARY OF THE INVENTION This invention relates to compounds, and to pharmaceutical compositions thereof, which can bind with natural β-amyloid (β-AP) peptides, modulate the aggregation of natural β-APs and / or inhibit the neurotoxicity of β- Natural APs. The compounds are modified in a manner that allows increased biostability and prolonged elevated plasma levels. The β-amyloid modulator compounds of the invention comprise a peptide structure, preferably based on β-amyloid peptide, consisting entirely of D-amino acids. In various embodiments, the peptide structure of the modulator compound comprises a D-amino acid sequence corresponding to an L-amino acid sequence found within natural β-AP, a D-amino acid sequence that is an inverse isomer of a sequence of L-amino acids found within natural β-AP, a D-amino acid sequence that is a retro-inverso isomer of an L-amino acid sequence found within natural β-AP, or a sequence of D-amino acids that is a revolved or substituted version of a sequence of L-amino acids found in natural β-AP. Preferably, the D-amino acid peptide structure of the modulator is designed based on a subregion of natural β-AP at positions 17-21 (Aβ1-2o and ββ7-2, respectively), which has the Leu-amino acid sequences. Val-Phe-Phe-Ala (SEQ ID NO: 4). In preferred embodiments, a phenialanine in the compounds of the invention is substituted by a phenylalanine analog which is more stable and has a lower tendency, for example, to oxidative metabolism, or allows increased cerebral levels of the compound. In another embodiment, a modulator compound of the invention includes a β-amyloid peptide consisting of D-amino acids, L-amino acids or both of an inverse isomer of a β-amyloid peptide, or a retro-inverso isomer of a amyloid peptide fixed on a hydrazine moiety, wherein the compound binds to natural β-amyloid peptides or modulates aggregation or inhibits the neurotoxicity of natural β-amyloid peptides when in contact with natural β-amyloid peptides. A modulator compound of the present invention preferably comprises from 3 to 20 D-amino acids, more preferably from 3 to 10 D-amino acids and preferably even greater than 3 to 5 D-amino acids. The D-amino acid peptide structure of the modulator can have free amino, carboxy or carboxyamide terminals. Alternatively, the amino terminus, the carboxy terminus or both can be modified. For example, a N-terminal modification group can be employed which increases the ability of the compound to inhibit Aβ aggregation. In addition, the amino and / or carboxy terminals of the peptide can be modified to alter a pharmacokinetic property of the compound (such as stability, bioavailability, e.g., increased administration of the compound through the blood-brain barrier and penetration into the brain, and the like). Preferred amino terminal modification groups include alkyl groups, eg, methyl, ethyl or isopropyl groups Preferred carboxy terminal modification groups include amide groups, alkyl or arylamide groups (e.g., phenethylamide), hydroxy groups (e.g. peptide acid reduction products, which result in peptide alcohols), acylamide groups, and ethyl groups In addition, a modulator compound can be modified to label the compound with a detectable substance (eg, a radioactive label). Preferred embodiments, the invention offers a compound having the structure: N, N-dimethyl- (Gl y-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N, N-dimethyl (D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH_; N-methyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-ethyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-isopropyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Ala) -isopropylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Ala) -dimethylamide; N, N-diethyl (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N, N-diethyl- (D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N, N-dimethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N, N-dimethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2: N, N-dimethyl- (D-Leu-D-Phe-D-Phe-D) -Val-D-Leu) -NH2; H- (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N-ethyl (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH; N-ethyl- (Gly-D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-methyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-ethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N-propyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2 N, N-diethyl- (Gly-D-Leu-D-Val-D-Phe-D- Phe-D-Leu) -NH; H- (D-Ile-D-Val-D-Phe-D-Phe-D-Ile) -NH2; H- (D-Ile-D-Val-D-Phe-D-Phe-D-Ala-) -NH2; H- (D-Ile-D-Ile-D-Phe-D-Phe-D-Ile) -NH2; H- (D-Nle-D-Val-D-Phe-D-Phe-D-Ala-) -NH2; H- (D-Nle-D-Val-D-Phe-D-Phe-D-Nle) - NH 2; 1-piperidin-acetyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2: 1-piperidin-acetyl- (D-Leu-D-Phe-D-Phe-D) -Val-D-Leu) -NH2; H-D-Leu-D-Val-D-Phe-D-Phe-D-Leu-isopropyl-lamide; H-D-Leu-D-Phe-D-Phe-D-Val-D-Leu-isopropylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -methylamide; H- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -methylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -OH; N-methyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D-Cha-D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D- [p-F] Phe-D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D- [F5] Phe-D-Leu) -NH2; H- (D-Leu-D-Phe-D-Cha-D- Val-D-Leu) -NH2; H- (D-Leu-D-Phe-D- [p-F] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Phe-D- [F5] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Phe-D-Lys-D-Val-D-Leu) -NH2; H- (D-Leu-D-Cha-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D- [p-F] Phe-D-Phe-D-Val-D-Leu) -NH:; H- (D-Leu-D- [F5] Phe-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Lys-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Cha-D-Cha-D-Val-D-Leu) -NH2; H- (D-Leu-D- [p-F] Phe-D- [p-F] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D [F5] Phe-D- [F5] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Lys-D-Lys-D-Val-D-Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D-Cha-D-Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D- [p-F] Phe-D-Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D- [F5] Phe-D-Leu) -NH2; H-D-Leu-D-Val-D-Phe-NH- (H-D-Leu-D-Val-D-Phe-) NH; H-D-Leu-D-Val-D-Phe-NH-NH-COCH3; and H-D-Leu-D-Val-D-Phe-NH-NH2. Particularly preferred compounds of the invention are presented in the examples. Another aspect of the invention relates to pharmaceutical compositions. Typically, the pharmaceutical composition comprises a therapeutically effective amount of a modulator compound of the invention and a pharmaceutically acceptable carrier. In another aspect, the invention relates to a method for inhibiting the aggregation of natural β-amyloid peptides. These methods comprise contacting the natural β-amyloid peptides with a modulator compound of the invention in such a way that the aggregation of the natural β-amyloid peptides is inhibited. Another aspect of the invention relates to methods for detecting the presence or absence of natural β-amyloid peptides in a biological sample. These methods comprise contacting a biological sample with a compound of the invention, wherein the compound is labeled with a detectable substance, and detecting the compound bound to natural β-amyloid peptides to thereby detect the presence or absence of amyloid peptides in the biological sample. Another aspect of the invention relates to methods for the treatment of a subject for a disorder associated with β-amyloidosis. These methods comprise administering to the subject a therapeutically effective amount of a modulator compound of the invention such that the subject is treated for a disorder associated with β-amyloidosis. Preferably, the disorder is Alzheimer's disease. The use of modulators of the invention for therapy or for the preparation of a drug for the treatment of a disorder associated with β-amyloidosis is also within the scope of the invention. BRIEF DESCRIPTION OF THE FIGURES Figure 1 is a table showing the results of a cerebral absorption test. Figure 2 is a graph showing the results of a fibril binding assay described in Example 2. DETAILED DESCRIPTION OF THE INVENTION This invention relates to compounds, and pharmaceutical compositions thereof, that can be linked to β-peptides. natural amyloids, modulate the aggregation of natural β-amyloid peptides (β-AP) and / or inhibit the neurotoxicity of natural β-APs. The compounds are modified in a manner that allows increased biostability and prolonged elevated plasma levels. A compound of the invention that modulates the aggregation of natural β-AP, which is here known interchangeably as β-amyloid modulator compound, β-amyloid modulator or simply modulator, alters the aggregation of a natural β-AP when the modulator enters in contact with natural ß-AP. Thus, a compound of the invention acts to alter the natural aggregation process or natural aggregation rate for β-AP, thereby disrupting this process. Preferably, the compounds inhibit the aggregation of β-AP. The compounds of the invention are characterized in that they comprise a peptide structure consisting entirely of D-amino acid residues. This peptide structure is preferably based on β-amyloid peptide and may comprise, for example, a D-amino acid sequence corresponding to an L-amino acid sequence found within β-AP, a D-amino acid sequence which is an inverse isomer of an L-amino acid sequence found within natural β-AP, a D-amino acid sequence that is a retro-inverso isomer of an L-amino acid sequence found within β-AP, or a D-sequence amino acid which is a revolved or substituted version of a sequence of L-amino acids found in natural β-AP. In preferred embodiments, the phenylalanines in the compounds of the invention are substituted with phenylalanine analogues that are more stable and have a lower tendency, for example, to oxidative metabolism. The invention encompasses modulator compounds comprising a peptide structure of D-amino acids having free amino, carboxy or carboxyamide terminals, as well as modulator compounds wherein the amino terminal, the carboxy terminal, and / or the side chain (s) (en) of the peptide structure are modified. The β-amyloid modulating compounds of the invention can be selected based on their ability to bind with natural β-amyloid peptides, modulate the aggregation of natural β-AP in vitro and / or inhibit the neurotoxicity of β-AP fibrils natural for cultured cells (using assays described herein, for example, the neurotoxicity assay, the nucleation assay, or the fibril binding assay). Preferred modulator compounds inhibit the aggregation of native β-AP and / or inhibit the neurotoxicity of natural β-AP. However, modulating compounds selected based on one of these properties or both of these properties may have additional in vivo properties that may be beneficial in the treatment of amyloidosis (JS Pachter et al. (1998) "Aßl-40 induced neurocytopathic activation of human monocytes is blocked by Aβ peptide aggregation inhibitors. "NeurOjbiology of Aging (Abstracts: 6th International Conference on Alzheimer's Disease and related disorders, Amsterdam, July 18-23, 1998), 19, S128 (abstract 540); R. Weltzein, A. et al. (1998) "Phagocytosis of Beta-Amyloid: A Possible Requisite for Neurotoxicity." J. Neu r o immunology (Special issue: abstracts of the International Neuroimmunology Society - Fifth International Congress, Montreal, Canada, August 23-27, 1998) 1998, 90, 32 (summary 162)). For example, the modulator compound can interfere with the processing of natural β-AP (either by direct or indirect protease inhibition) or by modulation of processes that produce toxic β-AP, or other fragments of APP, in vivo. Alternatively, modulator compounds can be selected based on these latter properties, rather than the inhibition of Aβ aggregation in vitro. In addition, the modulator compounds of the invention that are selected based on their interaction with natural β-AP can also interact with APP or other APP fragments. In addition, a modulator compound of the invention can be characterized by its ability to bind β-amyloid fibrils (which can be determined, for example, by radiolabeling the compound, contacting the compound with a β-amyloid plaque). and counting or detecting, for example, by imaging, the bound compound on pathological forms of β-AP eg the plate), without significantly altering the aggregation of the β-amyloid fibrils. Said compound that effectively binds with β-amyloid fibrils without significantly altering the aggregation of β-amyloid fibrils can be used, for example, to detect β-amyloid fibrils (eg, for diagnostic purposes, in accordance with what is described below). It will be noted, however, that the ability of a particular compound to bind β-amyloid fibrils and / or modulate their aggregation may vary according to the concentration of the compound. Accordingly, a compound which, at low concentration, binds with β-amyloid fibrils without altering their aggregation may nevertheless inhibit the aggregation of the fibrils at a higher concentration. All compounds that have the property of binding to β-amyloid fibrils and / or modulating the aggregation of fibrils are included within the scope of the present invention. As used herein, the term "a modulator" of β-amyloid aggregation refers to an agent that, when in contact with natural β-amyloid peptides, alters the aggregation of the natural β-amyloid peptides. The term "aggregation of β-amyloid peptides" refers to a process through which peptides associate with each other to form a multimeric, largely insoluble complex. The term "aggregation" also encompasses the formation of β-amyloid fibrils and also encompasses ß-amyloid plaques. The terms "natural β-amyloid peptide", "natural β-AP" and "native Aβ peptide", used interchangeably herein, encompass naturally occurring proteolytic cleavage products of the β-amyloid precursor protein (APP) which are involved in the aggregation of ß-AP and in β-amyloidosis. These natural peptides include ß-amyloid peptides having from 39 to 43 amino acids (ie, Alii-39, Aβ? -40, AJi? -41, β? A) and Aβ? -3). The amino terminal residue of natural β-AP corresponds to the residue of aspartic acid at position 672 in the form of 770 amino acid residues of the amyloid precursor protein ("APP-770"). The 43 amino acid long form of atural β-AP has the amino acid sequence DAEFRHDSGYEVHHQKLVFFAEDVGSNKGAIIGLMVGGVVATAT (also shown in SEQ ID NO: 1), while the shorter forms have 1-4 amino acid residues deleted from the carboxy terminal end. . The amino acid sequence of APP-770 from position 672 (ie, the amino terminal of natural β-AP) up to its C-terminal end (103 amino acids) is shown in SEQ ID NO: 2. The preferred form of β- Natural AP for use in aggregation assays described herein is Aβ? -40 or Aβ? -42. In the presence of a modulator of the invention, the aggregation of natural β-amyloid peptides is "altered" or "modulated". The various forms of the term "alteration" or "modulation" are intended to encompass both the inhibition of ß-AP aggregation and the promotion of ß-AP aggregation. Aggregation of natural β-AP is "inhibited" in the presence of the modulator when there is a decrease in the amount and / or rate of aggregation of β-AP compared to the amount and / or rate of aggregation of β-AP in the absence of the modulator The various forms of the term "inhibition" include both complete inhibition and partial inhibition of β-AP aggregation. The inhibition of aggregation can be quantified as the increase in times in the delay of aggregation or the decrease in the aggregate plateau level of aggregation (ie total amount of aggregation), using an aggregation assay in accordance with what is described in the examples. In various embodiments, a modulator of the invention increases the aggregation time delay by at least 1.2 times, 1.5 times, 1.8 times, 2 times, 2.5 times, 3 times, 4 times, or 5 times, for example, when the compound it is in a molar equivalent in relation to ß-AP. In various other embodiments, a modulator of the invention inhibits aggregation plateau level by at least 10%, 20%, 30%, 40%, 50%, 75% or 100%. A modulator that inhibits the aggregation of β-AP (a "inhibitory modulator compound") can be used to prevent or delay the onset of ß-amyloid deposition. Preferably, inhibitory modulating compounds of the invention exhibit the formation and / or activity of neurotoxic aggregates of natural Aβ peptide (i.e., the inhibitory compounds can be used to inhibit the neurotoxicity of β-AP). In addition, the inhibitory compounds of the present invention can reduce the neurotoxicity of preformed β-AP aggregates, indicating that the inhibitory modulators can either bind with preformed Aβ fibrils or soluble aggregate and modulate their inherent neurotoxicity or that the modulators can disrupt the balance between the monomeric and aggregated forms of ß-AP in favor of the non-neurotoxic form. Alternatively, in another embodiment, a modulator compound of the invention promotes the aggregation of natural Aβ peptides. The various forms of the term "promotion" refer to an increase in the amount and / or rate of aggregation of β-AP in the presence of a modulator, compared to the amount and / or rate of aggregation of β-AP in the absence of the modulator Said compound that promotes the aggregation of Aβ is known as a stimulator modulator compound. Stimulating modulator compounds may be useful for sequestering β-amyloid peptides, for example, in a biological compartment where the aggregation of β-AP can not be detrimental to thereby decrease β-AP from a biological compartment where the aggregation of ß-AP is harmful. In addition, stimulatory modulator compounds can be employed to promote aggregation of Aβ in in vitro aggregation assays (e.g., assays such as those described in Example 2) for example, in screening assays for test compounds that can then inhibit or reverse this aggregation of Aβ (ie, a modulating stimulator compound can act as a "seed" to promote the formation of aggregates of Aβ). In a preferred embodiment, the modulators of the invention can alter the aggregation of β-AP when they come in contact with an excess molar amount of natural β-AP. An "excess molar amount of natural β-AP" refers to a concentration of β-AP, in moles, which is greater than the concentration, in moles, of the modulator. For example, if the modulator and β-AP are both present at a concentration of 1 μM, they are said to be "equimolar", whereas if the modulator is present at a concentration of 1 μM and β-AP is present in a concentration of 5 μM, it is said that β-AP is present in an amount of excess 5 times molar compared to the modulator. In preferred embodiments, a modulator of the invention is effective to alter the aggregation of natural β-AP when natural β-AP is present in at least a molar excess of 2 times, 3 times or 5 times compared to the modulator concentration . In other embodiments, the modulator is effective in altering aggregation of β-AP when natural β-AP is present in a molar excess of at least 10 times, 20 times, 33 times, 50 times, 100 times, 500 times or 1000 times compared to the concentration of the modulator. As used herein, the term "β-amyloid peptide formed entirely of D-amino acid", as used in a modulator of the invention, encompasses peptides having an amino acid sequence identical to the amino acid sequence of the natural sequence in APP, as well as peptides that have acceptable amino acid substitutions from the natural sequence, but which consist of D-amino acids instead of the natural L-amino acids present in natural β-AP. Acceptable amino acid substitutions are substitutions that do not affect and / or may improve the ability of the D-amino acid-containing peptide to alter the aggregation of natural β-AP. In addition, particular amino acid substitutions may additionally contribute to the ability of the peptide to alter the aggregation of natural β-AP and / or may provide additional beneficial properties to the peptide (eg, increased solubility, reduced association with other amyloid proteins, etc.). ). A peptide having an amino acid sequence identical with the sequence found in a peptide of origin but where all L-amino acids have been substituted with D-amino acids is also known as an "inverse" compound. For example, if a peptide of origin is Thr-Ala-Tyr, the inverse form is D-Thr-D-Ala-D-Tyr. As used herein, the term "retro-inverso isomer of a β-amyloid peptide", as used in a modulator of the invention, is intended to encompass peptides wherein the amino acid sequence is inverted as compared to the sequence in natural β-AP and all L-amino acids are replaced with D-amino acids. For example, if a peptide of origin is Thr-Ala-Tyr, the retro-inverso form is D-Tyr-D-Ala-D-Thr. Compared to the origin peptide, a retro-inverso peptide has a reverse structure while substantially retaining the original spatial conformation of the side chains, resulting in a retro-inverso isomer with a topology that closely resembles the origin peptide. See, Goodman et al. "Perspectives in Peptide Chemistry", pages 283-294 (1981). See also, US Patent No. 4,522,752 by Sisto for an additional description of "reverse-reverse" peptides. Several additional aspects of the modulators of the invention, and their uses, are described with additional details in the following subsections. I. Modulating Compounds In one embodiment, a modulator compound of the invention comprises a β-amyloid peptide, the β-amyloid peptide consists entirely of D-amino acids, wherein the compound binds with natural β-amyloid peptides or modulates the aggregation or inhibits the neurotoxicity of natural β-amyloid peptides when contacted with the natural β-amyloid peptides. Preferably, the β-amyloid peptide of the modulator consists of 3-20 D-amino acids, more preferably 3-10 D-amino acids, and preferably even greater than 3-5 D-amino acids. In preferred embodiments, a phenylalanine in the compounds of the invention is substituted by a phenylalanine analogue that is more stable and has a lower tendency, for example, to oxidative metabolism. In one embodiment, the β-amyloid peptide of the modulator is modified at the amino terminus, for example, with a modifying group comprising an alkyl group such as, for example, a lower C 1 -C 6 alkyl group, for example, a methyl, ethyl or propyl group; or a cyclic, heterocyclic, polycyclic or branched alkyl group. Examples of suitable N-terminal modification groups are further described in subsection II below. In another embodiment, the β-amyloid peptide of the modulator is carboxy-terminally modified, for example, the modulator may comprise an amide peptide, an alkylamide or arylamide peptide (e.g., a phenethylamide peptide) or a peptide alcohol . Examples of suitable C-terminal modification groups are described in greater detail in subsections II and III below. The β-amyloid peptide of the modulator can be modified to increase the ability of the modulator to alter the aggregation of β-AP or its neurotoxicity. In addition or alternatively, β-amyloid peptide of the modulator can be modified to alter a pharmacokinetic property of the modulator and / or to label the modulator with a detectable substance (described below in subsection III below). In another embodiment, a modulator compound of the invention comprises a retro-inverso isomer of a β-amyloid peptide, wherein the compound binds with natural β-amyloid peptides or modulates the aggregation or inhibits the neurotoxicity of β-peptides. natural amyloids when placed in contact with the natural β-amyloid peptides. Preferably, the retro-inverso isomer of the β-amyloid peptide consists of 3-20 D-amino acids, more preferably 3-10 D-amino acids, and preferably even greater than 3-5 D-amino acids. In preferred embodiments, the phenylalanines in the compounds of the invention are substituted by phenylalanine analogues that are more stable and have a lower tendency, for example, to oxidative metabolism. In one embodiment, the retro-inverso isomer is modified at the amino terminus, for example, with a modifying group consisting of an alkyl group such as, for example, C1-C6 lower alkyl group, for example, a methyl, ethyl, or propyl group; or a cyclic, heterocyclic, polycyclic or branched alkyl group. Examples of suitable N-terminal modifier groups are further described in subsection II below. In another embodiment, the retro-inverso isomer is modified at carboxy terminus such as, for example, with an amide group, an alkylamide or arylamide group (eg, phenethylamide) or a hydroxy group (i.e., the product of acid reduction). of peptide, resulting in a peptide alcohol). Examples of suitable C-terminal modification groups are further described in subsections II and III below. The retro-inverso isomer can be modified to increase the modulator's ability to alter ß-AP aggregation or neurotoxicity. In addition or alternatively, the retro-inverso isomer can be modified to alter a pharmacokinetic property of the modulator and / or to label the modulator with a detectable substance (further described in subsection III below). In another embodiment, a modulator compound of the invention includes a β-amyloid peptide that contains all or part of D-amino acids, a reverse isomer of a β-amyloid peptide, or a retro-inverso isomer of a β-peptide. -aminoid that is fixed on a hydrazine moiety, where the compound binds with natural β-amyloid peptides or modulates the aggregation or inhibits the neurotoxicity of natural β-amyloid peptides when in contact with the β-amyloid peptides natural Preferably, the modulator compound of the invention consists of 1-20 D-amino acids, more preferably 1-10 D-amino acids, preferably even greater than 1-5 D-amino acids, and especially 2-4 D-amino acids fixed on a hydrazine portion. In one embodiment, the modulator compounds of the invention that include a hydrazine moiety are modified at the amino terminus, for example, with a modification comprising an alkyl group, for example, a methyl, ethyl or isopropyl group. Examples of suitable N-terminal modifier groups are described in greater detail in subsection II below. In another embodiment, modulator compounds of the invention that include a hydrazine moiety are modified at the carboxy terminus, for example, with an acetyl. Examples of suitable C-terminal modifying groups are described in greater detail in subsections II and III below. The modulator compounds of the invention that include a hydrazine moiety can be modified to increase the ability of the modulator to alter the aggregation of β-AP or its neurotoxicity. In addition or alternatively, the modulator compounds of the invention that include a hydrazine moiety can be modified to alter a pharmacokinetic property of the modulator and / or to label the modulator with a detectable substance (described in greater detail in subsection III below). The modulators of the invention are preferably designed based on the amino acid sequence of a sub region of β-AP. The term "subregion of a natural β-amyloid peptide" encompasses terminal amino and / or carboxy terminal deletions of β-AP. The term "natural β-AP subregion" is not intended to include full-length natural β-AP (ie, the term "subregion" does not include Aβ? -39, Aβ? -40, Aβ? -4, Aβ? 2 and Aβ? -3). A preferred sub-region of natural β-amyloid peptide is an "Aβ aggregation core domain" (ACD). As used herein, the term "Aβ aggregation core domain" refers to a sub-region of natural β-amyloid peptide that is sufficient to modulate the aggregation of natural β-APs when this subregion, in its L-form, amino acid, is appropriately modified (eg, modified at the amino terminus), in accordance with what is described in detail in U.S. Patent Application Serial No. 08 / 548,998 and in U.S. Patent Application Serial No. 08 / 616,081 , whose entire contents of each of them are expressly incorporated herein by reference. Preferably, the ACD is modeled from a subregion of natural β-AP that is less than 15 amino acids in length and more preferably between 3 and 10 amino acids in length. In several modalities, the ACD is based on a subregion of β-AP that is 10, 9, 8, 7, 6, 5, 4 or 3 amino acids in length. In one embodiment, the sub-region of β-AP, on the basis of which ACD is modeled is a carboxy or internal terminal region of β-AP (ie, downstream of the amino terminus at amino acid position 1). In another modality, the ACD is modeled based on a subregion of ß-AP that is hydrophobic. Preferred Aβ aggregation core domains encompass amino acid residues 17-20 or 17-21 of natural β-AP (Aβ 7-2o and Aβ? 7-2i, respectively) and analogs thereof, in accordance with described here. The amino acid sequences of Aß? 7-2o and Aß1-2? are Leu-Val-Phe-Phe (SEQ ID NO: 3) and Leu-Val-Phe-Phe-Ala (SEQ ID NO: 4), respectively. As demonstrated in the examples, modulators containing D-amino acids designed based on the amino acid sequences of Aβ-20 and Aβ? _2? they are particularly effective inhibitors of Aβ aggregation and exhibit increased biostability and prolonged elevated plasma levels. These modulators may comprise a D-amino acid sequence corresponding to the L-amino acid sequence of Aβ7-2o or Aββ 7.2β, a D-amino acid sequence that is a reverse isomer of the L-amino acid sequence of Aß7.2o or Aβ? 7_2 ?, a sequence of D-amino acids that is a retro-inverso isomer of the sequence of L-amino acids of Aß? 7-2-jo ßi7-2i, or a sequence of D-amino acids which is a revolved or substituted version of the L-amino acid sequence of Aβ? 7-2 or Aβ? 7-2 ?. In preferred embodiments, a phenylalanine in modulators designed based on the amino acid sequences of Aβ 7-20 and Aβ 7-2? is substituted with a more stable phenylalanine analogue and therefore has a lower tendency, for example, to oxidative metabolism. In other preferred embodiments, modulators designed based on the amino acid sequences of Aβ? 7_2o and Aβ? 7-2, further comprise a hydrazine moiety. Modulators based on D-amino acids may have their amino and / or carboxy terminals and / or unmodified carboxyamide terminals or, alternatively, the amino terminus, the carboxy terminus, or both may exhibit modifications (described in more detail below) ). Peptide structures of effective modulators are generally hydrophobic and are characterized by the presence of at least two D-amino acid structures selected independently within the group consisting of a D-leucine structure, a D-phenylalanine structure and a structure of D-Valine As used herein, the term "a D-amino acid structure" (such as a D-leucine structure, "a D-phenylalanine structure", or a "D-valine structure") has the purpose of include the D-amino acid, as well as analogs, derivatives and mimetics of the D-amino acid that maintain the functional activity of the compound (discussed in more detail below). For example, the term "D-phenylalanine structure" includes D-phenylalanine as well as D-cyclohexylalanine [D-cha], D-4-fluorophenylalanine (para-fluorophenylalanine). { [p-F] f or D- [p-F] Phe} , D-pentafluorophenylalanine. { [F5] f or D- [F5] Phe} , chlorophenylalanine, bromophenylalanine, nitrophenylalanine, D-pyridylalanine, D-homophenylalanine, methyltyrosine, and benzyl serine, as well as substitution with D-lysine structure, D-valine structure, or a structure of D-leucine. The term "D-leucine structure" encompasses D-leucine, as well as substitution with D-valine, D-isoleucine or other natural or non-natural amino acids having an aliphatic side chain, such as D-norleucine or D- norvaline The term "D-valine structure" is intended to include D-valine as well as substitution with D-leucine or another natural or non-natural amino acid having an aliphatic side chain.

In other embodiments, the peptide structure of the modulator comprises at least two D-amino acid structures independently selected from the group consisting of a D-leucine structure, a D-phenylalanine structure, a D-valine structure, a structure of D-alanine, a structure of D-tyrosine, a structure D-iodotyrosine and a structure of D-lysine. In another embodiment, the peptide structure consists of at least three D-amino acid structures independently selected within the group consisting of a D-leucine structure, a D-phenylalanine structure, and a D-valine structure. In another embodiment, the peptide structure consists of at least three D-amino acid structures independently selected from the group consisting of a D-leucine structure, a D-phenylalanine structure, a D-valine structure, a D-structure, -alanine, a structure of D-tyrosine, a structure of D-iodotyrosine and a structure of D-lysine. In another embodiment, the peptide structure comprises at least four D-amino acid structures independently selected from the group consisting of a D-leucine structure, a D-phenylalanine structure, and a D-valine structure. In another embodiment, the peptide structure comprises at least four D-amino acid structures independently selected from the group consisting of a D-leucine structure, a D-phenylalanine structure, and a D-valine structure. In preferred embodiments, the peptide structure includes at least one phenylalanine analogue which is more stable than phenylalanine and which exhibits a lower tendency to oxidative metabolism. In one embodiment, the invention provides a β-amyloid modulator compound comprising a formula (I): An (Y-Xaa? -Xaa2-Xaa-Xaa-Z) '(I) wherein Xaai, Xaa2, Xaa3 and Xaa4 are each structures of D-amino acids and at least two of Xaai, Xaa2, Xaa3 and Xaa4 are, independently, selected within the group consisting of a structure of D-leucine, a structure of D-phenylalanine, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bro-ofhenylalanine, nitrophenylalanine, and D-homophenylalanine, and a D-valine structure; And, which may be present or not, is a structure having the formula (Xaa) a, wherein Xaa is any structure of D-amino acid and "a" is an integer from 1 to 15; Z, which may or may not be present, is a structure having the formula (Xaa) b # where Xaa is any D-amino acid structure and "b" is an integer from 1 to 15; A, which may or may not be present, is a modifying group fixed directly or indirectly on the compound; And "n" is an integer from 1 to 15; wherein Xaai, Xaa2, Xaa3, Xaa4, Y, Z, A and "n" is selected such that the compound binds to natural β-amyloid peptides or modulates the aggregation or inhibits the neurotoxicity of β-amyloid peptides natural when it comes into contact with the natural β-amyloid peptides and has a lower tendency to metabolism, for example, oxidant metabolism. In a submodality of this formula, a fifth amino acid residue Xaa5, is a C-terminal specific for Xaa4 and Z, which may or may not be present, is a structure having the formula (Xaa) b, wherein Xaa is any structure of D-amino acids and "b" is an integer from 1 to 14. Accordingly, the invention provides a β-amyloid modulator compound comprising a formula (II): An (Y-Xaai-Xaa2-Xaa3-Xaa.j -Xaa5-Z'5 (II) wherein "b" is an integer from 1 to 14. In a preferred embodiment, Xaai, Xaa2, Xaa3, Xaa4, of the formula (I) are selected based on the sequence of Aβ 7_20, or alternatively acceptable substitutions thereof Accordingly, in preferred embodiments, Xaai is a structure of D-alanine or a structure of D-leucine, Xaa2 is a structure of D-valine or a structure of D-phenylalanine., Xaa3 is a structure of D-felilalanine, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, and D-homophenylalanine, a structure of D-tyrosine, a structure of D-iodotyrosine, or a structure of D-lysine and Xaa4 is a structure of D-phenylalanine, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine , nitrophenylalanine, and D-homophenylalanine, a structure of D-tyrosine, a structure of D-iodotyrosine, or a structure of D-lysine. In another preferred embodiment, Xaa2, Xaa2, Xaa2, Xaa4 and Xaa; of the formula (I) are selected based on the sequence of Aβ1-2i, or acceptable substitutions thereof. Accordingly, in preferred embodiments, Xaai is a structure of D-alanine or a structure of D-leucine, Xaa2 is a structure of D-valine, Xaa3 is a structure of D-felilalanine, for example, D-cyclohexylalanine, D-4 -fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, and D-homophenylalanine, a structure of D-tyrosine, a structure of D-iodotyrosine, or a structure of D-lysine, Xaa4 is a structure of D-phenylalanine, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, D-pyridylalanine, and D-homophenylalanine, a structure of D-tyrosine, a structure of D-iodotyrosine, or a structure of D-lysine and Xaas is a structure of D-alanine or a structure of D-leucine. In another preferred embodiment, Xaa, Xaa, Xaa3 and Xaa4 of the formula (I) are selected based on the retro-inverse isomer of Aβ 7-2o / or acceptable substitutions thereof. Accordingly, in preferred embodiments, Xaai is a D-alanine structure, a D-leucine structure, or a D-phenylalanine structure, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D -pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, and D-homophenylalanine, a D-tyrosine structure, a D-iodotyrosine structure, a D-leucine structure, a D-valine structure, or a D-lysine structure; Xaa2 is a structure of D-phenylalanine, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, D-pyridylalanine, and D-homophenylalanine, a D-structure. tyrosine, a structure of D-iodotyrosine, or a structure of D-lysine; Xaa3 is a structure of D-felilalanine, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, D-pyridylalanine, and D-homophenylalanine, a D-structure. -tyrosine, a structure of D-iodotyrosine, or a structure of D-lysine; and Xaa4 is a structure of D-valine or a structure of D-leucine. In another preferred embodiment, Xaa :, Xaa2, Xaa3, Xaa4 and Xaas of the formula (I) are selected based on the retro-inverso isomer of Aβ? 2--2 ?, or acceptable substitutions thereof. Accordingly, in preferred embodiments, Xaa2 is a D-alanine structure, a D-leucine structure, or a D-phenylalanine structure, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D -pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, D-pyridylalanine, and D-homophenylalanine, a structure of D-tyrosine, a structure of D-iodotyrosine or a structure of D-lysine; Xaa2 is a structure of D-phenylalanine, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, D-pyridylalanine, and D-homophenylalanine, a D-structure. tyrosine, a structure of D-iodotyrosine, or a structure of D-lysine; Xaa3 is a structure of D-felilalanine, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, D-pyridylalanine, and D-homophenylalanine, a D-structure. -tyrosine, a structure of D-iodotyrosine, or a structure of D-lysine; and Xaa4 is a structure of D-valine or a structure of D-leucine and Xaa5 is a structure of D-leucine. In another embodiment, the invention provides a β-amyloid modulator compound comprising a formula (III): An (Y-Xaa? -Xaa2-NH- [(Z-Xaai '-Xaa2' -Xaa3 '-) NHf (III) wherein Xaai and Xaa2 are each structures of D-amino acids and at least two of Xaai and Xaa2 are independently selected within the group comprising a D-leucine structure, D-phenylalanine structure, eg, D- cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, and D-homophenylalanine, a D-tyrosine structure, a D-iodotyrosine structure, a D-lysine structure, or well a structure of D-valine; NH-NH is a hydrazine structure; And, which may be present or not, is a structure having the formula (Xaa) a, wherein Xaa is any structure of D-amino acid and "a" is an integer from 1 to 15; Xaa? ', Xaa2'and Xaa3'which may or may not be present, are each structures of D-amino acids or L-amino acids and at least two of Xaa?', Xaa2'and Xaa3 'are selected, independently within the group which consists of a D-leucine structure, D-phenylalanine structure or an L-phenylalanine structure, for example, D-cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine , and D-homophenylalanine, a structure of D-tyrosine or L-tyrosine, a structure of D-iodotyrosine or L-iodotyrosine, a structure of D-lysine or L-lysine, or a structure of D-valine or L- valina; Z, which may or may not be present, is a structure having the formula (Xaa) b, wherein Xaa is any structure of D-amino acid and "b" is an integer from 1 to 15; A, which may or may not be present, is a modifying group fixed directly or indirectly on the compound; And "n" is an integer from 1 to 15; wherein Xaai ', Xaa2', Xaa3 ', Y, Z, A and "n" is selected such that the compound binds to natural β-amyloid peptides or modulates the aggregation or inhibits the neurotoxicity of β-peptides natural amyloids when it comes into contact with the natural β-amyloid peptides and has a lower tendency to metabolism, for example, oxidative metabolism. In the modulators of the invention having the formula (I), (II) or (III) shown above, an optional modifier group ("A") is directly or indirectly fixed on the peptide structure of the modulator. As used herein, the term "modulating group" and "modifying group" are used interchangeably to describe a chemical group directly or indirectly fixed on a peptide structure. For example, a modifying group (s) can be directly fixed by covalent coupling on the peptide structure or a modifying group (s) can be fixed (s) indirectly through a stable non-covalent aiation. In one embodiment of the invention, a modifier group is fixed on the amino terminal of the modulator. Alternatively, in another embodiment of the invention, a modifier group is fixed on the carboxy terminal of the modulator. In other embodiments, the modifier group is fixed both on the amino terminal and on the carboxy terminal of the modulator. In another embodiment, a modulatory group (s) is (are) fixed on the side chain of at least one amino acid residue of the modulator peptide structure (e.g., through the group). epsilon-amino of a lysyl residue (s), through the carboxyl group of an acetic acid residue (s) or a glutamic acid residue (s), through a hydroxyl group of a tyrosyl residue, a serine residue (s) or a threonine residue (s), or another suitable reactive group on a side chain of amino acids.) If one (a) group (s) ) modifier (s) present (s), the modifier group is selected such that the compound inhibits the aggregation of natural β-amyloid peptides when in contact with the natural β-amyloid peptides., since the β-AP peptide of the compound is modified from its natural state, the modifying group "A" as used herein is not intended to include hydrogen. In a modulator of the invention, a single modifying group can be fixed on the peptide structure or several modifying groups can be fixed on the peptide structure. The number of modifying groups is selected such that the compound inhibits the aggregation of natural β-amyloid peptides when in contact with the natural β-amyloid peptides. However, "n" is preferably an integer between 1 and 60, more preferably between 1 and 30, and preferably even greater between 1 and 10 or between 1 and 5. In a preferred embodiment, A is a group amino terminal modifier comprising a cyclic, heterocyclic, polycyclic, linear or branched alkyl group and n = 1. In another preferred embodiment, A is a carboxy terminal modifying group comprising an amide group, an alkylamide group, an arylamide group or a hydroxy group and n = 1. Suitable modifying groups are described in greater detail in subsections II and III below. In preferred specific embodiments, the invention features a β-amyloid modulator compound comprising a peptide structure selected from the group consisting of (D-Leu-D-Val-D-Phe-D-Cha-D-Leu) (SEQ ID NO: 5); (D-Leu-D-Val-D-Cha-D-Phe-D-Leu) (SEQ ID NO: 6); (D-Leu-D-Val-D-Phe-D- [p-F] Phe-D-Leu) (SEQ ID NO: 7); (D-Leu-D-Val-D- [p-F] Phe-D-Phe-D-Leu) (SEQ ID NO: 8); (D-Leu-D-Val-D-Phe-D- [Fs] Phe-D-Leu) (SEQ ID NO: 9); (D-Leu-D-Val-D- [F5] Phe-D-Phe-D-Leu) (SEQ ID NO: 10); (D-Leu-D-Phe-D-Cha-D-Val-D-Leu) (SEQ ID NO: 11); (D-Leu-D-Phe-D- [p-F] Phe-D-Val-D-Leu) (SEQ ID NO: 12); D-Leu-D-Phe-D- [F5] Phe-D-Val-D-Leu) (SEQ ID NO: 13); (D-Leu-D-Phe-D-Lys-D-Val-D-Leu) (SEQ ID NO: 14); (D-Leu-D-Cha-D-Phe-D-Val-D-Leu) (SEQ ID NO: 15); (D-Leu-D- [p-F] Phe-D-Phe-D-Val-D-Leu) (SEQ ID NO: 16); (D-Leu-D- [F5] Phe-D-Phe-D-Val-D-Leu) (SEQ ID NO: 17); (D-Leu-D-Lys-D-Phe-D-Val-D-Leu) (SEQ ID NO: 18); (D-Leu-D-Cha-D-Cha-D-Val-D-Leu) (SEQ ID NO: 19); (D-Leu-D-Val-D-Cha-D-Cha-D-Leu) (SEQ ID NO: 20); (D-Leu-D- [p-F] Phe-D- [p-F] Phe-D-Val-D-Leu) (SEQ ID NO: 21); (D-Leu-D-Val-D- [p-F] Phe-D- [p-F] Phe-D-Leu) (SEQ ID NO: 22); (D-Leu-D- [F5] Phe-D- [F5] Phe-D-Val-D-Leu) (SEQ ID NO: 23); (D-Leu-D-Val-D- [F_] Phe-D- [F5] Phe-D-Leu) (SEQ ID NO: 24); (D-Leu-D-Val-D-Phe) (SEQ D NO: 25). Any of the specific peptide structures mentioned above can be modified at amino and / or carboxy terminal and are described below in subsections II and / or III. Particularly preferred modulators of the invention include the following: N, -dimethyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH:; N, N-dimethyl- (D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-methyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) NH 2; N-ethyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH ?; N-isopropyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Ala) -isopropylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Ala) -dimethylamide; N, N-diethyl (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N, N-diethyl- (D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2: N, N-dimethyl- (D-Leu-D-Val-D-Phe-D) -Phe-D-Leu) -NH_; N, N-dimethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N, N-dimethyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH2; H- (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N-ethyl (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N-ethyl- (Gly-D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-methyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-ethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N-propyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N, N-diethyl- (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; H- (D-Ile-D-Val-D-Phe-D-Phe-D-Ile) -NH2; H- (D-Ile-D-Val-D-Phe-D-Phe-D-Ala -) - NH 2; H- (D-Ile-D-Ile-D-Phe-D-Phe-D-Ile) -NH2; H- (D-Nle-D-Val-D-Phe-D-Phe-D-Ala-) -NH2; H- (D-Nle-D-Val-D-Phe-D-Phe-D-Nle) -NH2; 1-piperidine-acetyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; 1-piperidine-acetyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu.). -NH :; HD-Leu-D-Val-D-Phe-D-Phe-D -Leu-isopropylamide; HD-Leu-D-Phe-D-Phe-D-Val-D-Leu-isopropylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -methylamide; H- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -methylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-) Leu) -OH; N-methyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH:; H- (D-Leu-D-Val-D-Phe-D) -Cha-D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D- [pF] Phe-D-Leu) -NH;; H- (D-Leu-D-Val -D-Phe-D- [F5] Phe-D-Leu) -NH2; H- (D-Leu-D-Phe-D-Cha-D- Val-D-Leu) -NH2; H- (D- Leu-D-Phe-D- [pF] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Phe-D- [F5] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Phe-D-Lys-D-Val-D-Leu) -NH2; H- (D-Leu-D-Cha-D-Phe-D-Val-D-) Leu) -NH2; H- (D-Leu-D- [pF] Phe-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D- [F5] Phe-D- Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Leu-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Cha-D-Cha-D-Val-D-Leu) -NH2; H- (D-Leu-D- [p-F] Phe-D- [p-F] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D [F5] Phe-D- [F5] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Lys-D-Lys-D-Val-D-Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D-Cha-D-Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D- [p-F] Phe-D-Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D- [F5] Phe-D-Leu) -NH2; H-D-Leu-D-Val-D-Phe-NH- (H-D-Leu-D-Val-D-Phe-) NH; H-D-Leu-D-Val-D-Phe-NH-NH-COCH3; and H-D-Leu-D-Val-D-Phe-NH-NH2. Even more preferred compounds of the invention include PPI-1319: H- (D-Leu-D-Phe- [pF] D-Phe-D-Val-D-Leu) -NH2 and PPI: 1019: N-methyl- ( D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2. (As described above, D-Cha represents D-cyclohexylalanine; [pF] fo D- [pF] Phe represents D-4-fluorophenylalanine (also para-fluorophenylalanine); [F5] fo D- [F5] Phe represents D-pentafluorophenylalanine, and D-Nle represents D-norleucine). The D-amino acid peptide structures of the modulators of the invention further contemplate the inclusion of other peptide modifications, including analogs, derivatives and mimetics, which retain the ability of the modulator to alter natural β-AP aggregation in accordance with what is described herein. . For example, a peptide structure of D-amino acids of a modulator of the invention can be further modified to increase its stability, bioavailability, and solubility. The terms "analog", "derivative" and "mimetic" as used herein are intended to include molecules that mimic the chemical structure of a D-peptide structure and retain ^ fc the functional properties of the D-peptide structure. Approaches to design analogs, derivatives and peptide mimetics are known in the art. For example, see Farmer, P.S. in Drug Design (EJ Ariens, ed.) (Academic Press, New York, 1980, vol 10, pages 119-143; Ball, JB and Alewood, PF (1990) J. Mol. Recognition 3:55; Morgan, BA and Gainor, JA (1989) Ann. Rep. Med. Chem. 24: 243; W 10 Freidinger, R.M. (1989) Trends Pharmacol. Sci. 10: 270 See also Sawyer, T.K. (1995) "Peptidomimetic Design and Chemical Approaches to Peptide Metabolism" in Taylor, M.D. and Amidon, G.L. (eds.) Peptide-Based Drug Design: Controlling Transport and Metabolism, chapter 17; Smith, A.B. 3era, et 15 al. (1995) J. Am. Chem. Soc. 117: 11113-11123; Smith, A.B. 3era, et al. (1994) J. Am. Chem. Soc. 116: 9947-9962; and Hirschman, R., et al. (1993) J. Am. Chem. Soc. 115: 12550-12568. As used herein, a "derivative" of a compound X (for example, a peptide or amino acid) refers to an X form wherein one or several reaction groups in the compound have been derivatized with a substituent group. Examples of peptide derivatives include peptides in which a side chain of amino acids, the peptide structure, or the amino terminal or carboxy has been derived (for example, peptide compounds with methylated amide bonds). As used herein, an "analog" of a compound X refers to a compound that retains chemical structures of X necessary for the functional activity of X and which nevertheless also contains certain chemical structures that differ from X. An example of an analog of a peptide that occurs naturally is a peptide that includes one or several amino acids that do not occur naturally. As used herein, a "mimetic" of a compound X refers to a compound wherein the chemical structures of X necessary for the functional activity of X have been replaced by other chemical structures that mimic the conformation of X. Examples of peptidomimetics include peptide compounds wherein the peptide structure is substituted by one or more benzodiazepine molecules (see, James, GL et al (1993) Science 260: 1937-1942). Analogs of the modulator compounds of the invention include compounds in which one or more D-amino acids of the peptide structure are replaced by a homologous amino acid such that the properties of the original modulator are maintained. Preferred conservative amino acid substitutions are made in one or more amino acid residues. A "conservative amino acid substitution" is a constitution in which the amino acid residue is replaced by an amino acid residue having a similar side chain. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (eg, lysine, arginine, histidine), acid side chains (eg, aspartic acid, glutamic acid), polar side chains not charged (eg, glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine), non-polar side chains (eg, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), branched ß-side chains ( for example, threonine, valine, isoleucine) and aromatic side chains (eg, tyrosine, phenylalanine, tryptophan, histidine). Non-limiting examples of homologous substitutions that can be made in the peptide structures of the modulators of the invention include substitution of D-phenylalanine with D-tyrosine, D-pyridylalanine or D-homophenylalanine, substitution of D-leucine with D-valine or other natural or non-natural amino acid having an aliphatic side chain and / or substitution of D-valine with D-leucine or another natural or non-natural amino acid having an aliphatic side chain. The term mimetic, and particularly mimetic peptide, includes isosteres. The term "isostere" as used herein, includes a chemical structure that may be substituted by a second chemical structure due to the fact that the steric conformation of the first structure is adjusted at a specific binding site for the second structure. The term specifically includes structure modifications peptide fc (ie, amide bond mimetics) well known to those skilled in the art. Such modifications include modifications of the amide nitrogen, alpha-carbon, amide carbonyl, complete replacement of the amide bond, extensions, removals or cross-links of structure. Several modifications of peptide structure are known, including? [CH2S], 10? [CH2NH],? [CSNH2],? [NHCO],? [COCH2] and? [(E) or (Z) CH = CH] . In the nomenclature used above,? indicates the absence of an amide bond. The structure that replaces the amide group is specified between the brackets. Other possible modifications include a substitution of N-alkyl (or aryl) (? [C0NR]), or a crosslinking of structure to build lactams and other cyclic structures. Other derivatives of the modulator compounds of the invention include C-terminal hydroxymethyl derivatives, O-modified derivatives (e.g., C-terminal hydroxymethyl benzylester), N-terminal modified derivatives including substituted amides such as alkylamides and hydrazides and compounds in which a C-terminal phenylalanine residue is replaced by a phenethylamine analog (e.g., Val-Phe-phenethylamide 25 as the tripeptide analogue Val-Phe-Phe).

The modulator compounds of the invention can be incorporated into pharmaceutical compositions (described below in subsection V) and can be employed in methods of detection and treatment in accordance with what is described in greater detail in subsection VI below. II. Modifier groups In certain embodiments, the modulator compounds of the invention are coupled directly or indirectly with at least one modifier group (abbreviated MG). The term "modifying group" includes structures directly attached to the peptide structure of D-amino acid (eg, by covalent coupling), as well as structures indirectly fixed on the peptide structure (eg, through a stable non-covalent association or either through a covalent coupling with additional amino acid residues or mimetics, analogs or derivatives thereof, which may flank the peptide structure of D-amino acid derived from Aβ). For example, the modifier group can be coupled to the amino terminal or the carboxy terminal of a D-amino acid-derived peptide structure or to a peptidomimetic or peptide region that flanks the core domain. Alternatively, the modifier group can be coupled to a side chain of at least one D-amino acid residue of a D-amino acid peptide structure derived from Aβ, or to a flanking peptide or peptidomimetic region (ie, the core domain). (for example, through the epsilon amino group of a lysyl residue (s), through the carboxyl group of a residue (s) of aspartic acid or a residue (s) of glutamic acid, through a hydroxyl group of a tyrosyl residue (s), a serine residue (s), or a threonine residue (s) or other suitable reactive group in a side chain of amino acids.

Modifying groups covalently coupled to the D-amino acid peptide structure can be fixed by means and using methods well known in the art to link chemical structures, including, for example, amide, alkylamino, carbamate, urea or ester linkages. The term "modifying group" is intended to include groups that are not naturally coupled to native Aβ peptides in their native form. Accordingly, the term "modifying group" is not intended to include hydrogen. The modifying group (s) is selected in such a way that The modulator compound alters and preferably inhibits the aggregation of natural β-amyloid peptides when in contact with the natural β-amyloid peptides or in such a way as to inhibit the neurotoxicity of natural β-amyloid peptides when in contact with the peptides of natural ß-amyloids. Even though we do not intend to limit ourselves to a mechanism, in modalities where the modulator comprises a modifying group (s) (s) the modifying group (s) functions as a key pharmacophore that increases the ability of the modulator to upset the polymerization of Aß. In a preferred embodiment, the modifying group (s) comprises (s) an alkyl group. The term "alkyl", as used herein, refers to a straight or branched chain hydrocarbon group having from about 1 to about 10 carbon atoms. Exemplary alkyl groups include methyl, ethyl, dimethyl, diethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, and n-hexyl. An alkyl group may be unsubstituted or may be substituted in one or several positions for example with halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, heterocycles, hydroxyls, amines, nitros, thiols, amines, imines, amides, phosphonates, phosphines carbonyls, carboxyls, silyles, ethers, thioethers, sulfonyl, selenoethers, ketones, aldehydes, esters, -CF3, -CN, or the like. Preferred alkyls are methyl, ethyl, dimethyl, diethyl, n-propyl, isopropyl. In another embodiment, a modifying group, such as an alkyl group, is coupled to another modifying group. In another embodiment, a D-amino acid in a modulator compound of the invention is modified with two modifying groups. Accordingly, preferred modifier groups include a 1-piperidinacetyl group. • In a preferred embodiment, the modifying group (s) comprises (s) a cyclic, heterocyclic, polycyclic or branched alkyl group. The term "cyclic group", as used herein, is intended to include saturated or unsaturated (i.e., aromatic) cyclic group having from about 3 to 10, preferably from about 4 to 8, and with greater Preference of about 5 to 7 carbon atoms. Exemplary cyclic groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclooctyl. The cyclic groups can be unsubstituted or substituted in one or several ring positions. Thus, a cyclic group may be substituted, for example, with halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, heterocycles, hydroxyls, amines, nitros, thiols, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyles, ethers, thioethers, sulfonyls, sulfonates, selenoethers, Ketones, aldehydes, esters, -CF3, -CN, or the like. The term "heterocyclic groups" is intended to include a saturated or unsaturated (i.e., aromatic) cyclic group of about 3 to 10, preferably about 4 to 8, and more preferably about 5 to 7 carbon atoms.

Carbon, wherein the ring structure includes about one to four heteroatoms. Heterocyclic groups include pyrrolidine, oxolane, thiolane, imidazole, oxazole, piperidine, piperazine, morpholine and pyridine. The heterocyclic ring can be substituted at one or several positions with substituents such as, for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, aryls, other heterocycles, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyles, ethers, thioethers, sulfonyl, selenoethers, ketones, aldehydes, esters, -CF3, -CN or the like. The heterocycles may also be bridged or fused to other cyclic groups in accordance with what is described below. The term "polycyclic group" as used herein is intended to refer to two or more saturated or unsaturated (i.e., aromatic) cyclic rings wherein two or more carbon atoms are common to two adjacent rings, for example, the rings are "rings" merged. " Rings joined through non-adjacent atoms are known as "bridged" rings. Each of the rings of the polycyclic group can be substituted with substituents described above such as, for example, halogens, alkyls, cycloalkyls, alkenyls, alkynyls, hydroxyl, amino, nitro, thiol, amines, imines, amides, phosphonates, phosphines, carbonyls, carboxyls, silyles, ethers, thioethers, sulfonyl, selenoethers, ketones, aldehydes, esters, -CF3, -CN or similar. A preferred polycyclic group is a group that contains a cis-decalin structure. Although we do not intend to be limited by the mechanism, it is thought that the "bent" conformation provided in a modifying group by the presence of a cis-decalin structure contributes to the efficacy of the modifying group in upsetting the Aβ polymerization. Accordingly, other structures that mimic the "bent" configuration of the cis-decalin structure can also be employed as modifying groups. An example of a cis-decalin-containing structure that can be used as a modifying group is a collanoyl structure, such as a colyl group. For example, a modifying compound can be modified at its amino terminus with a colyl group by reaction of the aggregation core domain with cholic acid, a bile acid. In addition, a modulator compound can be modified at its carboxy terminus with a colyl group in accordance with methods known in the art (see, for example, Wess, G. et al. (1993) Tetrahedron Letters, 34: 817-822; Wess, G. et al. (1992) Tetrahedron Letters 33: 195-198; and Kramer, W. et al. (1992) J. Biol. Chem. 267: 18598-18604). Derivatives and colyl analogues can also be used as modifying groups. For example, a preferred colyl derivative is Aic (3- (O-aminoethyl-iso) -colyl), which has a free amino group that can be used to further modify the modulator compound (for example, a chelation group for 99mTc can be introduced through the free amino group of Aic). As used herein, the term "collanoyl structure" is intended to include the colyl group and derivatives and analogs thereof, particularly those which retain a four-ring cis-decalin configuration. Examples of collanoyl structures include groups derived from other bile acids such as deoxycholic acid, lithocholic acid, ursodeoxycholic acid, chenodeoxycholic acid and hiodeoxycholic acid, as well as other related structures such as for example colanic acid, bufalin and resibufogenin (although these latter two compounds they are not preferred for use as a modifier group). Another example of a cis-decalin-containing compound is 5β-cholestan-3-a-ol (the cis-decalin isomer of (+) - dihydrocholesterol). For a more detailed description of steroid bile acid structure and nomenclature, see Nes, W. R. and McKean, M.L. Biochemistry of Steroids and Other Isopentanoids, University Park Press, Baltimore, MD, Chapter 2. In addition to groups containing cis-decalin, other polycyclic groups can be used as modifying groups. For example, modifying groups derived from steroids or β-lactams can be suitable modifying groups. In one embodiment, the modifying group is a "biotinyl structure", which includes biotinyl groups and analogs and derivatives thereof (such as, for example, 2-iminobiotinyl group). In another embodiment, the modifying group may comprise a "fluorescein-containing group", such as, for example, a group derived from the reaction of a peptide structure derived from Aβ with 5- (and 6 -) - carboxyfluorescein, succinimidylester or isothiocyanate fluorescein. In various other embodiments, the modifying group (s) can (n) comprise an N-acetylneuraminyl group, a trans-4-cotinincarboxyl group, a 2-imino-l-imidazolidineacetyl group, a group (S) ) - (-) - indolin-2-carboxyl, a (-) -mentoxyacetyl group, a 2-norboronacetyl group, a? -oxo-5-acenaphthenbutyryl group, a (-) -2-oxo-4-thiazolidincarboxyl group, a tetrahydro-3-furoyl group, a 2-iminobiotinyl group, a diethylenetriaminpentaacetyl group, a 4-morpholinecarbonyl group, a 2-thiopheneacetyl group, or a 2-thiophenesulfonyl group. In addition to the cyclic, heterocyclic and polycyclic groups discussed above, other types of modifying groups can be employed in a modulator of the present invention. For example, hydrophobic groups and branched alkyl groups can be suitable modifying groups. Examples include acetyl groups, phenylacetyl groups, diphenylacetyl groups, triphenylacetyl groups, isobutanoyl groups, 4-methylvaleryl, trans-cinnamoyl groups, butanoyl groups and 1-adamantanecarbonyl groups. Another type of modifier group is a compound that contains an unnatural amino acid that acts as a beta-turn mimic such as for example an amino acid based on dibenzofuran described in Tsang, K.Y. et al. (1994) J. Am. Chem. Soc. 116: 3988-4005; Diaz, H and Kelly, J.W. (1991) Tetrahedron Letters 41: 5725-5728; and Diaz. H et al. (1992) J. Am. Chem.

Soc. 114: 8316-8318. An example of a modifying group of this type is a peptide-aminoethyldibenzofuranyl-propionic acid (Adp) group (eg, DDIIL-Adp) (SEQ ID NO: 31).

This type of modifier group can further comprise one or several N-methyl peptide bonds to introduce additional steric hindrance to the aggregation of natural β-AP when compounds of this type interact with natural β-AP. Another type of group or modifier is an NH-OR group, where R can be any modified or unmodified alkyl or cycloalkyl group described herein. Non-limiting examples of suitable modifying groups, with their corresponding modifying reagents, are presented in the following list: Modifying reagent modifier methyl-methylamine, Fmoc-D- [Me] -Leu-OH, methylamine and a bromoacetylpeptide ethyl-ethylamine , acetaldehyde and sodium cyanoborohydride, ethylamine and a bromoacetylpeptide propyl propylamine, propionaldehyde and sodium cyanoborohydride, propylamine and a bromoacetylpeptide isopropyl isopropylamine, isopropylamine and a bromoacetylpeptide piperidinopiperidine and a bromoacetylpeptide acetyl anhydride acetic acid, acetic acid dimethylamine, formaldehyde and sodium cyanoborohydride diethyl acetaldehyde and sodium cyanoborohydride colyl- cholic acid lithocholyl lithocholic acid hiodeoxycholyl-hiodeoxycholic acid chenodeoxychol- chenodeoxycholic acid ursodeoxychol-ursodeoxycholic acid 3-hydroxycinnamoyl-3-hydroxycinnamic acid 4-hydroxycinnamoyl-4-hydroxycin 2-hydroxycinnamoyl-2-hydroxycinnamic acid 3-hydroxy-4-methoxy-3-hydroxy-4-methoxycinnamic acid namoyl 4-hydroxy-3-methoxy-4-hydroxy-3-methoxycinnamic acid namoyl-2-carboxycinomethyl acid 2 -carboxykinetic 3-formylbenzoyl 3-carboxybenzaldehyde 4-formylbenzoyl 4-carboxybenzaldehyde 3,4-dihydroxyhydrocycid-3,4-dihydroxyhydrocinnamic acid namoyl-3,7-dihydroxy-2-naph-3,7-dihydroxy-2-naphthoic acid - 4-formylcinnamoyl- 4-formyl cinnamic acid 2-formylphenoxyacetyl-2-formylphenoxyacetic acid 8-formyl-1-naphthoyl 1,8-naphthadehyde acid 4- (hydroxymethyl) benzoyl- 4- (hydroxymethyl) benzoic acid 4-hydroxyphenylacetyl-4-hydroxyphenylacetic acid 3-hydroxybenzoyl-3-hydroxybenzoic acid 4-hydroxybenzoyl-4-hydroxybenzoic acid 5-hydantoinacetyl-5-hydanto-acetic acid L-hydroorotyl-L-hydroorotic acid 4-methylvaleryl-4-methylvaleric acid 2, 4-dihydroxybenzoyl-2,4-dihydroxybenzoic acid 3,4-dihydroxycinnamoyl-3,4-dihydroxycinnamic acid 3,5-dihydroxy-2-naphthoyl-3,5-dihydroxy-2-naphthoic acid 3-trans-Cinamoil- benzoilpropanoil- acid 3-trans-cinnamic acid benzoilpropanoico phenylacetyl phenylacetic acid diphenylacetic acid difenilacetil- trifenilacetil- triphenylacetic 2-hidroxifenilaceti1- 2-hydroxyphenylacetic acid 3-hidroxifenilacetil- 4-hydroxyphenylacetic acid, 3-hidroxifenilaceti1- 4- -hydroxyphenylacetic (±) -mande1i1- (±) -mandelic acid (±) -2, -dihydroxy-3, 3- (±) -pantolactone dimethylbutanoyl butanoyl-butanoic anhydride isobutanoyl-isobutanoic anhydride hexanoyl-hexanoic anhydride propionyl-propionic anhydride 3 -hydroxybutyroyl β-butyrolactone 4-hydroxybutyroyl β-butyrolactone 3-hydroxypropionoyl β-propiolactone 2, -dihydroxybutyroyl α-hydroxy-β-butyrolactone 1-adamantanecarbonyl-1-adamantanecarbonic acid glycolyl glycolic acid DL-3- (4-hydroxyphenyl) acid DL-3- (4-hydroxyphenyl) lactic lactyl-3- (2-hydroxyphenyl) pro-3- (2-hydroxyphenyl) propionic pionyl-4- (2-hydroxyphenyl) pro 4- (2-hydroxyphenyl) propionic acid pionyl-D-3-phenylactyl-D-3-phenylactic acid hydrocinmoyl-hydrocinnamic acid 3- (4-hydroxyphenyl) pro-3- (4-hydroxyphenyl) propionic pionyl-L-3 -phenylactyl- L-3-phenylactic acid 4-methylvaleryl 4-methylvaleryl acid 3-pyridylacetyl 3-pyridylacetic acid 4-pyridylacetyl 4-pyridylacetic acid isonicotinoyl 4-quinolinecarboxyl 4-quinolinecarboxylic acid 1-isoquinolinecarboxyl 1-isoquinolinecarboxylic acid 3-isoquinolinecarboxyl acid 3 -isoquinolinecarboxylic Preferred modifier groups include methyl-containing groups, groups containing ethyl, groups containing propyl, and groups containing piperidine, for example, group 1-piperidin-acetyl. III. Additional Chemical Modifications of Aβ Modulators A β-amyloid modulator compound of the invention can be further modified to alter the specific properties of the compound while retaining the ability of the compound to alter Aβ aggregation and inhibit Aβ neurotoxicity. For example, in one embodiment, the compound is further modified to alter a pharmacokinetic property of the compound, such as in vivo stability or half-life. In another embodiment, the compound is further modified to label the compound with a detectable substance. In another embodiment, the compound is further modified to couple the compound to an additional therapeutic portion. Schematically, a modulator of the invention comprising a D-amino acid Aβ aggregation core domain coupled directly or indirectly with at least one modifier group can be illustrated as MG-ACD, while this compound has been further modified to alter the properties of the modulator can be illustrated as MG-ACD-CM, where CM represents an additional chemical modification. To further modify the compound chemically, as for example to alter the pharmacokinetic properties of the compound, reactive groups can be derived. For example, when the modifier group is clamped on the amino terminal end of the aggregation core domain, the carboxy terminal end of the compound can be further modified. Preferred C-terminal modifications include those modifications that reduce the ability of the compound to act as a substrate for carboxypeptidases. Examples of terminal modifiers Preferred Cs include an amide group (i.e., a peptide amide), an alkylamide or arylamide group (e.g., an ethylamide group or a phenethylamide group), a hydroxy group (ie, a peptide alcohol), and several non-natural amino acids such as for example D-amino acids and β-alanine.

Alternatively, when the modifying group is fixed on the carboxy terminal end of the aggregation core domain, the amino terminal end of the compound can be further modified, for example, to reduce the ability of the compound to act as a substrate for aminopeptidases. A modulator compound can be further modified to label the compound by reacting the compound with a detectable substance. Suitable detectable substances include various enzymes, prosthetic groups, fluorescent materials, luminescent materials and radioactive materials. Examples of suitable enzymes include sour horseradish peroxidase, alkaline phosphatase, β-galactosidase or acetylcholinesterase; examples of suitable prosthetic group complexes include streptavidin / biotin and avidin / biotin; examples of suitable fluorescent materials include umbelliferone, fluorescein, fluorescein isothiocyanate, rhodamine, dichlorotriazinylaminifluorescein, dansyl chloride, or phycoerythrin; an example of a luminescent material is luminol; and examples of suitable radioactive materials include 1C, 123I, I24I, 125I, 11I,? 9mTc, 3 £ S or 3H. In a preferred embodiment, a modulator compound is radioactively labeled with 14C, either by incorporation of 1C into the modifier group or one or more amino acid structures in the modulator compound. Marked modulator compounds can be used to evaluate the in vivo pharmacokinetic characteristics of the compounds as well as to detect aggregation of Aβ, for example, for diagnostic purposes. Aggregation of Aβ can be detected using a labeled modulator compound either in vivo or in an in vitro sample derived from a subject. Preferably, for use as an in vivo diagnostic agent, a modulator compound of the present invention is labeled with radioactive technetium or iodine. Accordingly, in one embodiment, the invention offers a modnet compound labeled with technetium, preferably 99 Tc. Methods for labeling peptide compounds with technetium are known in the art (see, for example, U.S. Patent Nos. 5,443,815, 5,225,180 and 5,405,597, all by Dean et al., Stepniak-Biniakiewicz, D., et al. (1992) J. Med. Chem .35: 274-279; Fritzberg, AR, et al. (1988) Proc Nati, Acad. Sci. USA 85: 4025-4029; Baidoo, KE, et al. (1990) Cancer Res. Suppl. : 799s-803s; and Regan L. and Smith, CK (1995) Science 270: 980-982). A modifier group can be selected which provides a site in which a chelation group for 99mTc can be introduced, such as the Aic derivative of cholic acid, which has a free amino group. In another embodiment, the invention offers a modulatory compound labeled with radioactive iodine. For example, a phenylalanine residue within the Aβ sequence (such as for example Pheig or Phe2o) can be substituted with radioactive iodotyrosyl. Any of the various isotopes of radioactive iodine can be incorporated to create a diagnostic agent. Preferably, 123I (half-life = 13.2 hours) is used for whole-body scentigraphy, 124I (half-life = 4 days) is used for positron emission tomography (PET), 125I (half-life = 60 days) is used for Studies of metabolic and 131I rotation (half-life = 8 days) are used for whole-body counting and slow-resolution delayed imaging studies. In addition, a further modification of a modulator compound of the present invention can serve to provide an additional therapeutic property in the compound. That is, the additional chemical modification may comprise an additional functional portion. For example, a functional portion that serves to decompose or dissolve amyloid plaques can be coupled with the modulator compound. In this form, the MG-ACD portion of the modulator serves to focus the compound towards Aβ peptides and disrupt the polymerization of the Aβ peptides, while the functional portion serves to decompose or dissolve amyloid plaques after the compound has been focused towards these sites. In an alternative chemical modification, a β-amyloid compound of the invention is prepared as a "prodrug", wherein the compound itself does not modulate Aβ aggregation, but can be transformed, upon in vivo metabolism, into a compound ß-amyloid modulator in accordance with what is defined here. For example, in this type of compound, the modulator group can be present in the form of a prodrug that can be converted by effecting the metabolism in the form of an active modulator group. Said pro-drug form of a modifying group is referred to herein as a "secondary modifying group". Several strategies are known in the art for preparing peptide prodrugs that limit metabolism for the purpose of optimizing the administration of the active form of the peptide-based drug (see, eg, Moss, J. (1995) in Peptide-Based Drug Design: Controlling Transport and Metabolics, Taylor, MD and Amidon, GL (eds), chapter 18. Additional strategies have been specifically designed to achieve administration to the central nervous system based on "sequential metabolism" (see, for example, Bodor, N., et al. (1992) Science 257: 1698-1700; Prokai, L., et al., (1994) J. Am. Chem. Soc. 116: 2643-2644; Bodor, N. and Prokai, L. (1995) in Peptide-Based Drug Design: Controlling Transport and Metabolics, Taylor, M.D. and Amidon, G.L. (eds), chapter 14. In one embodiment of a prodrug form of a modulator of the present invention, the modifying group comprises an alkyl ester to facilitate the permeability of the blood-brain barrier. Modulating compounds of the invention can be prepared by known standard techniques. The peptide component of a modulator can be synthesized using standard techniques such as those described in Bodansky, M. Principies of Peptide Synthesis, Springer Verlag, Berlin (1993) and Grant, G.A. (ed.) Syntheti c Peptides: A User's Guide, W.H. Freeman and Company, New York (1992). Automated peptide synthesizers are commercially available (see, for example, Advanced Chem Tech Model 396; Milligen / Biosearch 9600). In addition, one or more modulating groups can be fixed on the peptide component derived from Aβ (for example, an Aβ aggregation core domain) by standard methods, for example, using methods for reactions through an amino group ( for example, the alpha-amino group at the amino terminus of a peptide), a carboxyl group (for example, at the carboxyl terminus of a peptide), a hydroxyl group (for example, at a tyrosine, serine or threonine residue), or another suitable reactive group on an amino acid side chain (see, for example, Greene, TW and Wuts, PGM Protective Groups in Organic Synthesis, John Wiley and Sons, Inc., New York (1991). β-amyloid of D-amino acids are described in greater detail in Example 1.

IV. Sifting assays Another aspect of the invention relates to a method for selecting a β-amyloid aggregation modulator. In the method, a test compound comes into contact with natural β-amyloid peptides, the aggregation of a natural β-AP and is measured and a modulator is selected based on the ability of the test compound to alter the aggregation of β -AP natural (for example, inhibit or promote aggregation). In a preferred embodiment, the test compound comes in contact with a molar excess amount of the natural β-AP. The amount and / or rate of aggregation of natural β-AP in the presence of the test compound can be determined through a suitable assay indicating the aggregation of β-AP, in accordance with what is described herein (see, for example, Example 2) . In a preferred assay, the natural β-AP is dissolved in solution in the presence of the test compound and the aggregation of natural β-AP is evaluated in a nucleation assay (see, example 2) by evaluating the turbidity of the solution over time, as measured by the apparent absorbance of the solution at 405 nm (described in more detail in Example 2, see also Jarret et al (1993) Biochemistry 32: 4693-4697). In the absence of a β-amyloid modulator, the Ao5nm of the solution typically remains relatively constant for a period of time in which β-AP remains in solution, but then the A4o5nm of the solution rises rapidly as β-AP is added and leaves the solution, finally reaching a plateau level (ie, the A40snm of the solution has sigmoidal kinetic characteristics over time). In contrast, in the presence of a test compound that inhibits aggregation of β-AP, the A05nm of the solution is reduced compared to the case in which the modulator is absent. Thus, in the presence of the inhibitor modulator, the solution may exhibit an increased time delay, a decreased aggregation slope and / or a lower plateau level as compared to the case in which the modulator is absent. This method for selecting a β-amyloid polymerization modulator can be similarly used to select modulators that promote the aggregation of β-AP. A) Yes, in the presence of a modulator that promotes the aggregation of ß-AP, the 05nm of the solution is increased in comparison with the case in which the modulator is absent (for example, the solution may have a decreased time delay, an increased slope of aggregation and / or a higher plateau level compared to the case in which the modulator is absent). Another test suitable for use in the sieving method of the invention, a seeded extension test, is also described in more detail in Example 2. In this test, ß-AP monomer and a ß-AP "seed" added they are combined, in the presence and absence of a test compound, and the amount of ß-fibril formation is studied based on increased emission of the Thioflavine T dye when it comes in contact with ß-AP fibrils. In addition, the aggregation of ß-AP can be evaluated through electron microscopy (EM) of the ß-AP preparation in the presence or absence of the modulator. For example, the formation of β-amyloid fibrils, which is detectable through MS, is reduced in the presence of a modulator that inhibits the aggregation of β-AP (ie, that there is a reduced number of β-fibrils in the presence of modulator), while the formation of β-fibrils is increased in the presence of a modulator that promotes the aggregation of β-AP (ie, there is an increased amount of number of β-fibrils in the presence of the modulator). Another preferred test for use in the screening method of the present invention for selecting suitable modulators is the neurotoxicity assay described in Example 3. Compounds are selected which inhibit the formation of neurotoxic Aβ aggregates and / or which inhibit neurotoxicity of preformed Aß fibrils. This neurotoxicity assay is considered to be predictive of neurotoxicity in vivo. Accordingly, the inhibitory activity of a modulator compound in the in vitro neurotoxicity assay is predictive of a similar inhibitory activity of the compound for neurotoxicity in vivo. V. PHARMACEUTICAL COMPOSITIONS Another aspect of the invention relates to pharmaceutical compositions of the β-amyloid modulating compounds of the invention. In one embodiment, the composition includes a β-amyloid modulator compound in a therapeutically or prophylactically effective amount sufficient to alter, and preferably inhibit, the aggregation of natural β-amyloid peptides, and a pharmaceutically acceptable carrier. In another embodiment, the composition includes a β-amyloid modulator compound, a therapeutically or prophylactically effective amount sufficient to inhibit the neurotoxicity of natural β-amyloid peptides, and a pharmaceutically acceptable carrier. A "therapeutically effective amount" refers to an effective amount, in dosages and for periods of time necessary, to achieve the desired therapeutic result, such as reducing or reversing the β-amyloid deposit and / or reducing or reversing of neurotoxicity of Aß. A therapeutically effective amount of modulator may vary according to factors such as disease status, sex age, and weight of the individual, and the ability of the modulator to cause a -A -.- A. ,,,,, .- rtt '? ^ _. desired response in the individual. Dosage regimens can be adjusted to offer an optimal therapeutic response. A therapeutically effective amount is also an amount in which all toxic or detrimental effects of the modulator are more than offset by the beneficial effects from a therapeutic perspective. The potency neurotoxicity of the modulators of the invention can be tested using the cell-based assay described in Example 6, and a therapeutically effective modulator can be selected which does not exhibit significant neurotoxicity. In a preferred embodiment, a therapeutically effective amount of a modulator is sufficient to alter, and preferably inhibit, the aggregation of a molar excess amount of natural β-amyloid peptides. A "prophylactically effective amount" refers to an effective amount, in dosages and for periods of time necessary, to achieve the desired prophylactic result, such as to prevent or inhibit the β-amyloid deposition rate and / or Aβ neurotoxicity. in a subject predisposed to ß-amyloid deposition. A prophylactically effective amount can be determined in accordance with what is described above for the therapeutically effective amount. Typically, since a prophylactic dose is employed in subjects before or at an early stage of the disease, the prophylactically effective amount will be less than the therapeutically effective amount. One factor that can be considered when determining a therapeutically or prophylactically effective amount of a β-amyloid modulator is the concentration of natural β-AP in a biological compartment of a subject, such as the cerebrospinal fluid (CSF) of the subject. The concentration of natural β-AP in the cerebrospinal fluid has been estimated at 3 nM (Schwartzman, (1994) Proc. Nati Acad. Sci. USA 91 ^: 8368-8372). A non-limiting range for therapeutically or prophylactically effective amounts of a β-amyloid modulator is 0.01 nM-10 μM. It will also be noted that dosage values may vary according to the severity of the condition to be alleviated. It is further understood that for any particular subject, specific dosage regimens should be adjusted over time according to the need of the individual and the professional judgment of the person administering or supervising the administration of the compositions, and that the dosing ranges raised these are only examples and are not intended to limit the scope or practice of the claimed composition. The amount of active compound in the composition may vary in accordance with factors such as disease status, age, sex and weight of the individual, each of which may affect the amount of natural β-AP in the individual. Dosage regimens can be adjusted to provide the optimal therapeutic response. For example, a single bolus can be administered, several divided doses can be administered over time, or either the dose can be reduced or increased proportionally in accordance with the requirements of the therapeutic situation. It is generally advantageous to formulate parenteral compositions in dosage unit forms to facilitate administration and fl) for uniformity of dosage. A form of dosage unit as used herein refers to physically discrete units suitable as unit dosages for the mammalian subjects to be treated; Each unit contains a predetermined quantity of active compound that is calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier. The specification for dosage unit forms of the invention are dictated by (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the compounding technique for the treatment of sensitivity in individuals, and are directly dependent on such unique characteristics and inherent limitations. As used herein, the term "pharmaceutically vehicle "Acceptable" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption retardation agents, and the like physiologically compatible In one embodiment, the vehicle is suitable for parenteral administration. , the vehicle is suitable for administration in the central nervous system (eg, intraspinal or intracerebral) Alternatively, the vehicle may be suitable for intravenous, intraperitoneal or intramuscular administration In another embodiment, the vehicle is suitable for oral administration. acceptable include sterile aqueous solutions or sterile dispersions and powders for the extemporaneous preparation of sterile injectable solutions or dispersions.The use of such media and agents for pharmaceutically active substances is well known in the art, except insofar as conventional means or agents s are incompatible with the active compound, the use thereof in the pharmaceutical compositions is contemplated. Additional active compounds can also be incorporated into the compositions. Therapeutic compounds should typically be sterile and stable under the conditions of manufacture and storage. The composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable for high pharmacological concentration. The carrier may be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the use of coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants. In many cases, it is preferable to include isotonic agents, for example, sugars, polyalcohols, such as for example mannitol, sorbitol, or sodium chloride, in the composition. A prolonged absorption of the injectable compositions can be carried out by the inclusion in the composition of an agent that retards absorption, for example, salts of monostearate and gelatin. In addition, modulators can be administered in a sustained release formulation, for example, in a composition that includes a slow release polymer. The active compounds can be prepared with carriers that protect the compound against rapid release, such as for example controlled release formulation, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers can be employed such as for example ethylene, vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, polylactic acid, and polyglycolic, polylactic (PLG) copolymers. Many methods for the preparation of such formulations are patented or generally known to those skilled in the art. .dfc Sterile injectable solutions can be prepared by incorporating the active compound (eg, -amyloid moiety) in the required amount in an appropriate solvent with one of the ingredients mentioned above or a combination of the ingredients mentioned above, as required, followed by filtered sterilization. Generally, dispersions are prepared by the flB incorporation of the active compound in a sterile vehicle containing a basic dispersion medium and the other ingredients required from those enumerated above. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum dried and lyophilized which provides a powder of the active ingredient plus any additional desired ingredients from a pre-sterile filtered solution thereof. A modulator compound of the invention can be formulated with one or more additional compounds that increase the solubility of the modulator compound. Preferred compounds to be added to the formulations to increase the solubility of the modulators are cyclodextrin derivatives, preferably hydroxypropyl-β-cyclodextrin. Vehicles of The administration of drugs containing a cyclodextrin derivative for the administration of peptides to the central nervous system are described in Bodor, N., et al. (1992) Science 257: 1698-1700. In the case of the β-amyloid modulators described herein, the inclusion in the formulation of hydroxypropyl-β-cyclodextrin at a concentration of 50-200 mM increases the aqueous solubility of the compounds. In addition to an increased solubility, the inclusion of a cyclodextrin derivative in the formulation may have other beneficial effects, since β-cyclodextrin itself interacts, as reported, with the Aβ peptide and inhibits fibril formation in vitro ( Camilleri, P., et al. (1994) FEBS Letters 341: 256-258 Accordingly, the use of a modulator compound of the invention in combination with a cyclodextrin derivative can result in a greater inhibition of the aggregation of Aß that the use of the modulator alone Chemical modifications of cyclodextrins are known in the technique (Hanessian, S., et al. (1995) J. Org. Chem. 60: 4 ~? 86-4797). additive in a pharmaceutical composition containing a modulator of the invention, the cyclodextrin derivatives may also be useful as modifying groups and, therefore, may also be covalently coupled with a peptide compound of Aβ to form a modulator compound of the invention. Another preferred formulation of the modulator compounds for increasing brain absorption comprises the detergent Tween-80, polyethylene glycol (PEG) and ethanol in a saline solution. A non-limiting example of said preferred formulation is 0.16% Tween-80, 1.3% PEG-3000 and 2% ethanol in saline. In another embodiment, a pharmaceutical composition comprising a modulator of the invention is formulated in such a way that the modulator is transported through the blood-brain barrier (BBB). Several strategies known in the art to increase transport through the blood-brain barrier can be adapted to the modulators of the invention to thereby increase the transport of the modulators through the blood-brain barrier (for reviews of such strategies, see, for example, Pardridge, WM (1994) Trends in Biotechnology, l_2: 239-245, Van Bree, JB et al. (1993) Pharm. World Sci. 15: 2-9, and Pardridge, WM et al. (1992). ) Pharmacol Toxicol 71: 3-10). In one approach, the modulator is chemically modified to form a prodrug that increases transport through the membrane. Suitable chemical modifications include covalent bonding of a fatty acid on the modulator via an amide or ester linkage (see, for example, U.S. Patent No. 4,933,324 and PCT Publication WO 89/07938, both by Shashoua; US Patent No. 5,284,876 by Hesse et al., Toth, I. et al. (1994) J. Drug Target 2: 217-239; and Shashoua, VE et al. (1984) J. Med. Chem. 27: 659-664) and modulator glycope (see, for example, US Patent No. 5,260,308 by Poduslo et al.). Also, N-acylamino acid derivatives can be employed in a modulator to form a "lipid" prodrug (see, for example, 5,112,863 by Hashimoto et al.). In another approach to increase transport across the blood-brain barrier, a peptide or peptidomimetic modulator is conjugated with a second peptide or protein, thus forming a chimeric protein, wherein the second peptide or protein is subjected to a transcytosis mediated by absorption or mediated by receptor through the blood-brain barrier. Accordingly, by coupling the modulator with this second peptide or protein, the chimeric protein is transported across the blood-brain barrier. The second peptide or protein can be a ligand for brain capillary endothelial cell receptor ligand. For example, a preferred ligand is a monoclonal antibody that specifically binds to the transferrin receptor in brain capillary endothelial cells (see, for example, U.S. Patent Nos. 5,182,107 and 5,154,924 and PCT Publications WO 93/10819 and WO 95/02421, all by Friden. et al.). Other suitable peptides or other suitable proteins that can mediate transport across the blood-brain barrier include histones (see, for example, U.S. Patent No. 4,902,505 to Pardridge and Schimmel) and ligands such as, for example, biotin, folate, niacin, pantothenic acid , riboflavin, thiamine, priridoxal and ascorbic acid (see, for example, US Pat. Nos. 5,416,016 and 5,108,921, both by Heinstein). In addition, GLUT-1 glucose transporter has been reported as transporting glycopeptides (analogs of L-serinyl-β-D-glucoside of [Met5] enkephalin) through the blood-brain barrier (Polt, R. et al. (1994) Proc. Nati. Acad. Fl) 10 Sci. USA 91: 7114-1778). Accordingly, a modulator compound can be coupled to such a glycopeptide to focus the modulator towards the GLUT-1 glucose transporter. For example, a modified modulator compound at its amino terminus with the modifying group Aic (3- (O-aminoethyl-15 iso) -colyl, a cholic acid derivative having a free amino group) can be coupled to a glycopeptide via of the amino group of Aic by standard methods. Chimeric proteins can be formed by recombinant DNA methods (for example, by the formation of a chimeric gene encoding a fusion protein) or by chemical crosslinking of the modulator on the second peptide or the second protein to form a chimeric protein. Numerous chemical crosslinking agents are known in the art (for example, commercially available at Pierce, Rockford IL). A cross-linking agent can be selected which allows a high-throughput coupling of the modulator on the second peptide or the second protein and for a subsequent dissociation of the linker in order to release the bioactive modulator. For example, a biotin-avidin-based linker system can be employed. In another approach to increase transport through the blood-brain barrier, the modulator is encapsulated in a vehicle vector that mediates transport through the blood-brain barrier. For example, the modulator can be encapsulated in a liposome, such as a positively charged unilamellar liposome (see, for example, PCT Publications WO 88/07851 and WO 88/07852, both Faden) or in polymeric microspheres (see, for example, U.S. Patent 5,413,797 to Khan et al., U.S. Patent No. 5,271,961 to Mathiowitz et al., and 5,019,400 to Gombotz et al.). In addition, the vehicle vector can be modified to focus on transport through the blood-brain barrier. For example, the carrier vector (e.g., liposome) can be covalently modified with a molecule that is actively transported across the blood brain barrier or with a ligand for brain endothelial cell receptors, such as the monoclonal antibody that binds specifically to transferrin receptors (see, for example, PCT Publications WO 91/04014 by Collins et al., and WO 94/02178 by Greig et al.). In another approach to increase the transport of the modulator through the blood-brain barrier, the modulator is coadministered with another agent that functions to permeabilize the blood-brain barrier. Examples of such "permeabilization agents" of the blood-brain barrier include bradykinin and bradykinin agonists (see, for example, U.S. Patent No. 5,112,596 to Malfroy-Camine) and peptide compounds disclosed in U.S. Patent 5,268,164 by Kozarich et al. Assays measuring the in vitro stability of the modulating compounds in cerebrospinal fluid (CSF) and the degree of cerebral absorption of the modulator compounds in animal models can be used as predictors of the in vivo efficacy of the compounds. Suitable assays for measuring cerebrospinal fluid stability and brain absorption are described in Examples 7 and 8, respectively. A modulator compound of the invention can be formulated into a pharmaceutical composition wherein the modulator is the only active compound, or, alternatively, the pharmaceutical composition can contain additional active compounds. For example, two or more modulating compounds can be used in combination. In addition, a modulator compound of the invention can be combined with one or more other agents having anti-amyloidogenic properties. For example, a modulator compound can be combined with the nonspecific cholinesterase inhibitor tacrine (COGNEX®, Parke-Davis). In another embodiment, a pharmaceutical composition of the invention is provided as a packaged formulation. The packaged formulation may include a pharmaceutical composition of the invention in a container as well as printed instructions for the administration of the composition for the treatment of a subject having a disorder associated with β-amyloidosis, eg, Alzheimer's disease. SAW. Methods for using Aß modulators Another aspect of the invention relates to methods for altering the aggregation or inhibiting the neurotoxicity of natural β-amyloid peptides. In the methods of the invention, natural β-amyloid peptides are in contact with a β-amyloid modulator in such a way that the aggregation of the natural β-amyloid peptides is altered or in such a way that the neurotoxicity of the natural β-amyloid peptides is inhibited. In a preferred embodiment, the modulator inhibits the aggregation of the natural β-amyloid peptides. In another embodiment, the modulator promotes the aggregation of the natural β-amyloid peptides. Preferably, the aggregation of a molar excess amount of ß-AP, in relation to the amount of modulator, is altered by being in contact with the modulator. In the method of the invention, natural β-amyloid peptides can be in contact with a modulator either in vitro or in vivo. Thus, the term "in contact with" encompasses both the incubation of a modulator with a preparation of natural β-AP in vitro and the administration of the modulator to an in vivo site where β-AP is present. Since the modulator compound interacts with natural β-AP, the modulator compounds can be used to detect natural β-AP, either in vitro or in vivo. Accordingly, the use of the modulator compounds of the invention is as diagnostic agents for detecting the presence of natural β-AP, either in a biological sample or in vivo in a subject. In addition, the detection of natural β-AP using a modulator compound of the invention can be further employed to diagnose amyloidosis in a subject. In addition, since the modulator compounds of the invention disrupt aggregation of β-AP and inhibit the neurotoxicity of β-AP, the modulator compounds are also useful in the treatment of disorders associated with β-amyloidosis, either prophylactically or therapeutically. Accordingly, another use of the modulator compounds according to the present invention is as therapeutic agents to alter the aggregation and / or neurotoxicity of natural β-AP. In one embodiment, a modulator compound of the invention is used in vitro, for example, to detect and quantify natural β-AP in a sample (eg, a sample of biological fluid). To help detect, the modulator compound can be modified with a detectable substance. The source of natural β-AP that is employed in the method may be, for example, a sample of cerebrospinal fluid (eg, from a patient AD, an adult susceptible to AD due to family history, or a normal adult). ). The sample of natural β-AP is in contact with a modulator of the invention and aggregation of β-AP is measured as for example through the assays described in example 2. The degree of aggregation of the sample of β-AP it can then be compared with the degree of aggregation of a control sample or of several control samples of a known concentration of β-AP, in similar contact with the modulator and the results can be used as an indication of whether a subject is susceptible to a disease associated with β-amyloidosis or has a disease associated with β-amyloidosis. In addition, ß-AP can be detected by detecting a modulator group incorporated in the modulator. For example, modulators that incorporate a biotin compound in accordance with that described auqí (eg, an amino terminal biotinylated β-AP peptide) can be detected using a streptavidin or avidin probe labeled with a detectable substance (e.g. an enzyme such as peroxidase). In another embodiment, a modulator compound of the invention is used in vivo to detect and, if desired, quantify natural β-AP deposition in a subject, for example, to help diagnose β-amyloidosis in the subject. To help detect, the modulator compound can be modified with a detectable substance, preferably 99mTc or radioactive iodine (described in more detail below) that can be detected in vivo in a subject. The labeled β-amyloid modulator compound is administered to the subject and, after sufficient time to allow the accumulation of the modulator at amyloid deposition sites, the labeled modulator compound is detected by standard imaging techniques. The radioactive signal generated by the labeled compound can be detected directly (e.g., whole body count), or, alternatively, the radioactive signal can be converted into an image on a computer screen or autoradiography to allow image formation of amyloid deposits in the subject. Methods for imaging amyloidosis using radiolabelled proteins are known in the art. For example, the serum P amyloid (SAP) component, radiolabeled with either 123I or 99raTc, has been used to image systemic amyloidosis (see, for example, Hawkins, PN and Pepys, MB (1995) Eur. J Nucí.

Med. 22: 595-599). Of the various isotopes of radioactive iodine, i23I (half-life = 13.2 hours) is used for whole-body scans, ~ i i (half-life = 4 days) in the case of positron emission tomography (PET), 125I (half-life = 60 days) is used for studies of metabolic rotation and 131I (half-life = 8 days) is used for whole-body counting and slow-resolution imaging studies. Analogously to studies using radiolabeled SAP, a labeled modulator compound of the present invention can be administered to a subject via an appropriate route (eg, intravenously, intraspinally, intracerebrally) in a single bolus, for example, containing 100 μg of labeled compound carrying approximately 180 MBq of radioactivity. The invention offers a method for detecting the presence or absence of natural β-amyloid peptides in a biological sample, comprising contacting a biological sample with a compound of the invention and detecting the compound bound to β-amyloid peptides. natural amyloids in order to detect in this way the presence or absence of natural β-amyloid peptides in the biological sample. In one embodiment, the β-amyloid modulator compound and the biological sample are in in vitro contact. In another embodiment, the β-amyloid modulator compound is in contact with the biological sample by administering the β-amyloid modulator compound to a subject. For in vivo administration, preferably the compound is labeled with radioactive tecnetium or radioactive iodine. The invention also provides a method for detecting natural β-amyloid peptides to facilitate the diagnosis of a β-amyloidogenic disease, comprising contacting a biological sample with the compound of the invention and detecting the compound bound to peptides from ß-natural amyloids to facilitate the diagnosis of an amyloidogenic disease. In one embodiment, the β-amyloid modulator compound and the biological sample are in in vitro contact. In another embodiment, the β-amyloid modulator compound is in contact with the biological sample by administering the β-amyloid modulator compound to a subject. For in vivo administration, preferably the compound is labeled with radioactive tecnetium or radioactive iodine. Preferably, the use of the method facilitates the diagnosis of Alzheimer's disease. In another embodiment, the invention offers a method for altering the aggregation of natural β-AP or for inhibiting the neurotoxicity of β-AP, which can be used prophylactically or in a therapeutic manner in the treatment of the prevention of disorders associated with β-amyloidosis , for example, Alzheimer's disease. Modulating compounds of the invention can reduce the toxicity of aggregates of natural β-AP for cultured neuronal cells. In addition, the modulators also have the ability to reduce the neurotoxicity of preformed Aß fibrils. Accordingly, the modulator compounds of the invention can be used to inhibit or prevent the formation of neurotoxic Aβ fibrils in subjects (eg, prophylactically in a subject predisposed to β-amyloid deposition) and can be used to therapeutically reverse the β- Amyloidosis in subjects who already have a β-amyloid deposit. A modulator of the invention is in contact with natural β-amyloid peptides present in a subject (e.g., in the cerebrospinal fluid or in the brain of the subject) to thereby alter the aggregation of natural β-AP and / or inhibit the neurotoxicity of natural β-APs. A modulator compound can only be administered to the subject, or alternatively, the modulator compound can be administered in combination with other therapeutically active agents (eg, in accordance with what is discussed above in subsection IV). When a combination therapy is employed, the therapeutic agents can be co-administered in a single pharmaceutical composition, co-administered in separate pharmaceutical compositions or sequentially administered.

The modulator can be administered to a subject through any suitable effective route to inhibit the aggregation of natural β-AP in the subject, although in a preferred embodiment, the modulator is administered parenterally, with greater preference to the central nervous system of the subject. Possible routes of administration to the central nervous system include trans-spinal administration and intercerebral administration (e.g., intracerebrovascular administration). Alternatively, the compound can be administered, for example, orally, intraperitoneally, intravenously or intramuscularly. In the case of routes of administration that are not the central nervous system, the compound can be administered in a formulation that allows transport through the blood-brain barrier. Certain modulators may be transported across the blood-brain barrier without any additional modification while other modulators may require an additional modification in accordance with that described above in subsection IV. Suitable modes and devices for administering the therapeutic compounds to the central nervous system of the subject are known in the art, and include cerebrovascular deposits (e.g., Ommaya or Rikker deposits, see, eg, Raney, JP et al. (1988), J. Neurosci, Nurs 20: 23-29, Sundaresan, N. et al (1989) Oncology 3: 15-22), catheters for intrathecal administration (eg, Port-a-Cath, catheters Y and the like; , for example, Plummer, JL (1991) Pain44: 215-220; Yaksh, TL et al. (1986) Pharmacol. Bi ochem. Behav. 25: 483-485), injectable intrathecal deposits (eg, Spinalgesic; see, for example, Brazenor, GA (1987) Neurosurgery 21: 484-491), implantable infusion pump systems (eg, Infusaid; see, eg, Zierski, J. et al. (1988) Acta Neurochem, Suppl .43: 94-99; Kanoff, RB (1994) J. Am. Osteopa th. Assoc. 9_4: 487-493) and osmotic pumps (sold by Alza Corporation). A particularly preferred mode of administration is through an externally programmable implantable infusion pump. Suitable infusion pump systems and suitable reservoir systems are also described in US Pat. No. 5,368,562 to Blomquist and in US Patent No. 4,731,058 to Doan, developed by Pharmacia Deltec Inc. The method of the invention for altering the aggregation of β-AP in vivo and particularly to inhibit the aggregation of β-AP, can be used therapeutically in diseases associated with an abnormal aggregation of β-amyloid and abnormal deposition of β-amyloid in order to reduce the rate of deposition of β-amyloid β-amyloid and / or reduce the degree of ß-amyloid deposition, thus improving the course of the disease. In a preferred embodiment, the method is used to treat Alzheimer's disease (e.g., sporadic or familial AD, including both individuals who exhibit AD symptoms and individuals susceptible to familial AD). The method can also be used prophylactically or therapeutically to treat other clinical occurrences of β-amyloid deposition, such as in individuals with Down syndrome and in patients with hereditary cerebral hemorrhage with Dutch-type amyloidosis (HCHWA-D). While the inhibition of β-AP aggregation is a preferred therapeutic method, modulators that promote the aggregation of β-AP may also be therapeutically useful because they allow the abduction of β-AP in sites that do not cause neurological involvement. In addition, the abnormal accumulation of β-amyloid precursor protein in muscle fibers has been implicated in the pathology of sporadic inclusion body myositis (IBM) (Askana, V. et al. (1996) Proc. Na ti. Acad. Sci. 93: 1314-1319; Askanas, V. et al. (1995) Current Opinion in Rheuma tol ogy 7: 486-496). Accordingly, the modulators of the invention can be used prophylactically or therapeutically for the treatment of disorders wherein β-AP, or APP, is abnormally deposited in non-neurological locations, such as for example IBM treatment by administration of the modulators to muscle fibers.

This invention is further illustrated through the following examples that should not be considered as limiting. The ability of a modulator to alter the aggregation of natural β-amyloid peptide and / or to inhibit the neurotoxicity of natural β-amyloid peptide in the assays described below are elements that allow predicting the ability of the modulator to perform the same function in vivo The invention is further illustrated by the following examples which should not be considered as limiting. The contents of all published references, patents and patent applications mentioned by this application, as well as all Figures, are incorporated herein by reference. EXAMPLE 1 Preparation of β-amyloid modulating compounds comprising D-amino acids β-amyloid modulators comprising D-amino acids can be prepared by peptide synthesis in solid phase, such as using a protection strategy based on Na 9 fluorenylmethyloxycarbonyl (FMOC) as follows. Starting with 2.5 mmoles of FMOC-D-Val-Wang resin, sequential additions of each amino acid are made using a fourfold excess of protected amino acids, 1-hydroxybenzotriazole (HOBt) and diisopropyl carbodiimide (DIC). Couplings are carried out as necessary as determined by ninhydrin test of the resin after coupling. Each cycle of synthesis is minimally described through a deprotection of three minutes (25% piperidine / N-methyl-pyrrolidone (NMP)), a deprotection of 15 minutes, five washes with NMP of one minute, a coupling cycle of 60 minutes, five washes with NMP and one ninhydrin test. For N-terminal modification, a reagent that modifies an N-terminus is replaced by an FMOC-D-amino acid and coupled to a 700-mg portion of fully-assembled peptide-resin through the above protocol. The peptide is removed from the resin by treatment with trifluoroacetic acid (TFA) (82.5%) water (5%), thioanisole (5%), phenol (5%), ethanedithiol (2.5%) for two hours followed by precipitation of the peptide in cold ether. The solid is formed into pellets by centrifugation (2400 rpm x 10 min.), And the ether is decanted. The solid is resuspended in ether, formed into pellets and decanted a second time. The solid is dissolved in 10% acetic acid and lyophilized to dryness. For a preparation purification and for a subsequent analytical characterization, 60 mg of solid is dissolved in 25% acetonitrile (ACN) / 0.1% TFA and applied to a high performance liquid chromatography column.

(HPLC) reverse phase C18. Alternatively, β-amyloid modulators comprising D-amino acids can be prepared in a Rainin PS3 peptide synthesizer using an automated protocol established by the manufacturer for a scale synthesis of 0.25 mmol. Couplings are carried out using 2- (lH-benzotriazol-1-yl) -1, 1,3,3-tetramethyl-uronium-hexafluoro-phosphate (HBTU) / FMOC-D-amino acid in quadruple excess in 0.4 M N-methylmorpholine ( NMM) / dimethylformamide (DMF) for 60 minutes. Between the couplings, the FMOC group is removed by reaction with 20% piperidine / DMF for 20 minutes. The peptide is removed from the resin by treatment with 95% TFA / water for 1 hour and precipitated with ether. The pellet is suspended in 40% acetonitrile / water and lyophilized. If necessary, the material was purified by preparative HPLC using 15% -50% acetonitrile for 60 minutes on a Vydac C18 column (21 x 250 mm). Several compounds of N-terminal modified amyloid modulators can be synthesized using standard methods. Fully protected resin bound peptides are prepared according to the above described in a suitable resin to optionally provide carboxyl terminal peptide acids. Small portions of each peptide resin (for example 13-20 μmoles) are formed in aliquots in separate reaction vessels. The N-terminal FMOC protection group of each sample is removed in a standard manner with 20% piperidine in NMM followed by broad washing with DMF. The unprotected N-terminal alpha-amino group of each peptide-resin sample can be modified using one of the following methods: Method A, coupling of modifying reagents containing free carboxylic acid groups: the modifying reagent (five equivalents) is previously dissolved in NMP, DMSO or a mixture of these two solvents. HOBT and DIC (five equivalents of each reagent) are added to the dissolved modifier and the resulting solution is added to a peptide-free amino resin equivalent. The coupling is allowed to take place overnight, followed by washing. If a ninhydrin test in a small sample of peptide-resin shows that the coupling is not complete, the coupling is repeated using l-hydroxy-7-azabenzotriazole (HOAt) instead of HOBt. Method B, coupling of modification reagents obtained in previously activated forms: the modification reagent (five equivalents) is previously dissolved in NMP, DMSO, or a mixture of these two solvents and is added to a peptide-resin equivalent. Diisopropylethylamine (DIEA) is added; six equivalents) to the suspension of activated modifier and peptide-resin. The coupling is allowed to continue overnight, followed by washing. If a ninhydrin test in a small sample of peptide-resin shows that the coupling is not complete, the coupling is repeated.

After the second coupling (if required), N-terminal modified peptides-resins are dried under reduced pressure and dissociated from the resin with removal of side chain protection groups according to that described above. Analytical reverse phase HPLC is employed to confirm that a major product is present in the resulting crude peptides, which are purified using Millipore Sep-Pak cartridges or reverse phase HPLC preparation. Mass spectrometry or high-field nuclear magnetic resonance spectrometry is used to confirm the presence of the desired compound in the product. Method C, preparation of N-terminal alkyl substituted peptides using bromoacetylpeptide intermediates: a resin-bound peptide can be coupled with bromoacetic acid (12 equivalents) with 1,3-diisopropylcarbodiimide (DIC) (13 equivalents) in DMF. The resulting bromoacetyl substituted peptide can be modified by reacting with primary or secondary amines including, methylamine, ethylamine, propylamine, isopropylamine and piperidine. The reaction is carried out in 60% DMSO / DMF and typically ends after 24 hours. Method D, preparation of peptides substituted by N-terminal alkyl through reductive alkylation: after the dissolution of the peptide (or its partial dissolution in water containing 0-10% methanol), it reacts with an aldehyde (5-8) equivalents) and sodium cyanoborohydride (10-16 equivalents) The number of equivalents can be adjusted according to the type of aldehyde and the degree of substitution that is desired.The pH of the resulting solution is adjusted to 2 with 1 M HCl and maintained in 2 for one hour The reaction is monitored by hplc and is usually completed within two hours The reaction mixture is concentrated at room temperature and purified by HPLC Method E, C terminal modification: the peptide was synthesized in resin of 2-chlorotryril using a standard Fmoc chemistry, however, the final coupled D-amino acid group was protected with Boc.The peptide was removed from the resin with 8/1/1 dichloromethane (DCM) / acetic acid. with trifluoroethanol and the mixture was concentrated. The peptide residue was dissolved in 20% acetonitrile, frozen and lyophilized overnight. The peptide acid protected with crude BOC was coupled under basic conditions (pH = 11, adjusted with DIEA) to an amine with one equivalent each of l-hydroxy-7-azobenzotriazole (HOAt) and DIC. The reaction was terminated after stirring overnight and the peptide was precipitated with water. The BOC group was dissociated by reacting with 25% TFA in DCM for one hour and the peptide was purified by HPLC. EXAMPLE 2: β-amyloid aggregation assay The ability of β-amyloid modulating compounds to modulate (eg, inhibit or promote the aggregation of natural β-AP when combined with natural β-AP can be examined in one or both assays of aggregation described below. ß-AP natural (ß-AP? -4 :) for use in aggregation assays is commercially available in Bachem (Torrance, CA) A. Nucleation assay The nucleation assay is used to determine the ability of the test compounds to alter (e.g., inhibit) the initial events in the formation of β-AP fibers from monomeric β-AP, typically in the case of a polymerization mechanism nucleated, a time delay is observed before nucleation, after which the peptide quickly forms fibers in accordance with what is reflected in a linear elevation of the turbidity.The time delay before polymerization of ß-AP monomer can be quantified as well as the magnitude of the insoluble fiber formation by light scattering (turbidity). The polymerization reaches an equilibrium when the maximum turbidity reaches a plateau. The turbidity of a natural β-AP solution in the absence or presence of various concentrations of β-amyloid modulator compound is determined by measuring the apparent absorbance of the solution at 405 nm (A4os nm) over time. The sensitivity threshold for the treatment of turbidity is within the range of 15 to 20 uM ß-AP. A decrease in turbidity with the passage of time in the presence of the modulator, in comparison with the turbidity in the absence of the modulator indicates that the modulator inhibits the formation of β-AP fibers from monomeric β-AP. This test can be performed using agitation or shaking to accelerate the polymerization, thus increasing the speed of the assay. In addition, the assay can be adapted to a 96-well plate format to screen several compounds. To perform the nucleation assay, the Aβ? - 'peptide is first dissolved in HFIP (1, 1, 3, 3, 3-Hexafluoro-2-propanol); Aldrich 10,522-8) in a concentration of 2 mg of peptide / ml and incubated at room temperature for 30 minutes. The peptide solubilized by HFIP is sonicated in a water bath sonicator for 5 minutes at the highest rate, and then evaporated to dryness in a stream of argon. The peptide film is resuspended in anhydrous dimethylsulfoxide (DMSO) at a concentration of 6.9 mg / ml (concentration 25x) sonicated for 5 minutes, before and after filtered through a nylon syringe filter 0. 2 miera (VWR Catalog No. 28196-050). The test compounds are dissolved in DMSO at a concentration of 100x. Four volumes of 25x Aβ? -40 peptide in DMSO are combined with a volume of test compound in DMSO in a glass flask, and mixed to produce a 1: 1 molar ratio between Aβ peptide and test compound. For different molar proportions, the test compounds are diluted with DMSO before addition Aβ? -40, in order to maintain the final concentrations of constant DMSO and Aβ? -0. Control samples do not contain the test compound. 10 microliters of the mixture is then added to the bottom of a well of a Corning Costar 96-well ultra-low link plate (Corning Costar, Cambridge MMA, Catalog No. 2500). Ninety microliters of water is added to the well, the plate is shaken on a rotary shaker at constant speed at room temperature for 30 seconds, an additional 100 μl of 2x PTL buffer is added (20 mM NaH 2 P 4, 300 mM NaCl, pH 7.4), the plate is shaken again for 30 seconds and a baseline turbidity reading (t = 0) is taken by measuring the apparent absorbance at 405 nm using a Bio-Rad microplate reader model 450. The plate it is then returned to the agitator and stirred continuously for 5 hours. Turbidity readings are taken at 15 minute intervals. The aggregation of β-amyloid in the presence of modulators results in an increased turbidity of the natural β-AP solution 8 ie an increase in apparent absorbance at 405 nm over time). Accordingly, a solution that includes an effective inhibitory modulator compound exhibits reduced haze in comparison to the control sample without the modulator compound (ie, less apparent absorbance at 405 nm over time compared to the control sample) . Alternatively to the use of turbidity to quantify the aggregation of β-amyloid, the fluorescence of thioflavin T (Th-T) can also be used to quantify the aggregation of β-amyloid in the nucleation assay (use of Th-T fluorescence for quantify the aggregation of ß-amyloid is described in more detail below for the sown extension test). B. Fibril Binding Assay The following materials are required for the fibril binding assay: a Millipore multi-filter apparatus; 12 x 75 glass tubes; GF / F 25 mm glass filters; PBS / 0.1% tween 20 at 4 ° C (PBST); Aß fibrils; radioactive compound; non-radioactive compound; Eppendorf repetitive pipette holder with tips; labels; forceps; and empty. In this test, each sample is carried out in triplicate. The "aged" Aß fibril is first prepared approximately 8 days before by aliquoting 1 ml of a 200 μM Aβl-40 peptide solution in 4% DMSO / PBS for 8 days at a temperature of 37 ° C with shaking. Said "aged" Aβ peptide can be directly tested in cells or else frozen at a temperature of -80 ° C. The 200 μM Aβ fibril is diluted in PBST to provide a 4 μM solution (320 μl in 16 ml of PBST). Aliquots of 100 μL of this solution are added per tube with the repeat pipette holder. The β-amyloid modulator compounds of the present invention are prepared in 2 μM - 200 fM dilutions as follows: A 5 mM 1: 3 stock solution is diluted in DMSO to provide 1.6667 of stock solution (200 μl in 400 μl of DMSO). A 1,667 μM 1: 3 stock solution is diluted in DMSO to provide 0.5556 of stock solution (200 μl in 400 μl of DMSO). Dilute a stock solution 555.556 μM 1: 3 in DMSO to provide 185.19 of stock solution (200 μL in 400 μL of DMSO). A 185.185 μM 1: 3 stock solution is diluted in DMSO to provide 61,728 of stock solution (200 μl in 400 μl of DMSO). A 61.728 μM stock solution is diluted 1: 3 in DMSO to provide 20.576 of stock solution (200 μL in 400 μL of DMSO). A 20.576 μM 1: 3 stock solution is diluted in DMSO to provide 6.8587 of stock solution (200 μl in 400 μl of DMSO). A 6,859 μM 1: 3 stock solution is diluted in DMSO to provide 2.2862 mother stock (200 μl in 400 μl DMSO). A 2,286 μM 1: 3 stock solution is diluted in DMSO to provide 0.7621 of stock solution (200 μl in 400 μl of DMSO)., 10 Dilute a stock solution 762,079 nM 1: 3 in DMSO to provide 254.03 of stock solution (200 μl in 400 μl of DMSO). A stock solution 254.026 nM 1: 3 is diluted in DMSO to provide 84,675 of stock solution (200 μl in 400 μl of DMSO). A 84.675 nM 1: 3 stock solution is diluted in DMSO to provide 28,225 mother stock (200 μl in 400 μl of DMSO). A 28.225 nM 1: 3 stock solution is diluted in DMSO to provide 9.4084 of stock solution (200 μl in 400 μl of DMSO). A 9.408 nM 1: 3 stock solution is diluted in DMSO to provide 3.1361 of stock solution (200 μl in 400 μl of DMSO). 15 A 3,136 nM 1: 3 stock solution is diluted in DMSO to provide 1.0454 stock solution (200 μl in 400 μl DMSO). A 1045 nM 1: 3 stock solution is diluted in DMSO to provide 0.3485 of stock solution (200 μl in 400 μl of DMSO). A stock solution 348.459 pM 1: 3 is diluted in DMSO to provide 116.15 of stock solution (200 μl in 400 μl of DMSO). A 116.153 pM stock solution 1: 3 is diluted in DMSO to provide 38,718 mother stock (200 μl in 400 μl DMSO). A 185.185 μM 1:25 stock solution is diluted in PBST to provide 7.4074 of stock solution (50 μl in 1.2 ml of PBST). 20 A 61,728 μM 1:25 stock solution is diluted in PBST to provide 2.4691 of stock solution (50 μl in 1.2 ml of PBST). A 20.576 μM 1:25 stock solution is diluted in PBST to provide 0.823 of stock solution (50 μl in 1.2 ml of PBST). A 6.859 μM 1:25 stock solution is diluted in PBST to provide 0.2743 of stock solution (50 μl in 1.2 ml of PBST). A 2,286 μM 1:25 stock solution is diluted in PBST to provide 0.0914 of stock solution (50 μl in 1.2 ml of PBST).

A 762,079 nM 1:25 stock solution is diluted in PBST to provide 30,483 of stock solution (50 μl in 1.2 ml of PBST). 25 A stock solution 254.026 nM 1:25 is diluted in PBST to provide 10,161 of stock solution (50 μl in 1.2 ml of PBST). A stock solution 84.675 nM 1:25 is diluted in PBST to provide 3.387 of stock solution (50 μl in 1.2 ml of PBST). A 28,225 nM 1:25 stock solution is diluted in PBST to provide 1129 of stock solution (50 μl in 1.2 ml of PBST). A 9.408 nM 1:25 stock solution is diluted in PBST to provide 0.3763 stock solution (50 μl in 1.2 ml PBST). A 3.136 nM 1:25 stock solution is diluted in PBST to provide 0.1254 of stock solution (50 μl in 1.2 ml of PBST). 30 A 1045 nM 1:25 stock solution is diluted in PBST to provide 0.0418 of stock solution (50 μl in 1.2 ml of PBST). A stock solution 348459 pM 1:25 is diluted in PBST to provide 13 938 of stock solution (50 μl in 1.2 ml of PBST). A 116.153 pM 1:25 stock solution is diluted in PBST to provide 4.6461 of stock solution (50 μl in 1.2 ml of PBST). The β-amyloid modulator compound (200 μl) is then added to the appropriate tube containing the Aβ fibril. The radiolabelled β-amyloid modulator compound is prepared using standard radioactive safety protocols by performing a dilution in a PBS / 0.1% tween 20 solution in such a way that a final concentration of 20,000 dpm per 100 μl is obtained. Aliquots of 100 μl of radiolabelled β-amyloid modulator compound are added per tube using the repetitive pipette handling device. The samples are covered with parafilm and incubated at a temperature of 37 ° C inside plastic radioactivity bags overnight. To filter the samples, the filters are pre-moistened in a small volume of PBST. Two Millipore multifiltration devices are equipped with GF / F filters in each filtration slot according to the manufacturer's instructions. The samples are removed from the 37 ° C incubator and each sample is filtered using a small volume (approximately 5 ml) of cold PBS buffer. The sample tube is then washed with two additional volumes of 5 ml of cold PBS buffer. The vacuum is allowed to pull a semi-dry filter for about 2 minutes after the addition of the last sample, and the filter is transferred to a tube marked for iodination counting. One-minute counts are recorded, the data is plotted, and the Prism program (GraphPAD) is used to analyze the graph, in accordance with the manufacturer's instructions. C. Sown Extension Test In the sown extension test, it can be used to measure the Aβ fiber rate formed in an Aβ monomer solution after addition of "seeds" of polymeric Aβ fiber. The ability of the test compounds to prevent additional deposition of monomeric Aβ on pre-deposited amyloid is determined using a direct ß sheet-forming indicator using fluorescence. In contrast to the nucleation assay, seed addition provides immediate nucleation and continuous growth of preformed fibrils without the need for continuous mixing, and therefore results in the absence of a time delay before the start of polymerization. Since this assay employs static polymerization conditions, the activity of positive compounds in the nucleation assay can be confirmed in this second assay under different conditions and with an additional probe of amyloid structure. In the seeded extension test, monomeric Aβ: -0 is incubated in the presence of a "seed" core (approximately 105 molar of Aβ which has previously been allowed to polymerize under controlled static conditions.) Samples of the solution are then diluted in Thioflavin T (Th-T). The specific association for Th-T polymer with Aβ produces a fluorescent complex that allows measurement of the extent of fibril formation (Levir.e, H. (1993) Protein Science 2: 404- 410) in particular, the association of Th-T with aggregated ß-AP, but not monomeric or loose-associated ß-AP, provides the formation of a new excitation peak (ex) at 45C nm and an increased emission (em ) at 482 nm, compared to 385 nm (ex) and 445 nm (em) for the free dye Small aliquots of the polymerization mixture contain enough fibril to be mixed with Th-T to allow monitoring of the reaction mixture by repeated sampling. a linear growth is observed in the presence of excess monomer. The formation of thioflavin T in response to ß sheet fibril is parallel to the increase in turbidity observed using the nucleation assay. A solution of Aβ monomer for use in the seeded extension test is prepared by dissolving an appropriate amount of β-4o peptide in 1/25 volume-r of dimethyl sulfoxide (DMSO), followed by water a. volume and i * volume 2x PBS 810 x PBS; 137 mM NaCl, 2.7 mM N KCl, 4.3 mM HPH 4 • 7H20, 1.4 itiM pH 7.2 KH2P04) at a final concentration of 200 μM. To prepare the seed stock, 1 ml of the Aß monomer preparation is incubated for approximately 8 days at a temperature of 37 ° C and cut sequentially from an 18 gauge needle, 23, 26 and 30, 25, 25, 50 and 100 times, respectively. Samples of 2 μL of the cut material are taken for fluorescence measurements after every 50 passages through the 30 gauge needle until the fluorescence units (FU) reach a plateau (approximately 100-150x). Test compounds are prepared by dissolving an appropriate amount of test compounds in lx PBS at a final concentration of 1 mM (lOx stock solution). If it is insoluble, the compound is dissolved in 1/10 volume of DMSO and diluted in lx PBS to 1 mM. An additional 1/10 dilution is also prepared for each candidate at both 100 μM and 10 μM. To carry out the sown extension test, each sample is prepared with 50 μL of 200 μM monomer, seed cut with 125 FU (a variable amount depending on the seed lot, usually 3-6 μl) and 10 μl of modulating solution lOx. The sample volume was then adjusted to a final volume of 100 μl with 1 x PBS. Two concentrations of each modulator are typically tested: 100 μM and 10 μM, equivalent to a 1: 1 and 1:10 molar ratio between monomer and modulator. The controls include an unseeded reaction to confirm that the fresh monomer does not contain seed, and a reaction sown in the absence of any modulator, as a reference for comparison against candidate modulators. The assay is incubated at 37 ° C for 6 hours, taking 2 μl samples every hour for fluorescence measurements. To measure the fluorescence, a sample of 2 μl of Aβ is added to 400 μl of a solution of thioflavin T (50 mM potassium phosphate, 10 mM thioflavin T pH 7.5). The samples are vortexed and the fluorescence is read in a microquartz cuvette of 0.5 ml at EX 450 nm and EM 482 nm (Hitachi fluorometer 4500). The aggregation of β-amyloid results in an increased emission of thioflavin-T. Accordingly, samples that include an effective inhibitory modulator compound have a reduced emission compared to the control samples without the modulator compound. EXAMPLE 3: Analysis of beta-amyloid-modulating compounds In this example, β-amyloid-modulating compounds described herein were prepared and tested for their ability to inhibit the aggregation of natural β-amyloid peptide using aggregation assays in accordance with described in example 2. The results of a first series of experiments are summarized below in Tables I, II, and III. TABLE 1 PPI # Delay D in assay Kds of fibril nucleation binding 5 μM 2 2..55 μ μM 1.25 μM cmpd ref cmpd ref Kd 803 < 1 < 1 < 1 913 1 1 1 968 > 5 > 5 2 969 > 5 > 5 3 1.13 x 10"9 PPI-558 3.7 x 10 ~ 9 970 > 5 > 5 1 992 3 1 1 2.43 x 10"9 PPI-5583.70 x 10" 9 993 1 1 1 1005 3 3 1 1006 1 1 1 * 1007 4 4 3 8.64 x ÍO'10 PPI-558 1.69 x 10"9 # 1007 1.5 1.5 1.5 6.27 x ÍO "10 PPI-558 2.75 x 10" 9 1008 1.75 x 10 ~ 9 PPI-558 1.00 x 10"9 # 1013 2 > 3 2 2.47 x 10"i0 PPI-558 1.69 x 10" 9 1017 3.89 x IO "10 PPI-558 2.42 x 10" 9 1018 7.01 x IO'10 PPI-558 2.42 x 10"9 1020 6.01 x IO" 10 PPI -558 2.42 x 10"9 1022 1.50 x IO" 10 PPI-558 1.00 x 10"9 1025 4.30 x IO "10 PPI-558 1.00 x 10" 9 1028 4.90 x IO "10 PPI-558 1.00 x 10" 9 1038 6.52 x IO "10 PPI-558 3.76 x 10" 9 1039 2.44 x IO "10 PPI- 558 3.76 x 10"9 1040 4.08 x IO" 10 PPI-558 2.4 x 10"9 1041 1.61 x IO "10 PPI-558 2.4 x 10" 9 1042 2. 34 x 10"10 PPI - 558 2. 4 x 10" 9 1088 3. 40 x 10"9 PPI-558 1. 93 x 10'9 1089 5.7 x 10"1 PPI-558 3.3 x 10" 9 1093 1.02 x 10"9 PPI-558 1.93 x 10" 9 1094 3.7 x 10 ~ 9 PPI-558 3.5 x 10"9 1179 6.04 x 10"10 PPI-5581.93 x 10" 9 1180 3.3 x 10"10 PPI-5583.5 x 10'9 1261 1.12 x 10" 8 PPI-558 3.34 x 10"9 Notes: * Means that the nucleation assay data were measured at 3, 1 and 0.3 μM of compound # Means that the nucleation assay data were measured at 2.5, 1.25 and 0.6 μM of compound TABLE II PPI # Data from Kds assay of fibril nucleation binding 3 μM 1 μM 0.3 μM cmpd ref cmpd ref Kd * 1019 > 2. 5 > 2. 5 2.0 4.11 x 10"15 PPI-558 1.69 x 10" 9 1019 5.34 x 10"1 PPI-558 1.93 x 10" 9 1301 1.1 x 10 ~ 9 PPI-1318 1.4 x 10"9 1302 2.2 x 10":: PPI-1318 1.4 x 10" 9 1303 1.1 x 10"9 PPI-1318 1.4 x 10-9 1318> 5 2 1 7.7 x 10" 11 PPI-558 2.3 x 10"9 1318 1.4 x 10" 9 1318 6.2 x 10"11 1319 > 5 > 5 1 1320> 55 3 1 1 1 1..44 x 1100"" 99 PPI-1318 6.2 x 10"11 1321 < 1 < 1 < 1 1322 11..22 x 1100"" 99 PPI-1318 6.2 x 10"11 1323 1324 1325 1.4 x IO" 9 PPI-1318 1.4 x 10-9 1326 5.6 x 10'10 PPI-1318 6.2 x 10"11 1327 8.2 x 10'10 PPI-1318 1.4 x 10"9 1328 2.4 x 10" 9 PPI-1318 6.2 x 10"11 1329 * 1125 > 2.5 > 2.5 2.0 1.27 x 10 PPI-558 2.08 x 10"9 1125 1.34 x 10 PPI-558 5.05 x 10" 9 1133 3.18 x 10 PPI-558 2.08 x 10"9 1155 1.24 x 10 PPI-558 2.08 x 10" 9 Notes: * Means that the nucleation assay data were measured at 2.5, 1.25 and 0.6 μM of compound. Modulator compounds were evaluated using 5 μM Aβ? -0 and test compound either 5 μM, 2.5 μM, 1.25 μM, 3 μM, 1 μM, or 0.3 μM. the change in delay time (D Lag) is presented as the ratio between the delay time in the presence of test compounds (either at 5 μM, 2.5 μM, 1.25 μM, 3 μM, 1 μM, or 0.3 μM) and the delay time of the control.

TABLE III PPI # STRUCTURE Fibril binding Kds cmpd PPI-504 TFA • H- (lv- [3-1] y-fa) -NH2 PPI-1181 TFA • H- (lvffl) -NH-Et PPI-1465 TFA • H-lvff1-NH-CH2CH2-NH2 3.6 x 10 ~ 9 PPI-1603 TFA • H- (GGClvff1) -NH2 PPI-1604 TFA • H- (GGClvfyl) -NH2 PPI-1605 TFA • H- (GGClvf- [ 3-1] yl) -NH2 PPI-1619 2TFA • H-LVF-NH-NH-FVL-H 3.5 x 10"8 (an analog of 1125) PPI-1621 2TFA • H-LVF-NH-NH-fvl- H 8.7 x 10"9 (an analog of 1125) PPI-1635 TFA • H-lff- (nvl) -1-NH2 1.4 x 10" "9 PPI-1636 TFA • H-lf-F] f- (nvl) 4-NR: 1.5 x 10"9 PPI-1637 TFA • Hl- [pF] f- [pF] f- (nvl) -1-NH2 1.8 x 10"PPI-1782 TFA • Me-lvyfl-NH2 PPI-1783 TFA • H- (lvyf 1) - NH2 PPI-1784 TFA • Me- (lv- [pF] ff 1) -NH2 2.5 x 10"9 PPI-1785 TFA »H- (Iv- [pF] ff 1) -NH2 2.8 x 10" 9 PPI-1786 TFA • H- (Ivf- [pF] f-1) -NH2 PPI-1787 TFA • Me-lvff [nvl]) ~ NH2 5.8 x 10 PPI-1788 TFA • Me- (lvff- [nle]) -NH: (~ 4 x 10"9) 3-point test PP1-1799 TFA • Me- (lvff1) -OH PPI-1800 TFA • Me- (lvffl) -NH-OH (~ 4 x 10"9) 3-point test PPI-1805 TFA • H- (lv- [pF] ff- (nvl)) -NH2 PPI-1806 TFA • Me- (1-v- [pF] ff- (nvl)) -NH2 PPI 1807 TFA »H- ((nvl) -v- [pF] ff-nvl) -NH2 PPI-1818 TFA • H- ( 1- (nvl > - [pF] ff- (nvl) -NH2 PPI 1819 TFA • H- ((nvl) - (nvl) - [pF] ff- (nvl)) - NH2 PPI 1820 TFA • Me- ( 1- (nvl) - [pF] ff- (nvl)) - NH2 PPI 1827 TFA »H- (lvff- (nvl)) -NH; PPI 1828 Ac- (lvffl) -NH2 PPI 1829 Ac- (lvffl) -OH PPI 1830 TFA • H- (lv- [3-1] -fi) -NH2 (nvl) = D-norvaline (nle) = D- norleucine [3-1] y = 3-iodo-D-tyrosine [pF] f = for fluoro-D-phenylalanine PPI-1801 is the acetylamide analog of H-LPFFD-OH that has been reported in the literature. This compound was prepared and tested to determine its activity for comparison purposes. The results indicate that this compound binds in a limited manner to the fibrils in test used here. In contrast, the results shown in Tables I, II, and III, and in Figure 2 demonstrate that the β-amyloid modulators of the invention are effective inhibitors of Aβ aggregation. EXAMPLE 6: Neurotoxicity Test The neurotoxicity of natural β-amyloid peptides aggregated, either in the presence or absence of β-amyloid modulator, can be tested in a cell-based assay using either a cell line derived neuronally from rat or of human being (PC-12 cells or NT-2 cells, respectively) and the viability indicator bromide of 3, (4,4-dimethylthiazol-2-yl) 2,5-diphenyl-tetrazolium (See, for example, Shearman , MS et al., (1994) Proc. Nati, Acad Sci USA 91: 1470-1474, Hansen, MB et al. (1989) J. Immun. Methods 119: 203-210 for a description of feasibility studies based in similar cells). PC-12 is a rat adrenal pheochromocytoma cell line and is available from the American Type Culture Collection, Rockville, MD (ATCC CRL 1721). MTT (commercially available from Sigma Chemical Co.) is a chromogenic substrate converted from yellow to blue into viable cells, which can be detected spectrophotometrically. To test the neurotoxicity of natural β-amyloid peptides, fresh mother liquors of Aß monomers and aged Aß aggregates are prepared first. Aβ? -40 is prepared in 100% DMSO from lyophilized powder and immediately diluted in one half of the final volume in H20 and then one half of the final volume in 2X PBS in such a way that a final peptide concentration of 200 is obtained. μM, 4% DMSO. The peptide prepared in this way and tested immediately in cells is known as "fresh" Aβ monomer. To prepare the "aged" Aß aggregates, a peptide solution is placed in a 1.5 ml Eppendorf tube and incubated at a temperature of 37 ° C for 8 days to allow the formation of fibrils. Such "aged" Aβ peptide can be directly tested in cells or frozen at a temperature of -80 ° C. The neurotoxicity of fresh monomers and aged aggregates is tested using PC12 and NT2 cells. PC12 cells are routinely cultured in Dulbecco's Modified Eagle medium (DMEM) containing 10% horse serum, 5% fetal calf serum, 4 mM glutamine and 1% gentamicin. NT2 cells are routinely cultured in OPTI-MEM medium (GIBCO BRL Catalog No. 31985) supplemented with 105 fetal calf serum, 2 mM glutamine and 1% gentamicin. Cells are plated at 10000-15000 cells per well in 90 μl of fresh medium in a 96-well tissue culture plate 3-4 hours before treatment. The fresh or aged Aβ peptide solutions (10 μL) are then diluted 1:10 directly in tissue culture medium such that the final concentration is within a range of 1-10 μM of peptide. The cells are incubated in the presence of peptide without changing the medium for 48 hours at a temperature of 37 ° C. During the final three hours of exposure of the cells to the preparation of β-AP, MTT is added to the medium at a final concentration of 1 mg / ml and the incubation proceeds at a temperature of 37 ° C. after a 2 hour incubation with MTT, the medium is removed and the cells are used in 100 μL isopropanol / 0.4 N HCl with stirring. An equal volume of PBS is added to each well and the plates are agitated for an additional 10 minutes. The absorbance of each well at 570 nm is measured using a plate vector to quantify viable cells. Using this trial, the neurotoxicity of aged Aß? -0 aggregates (5 days or 8 days) alone, but not of fresh Aβ? -0 monomers alone, was confirmed. Experiments showed that incubation of neuronal cells with increasing amounts of fresh Aβ? -or monomers was not significantly toxic to the cells while incubation of the cells with increasing amounts of aged Aβ? -40 aggregates of 5 days and 8 days. days caused an increasing amount of neurotoxicity. The EC50 for the toxicity of aged Aβ? -40 aggregates was 1-2 μM for both PC12 and NT2 cells. To determine the effect of a β-amyloid modulator compound on the neurotoxicity of aggregates of Aβ? -40, a modulator compound was pre-incubated with AB1-40 monomers under standard nucleation assay conditions in accordance with that described in Example 2, and at particular time intervals after incubation, aliquots of the β-AP / modulator solution are removed and 1) the turbidity of the solution is evaluated as a measure of aggregation and 29 the solution is applied to cultured neuronal cells for 48 hours at that time the viability of the cells is evaluated using MTT to determine the neurotoxicity of the solution. In addition, the ability of β-amyloid modulating compounds to reduce the neurotoxicity of aggregates to preformed Aβ? -40 can be tested. In these experiments, aggregates of Aβ? -40 are pre-formed by incubation of the monomers in the absence of a modulator. The modulator compound is then incubated with the Aβ? -40 aggregates preformed for 24 hours at a temperature of 37 ° C, after which the β-AP / modulator solution is collected and its neurotoxicity evaluated in accordance with that described above. EXAMPLE 7 Stability test of modulator compound in cerebrospinal fluid The stability of a modulator compound in cerebrospinal fluid (CSF) can be tested in an in vitro assay in the following manner. A cerebrospinal fluid solution is prepared which contains 75% Rhesus monkey cerebrospinal fluid (commercially available from Northern Biomedical Research), 23% sterile phosphate buffered saline and 2% dimethyl sulfoxide (volume / volume) (Aldrich Chemical Co. Catalog No. 27,685-5). Test modulating compounds are added to the cerebrospinal fluid solution at a final concentration of 40 μM or 15 μM. All sample handling is carried out in a laminar flow hood and the test solutions are maintained at a temperature of 37 ° C during the test. After 24 hours, the enzymatic activity of the solutions is rapidly quenched by the addition of acetonitrile to produce a final concentration of 25% (volume / volume). The samples are analyzed (at time point 0 and at the 24 hour time point) at room temperature using reverse phase HPLC. A microperforation formula is used to optimize sensitivity. The parameters for analytical HPLC are as follows: Solvent system A: 0.1% trifluoroacetic acid (TFA) in water (volume / volume) B: 0.085% TFA / acetonitrile, 1% H2O (volume / volume) Injection and gradient Injection: 100-250 μL test sample Experiment: 10% for B for 5 minutes, then 10-70% B for 60 minutes. A chromatographic analysis is carried out using HPLC 1090 series II of Hewlett Packard. The columan used for the separation is C4, 5 μM, 1 x 250 mm (Vydac # 214TP51). The flow rate is 50 μL / min and the elution profile of the test compounds is monitored at 214, 230, 260 and 280 nm. EXAMPLE 8: Brain Absorption Test The brain levels of our Aβ-derived peptides were determined in the rat after intravenous administration. Under anesthesia with ketamine / xylazine, male Sprague-Dawley rats (219-302g) received an intravenous injection through a catheter inserted into the left jugular vein (dose volume of 4 mL / kg administered in one minute). The actual dose administered of each compound tested is shown in figure 1. 60 minutes after administration, the left common carotid artery was cannulated to allow perfusion of the left anterior brain to remove cerebral blood. The left anterior brain without blood was subjected to capillary depletion in accordance with that described by (Triguero et al (1990) J. Neurochem, 54: 1882-1888). This established technique separates the cerebral vessels from the parenchyma and, therefore, allows a precsy determination of the concentration of compound under investigation that has crossed the blood-brain barrier. The amount of parent compound present in the brain was determined by LC / MS / MS. The test described above was used to measure brain absorption of the following modulators: Compounds Dose PPI Structure mwt Conc mg / kg (mg / mL) IV 1324 TFA • H- (l- [F5] f-fvl) -NH2 841 1.20 4.9 1318 TFA • H- (If-D-Cha-vl) -NH2 757 0.29 1.0 1319 TFA • H- (lf- [p-F] f-vl) -NH2 769 1.70 6.6 1327 TFA • H- (1- [p-F] f- [p-F) f-vl) -NH2 787 0.98 4.0 1301 TFA • H- (lvf-D-Cha-l) -NH2 757 0.70 2.9 1302 TFA • H- (Ivf- [pF] fl) -NH2 769 0.19 0.7 1328 TFA • H- (l- [F5] f- [F5] f-vl) -NH2 931 0.29 1.2 1322 TFA • H- (1 -D-Cha-fvl) -NH2 757 0.03 0.1 1303 TFA • H- (lvf- [F5] f-1) -NH2 841 0.27 1.0 1326 TFA • H- (1-D-Cha-D-Cha-vl) 763 0.05 0.2 NH2 1320 TFA • H- (lf- [F5] f-vl) -NH2 841 0.70 3.0 The lower case indication refers to a D configuration. The results appear in Figure 1. The β-amyloid modulator compounds described herein are presented in summary form in the following Table. TAJ3LA IV PP1 # Description SEQ ID NO 803 TFA • N, N-dimethyl- (Gaffvl) -NH2 913 TFA • N, N-dimethyl- (affvl) -NH2 918 TFA • H- (l- [Me] v-ffa ) -NH2 968 TFA • N-methyl- (Gaffvl) -NH2 969 TFA • N-ethyl- (Gaffvl) -NH2 970 TFA • N-isopropyl- (Gaffvl) -NH: 992 TFA • H- (lvffa) -isopropylamide 993 TFA • H- (lvffa) -dimethylamide 1005 TFA • N, N-diethyl- (Gaffvl) -NH; • 1006 TFA • N, N-diethyl- (affvl) NH2 1007 TFA • N, N-dimethyl- (lvffl) -NH; 1008 TFA • N, N-dimethyl- (lffvl) -NH: 1013 TFA • H- (Glvffl) -NH2 1017 TFA • N-ethyl- (Glvffl) -NH2 1018 TFA • N-ethyl- (Glffvl) -NH2 1020 TFA • N-methyl- (lffvl) -NR2 1022 TFA • N-ethyl- (lvffl) -NH2 1025 TFA • N-propyl- (lvffl) -NH2 1028 TFA • N, N-diethyl- (Glvffl) -NH2 1038 TFA • H- (ivffi) -NH2 1039 TFA • H- (ivffa) -NH2 1040 TFA • H- (iiffÍ) -NH2 1041 TFA • H- (D-Nle-vffa) -NH2 1042 TFA • H- (D -Nle-vff-D-Nle) -NH2 1088 TFA »1-piperidine-acetyl- (lvffl) -NH2 1089 TFA »1-piperidin-acetyl- (lffvl) -NH2 1093 TFA • H-lvffl-isopropylamide 1094 TFA • H-lffvl-isopropylamide 1179 TFA • H- (lvffl) -methylamide 1180 TFA • H- (lffvl) -methylamide 1261 TFA • H- (lvffl) -OH 1019 TFA • N -methyl- (lvffl) -NH: 1301 TFA • H- (lvf-D-Cha-l) -NH. 1302 TFA • H- (lvf- [pF] f-1) -NH: 1303 TFA • H- (lvf- [F5] f-1) -NH2 1306 N-methyl- (lvf-D-Cha-l) - NH: 1307 N-methyl- (lvf- [pF] f-1) -NH2 1308 N-methyl- (lvf- [F5] f-1) -NH2 1318 TFA • H- (lf-D-Cha-vl) -NH2 1319 TFA • H- (lf- [pF] -vi) -NH2 1320 TFA • H- (lf- [F5] f-vl) -NH2 1321 2TFA • H- (lfkvl) -NH2 1322 TFA • H- (1-D-Cha-fvl) -NH2 1323 TFA • H- (l- [pF] f-fvl) -NH2 1324 TFA • H- (l- [F5] f-fvl) -NH2 1325 2TFA • H- (lkfvl) -NH2 1326 TFA • H- (lD-Cha-D-Cha-vl) -NH2 1327 TFA • H- (1- [pF] f- [pF] f-vl) -NH2 1328 TFA • H- (l- [F5] f- [F5] f-vl) -NH2 1329 3 TFA • H- (lkkvl) -NH2 1125 2 TFA • H-lvf-NH-NH-fvl-H 1133 TFA • H-lvf- NH-NH-acetyl 1155 TFA • H-lvf-NH-NH2 EQUIVALENTS Those skilled in the art will recognize or be able to determine using only routine experiments many equivalent to the specific embodiments of the invention described herein. Such equivalents are encompassed by the following claims:

Claims (14)

1. CLAIMS 1. A compound comprising the structure: An (Y-Xaa? -Xaa2-NH- [(Z-Xaai '-Xaa2' -Xaa3 '-) NH wherein Xaai and Xaa2 are each structures of D-amino acids and at least two of Xaai and Xaa2 are independently selected within the group comprising a structure of D-leucine, structure of D-phenylalanine, a structure of D- tyrosine, a D-iodotyrosine structure, a D-lysine structure, or a D-valine structure; NH-NH is a structure of hydrazine; And, which may be present or not, is a structure having the formula (Xaa) a, wherein Xaa is any structure of D-amino acid and "a" is an integer from 1 to 15; Xaa? ', Xaa2'and Xaa3'which may or may not be present, are each structures of D-amino acids or L-amino acids and at least two of Xaa?', Xaa2'and Xaa3 'are selected, independently within the group which consists of a structure of D-leucine, structure of D-phenylalanine or an L-phenylalanine structure, a structure of D-tyrosine or L-tyrosine, a structure of D-iodotyrosine or L-iodotyrosine, a structure of D- lysine or L-lysine, c either a D-valine or L-valine structure; Z, which may or may not be present, is a structure having the formula (Xaa), wherein Xaa is any structure of D-amino acid and "b" is an integer from 1 to 15; A, which may or may not be present, is a modifying group fixed directly or indirectly on the compound; And "n" is an integer from 1 to 15; wherein Xaai ', Xaa2', Xaa3 ', Y, Z, A and "n" is selected such that the compound binds to natural β-amyloid peptides or modulates the aggregation or inhibits the neurotoxicity of β-peptides natural amyloids when it comes into contact with the natural β-amyloid peptides and has a lower tendency to metabolism.
2. 2. A compound having a structure selected from the group consisting of: H-D-Leu-D-Val-D-Phe-NH- (H-D-Leu-D-Val-D-Phe-) NH; H-D-Leu-D-Val-D-Phe-NH-NH-COCH3; and H-D-Leu-D-Val-D-Phe-NH-NH2.
3. 3. A compound comprising the structure: An (Y-Xaa? -Xaa2-Xaa3-Xaa4-Z) wherein Xaai, Xaa2, Xaa3 and Xaa4 are each structures of D-amino acids and at least two of Xaai, Xaa2, Xaa3 and Xaa4 are, independently, selected from the group consisting of a structure of D-leucine, D- cyclohexylalanine, D-4-fluorophenylalanine (para-fluorophenylalanine), D-pentafluorophenylalanine, chlorophenylalanine, bromophenylalanine, nitrophenylalanine, and D-homophenylalanine, a structure of D-lysine, and a structure of D-valine; And, which may be present or not, is a structure having the formula (Xaa) a, wherein Xaa is any structure of D-amino acid and "a" is an integer from 1 to 15; Z, which may or may not be present, is a structure having the formula (Xaa) b, wherein Xaa is any structure of D-amino acid and "b" is an integer from 1 to 15; A, which may or may not be present, is a modifying group fixed directly or indirectly on the compound; And "n" is an integer from 1 to 15; wherein Xaai, Xaa2, Xaa3, Xaa4, Y, Z, A and "n" is selected such that the compound binds to natural β-amyloid peptides or modulates the aggregation or inhibits the neurotoxicity of β-amyloid peptides natural when it comes into contact with the natural β-amyloid peptides and has a lower tendency to metabolism.
4. 4. A compound having a structure selected from the group consisting of: N, N-dimethyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N, N-dimethyl- (D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-methyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) NH 2; N-ethyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-isopropyl- (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Ala) -isopropylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Ala) -dimethylamide; N, N-diethyl (Gly-D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N, N-di-ethyl- (D-Ala-D-Phe-D-Phe-D-Val-D-Leu) -NH2: N, N-dimethyl- (D-Leu-D-Val-D-Phe-D) -Phe-D-Leu) -NH; N, N-dimethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N, N-dimethyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH2; H- (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N-ethyl (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N-ethyl- (Gly-D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-methyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -NH2; N-ethyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N-propyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; N, N-diethyl- (Gly-D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; H- (D-Ile-D-Val-D-Phe-D-Phe-D-Ile) -NH2; H- (D-Ile-D-Val-D-Phe-D-Phe-D-Ala -) - NH 2; H- (D-Ile-D-Ile-D-Phe-D-Phe-D-Ile) -NH; H- (D-Nle-D-Val-D-Phe-D-Phe-D-Ala-) -NH2; H- (D-Nle-D-Vai-D-Phe-D-Phe-D-Nle) -NH2; 1-piperidine-acetyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; 1-piperidine-acetyl- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu.) -NH2; HD-Leu-D-Val-D-Phe-D-Phe-D- Leu-isopropylamide; HD-Leu-D-Phe-D-Phe-D-Val-D-Leu-isopropylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) - methylamide; H- (D-Leu-D-Phe-D-Phe-D-Val-D-Leu) -methylamide; H- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) ) -OH; N-methyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D-Cha) -D-Leu) -NH2; H- (D-Leu-D-Val-D-Phe-D- [pF] Phe-D-Leu) -NH2; H- (D-Leu-D-Val-D- Phe-D- [F5] Phe-D-Leu) -NH2; H- (D-Leu-D-Phe-D-Cha-D-Val-D-Leu) -NH2; H- (D-Leu-D -Phe-D- [pF] Phe-D-Val-D-Leu) -NH:; H- (D-Leu-D-Phe-D- [F5] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Phe-D-Lys-D-Val-D-Leu) -NH2; H- (D-Leu-D-Cha-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D- [pF] Phe-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D- [F5] Phe-D-Phe- D-Val-D-Leu) -NH2; H- (D-Leu-D-Leu-D-Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Cha-D- Cha-D-Val-D-Leu) -NH2; H- (D-Leu-D- [pF] Phe-D- [pF] Phe-D-Val-D-Leu) -NH2; H- (D- Leu-D [F5] Phe-D- [F5] Phe-D-Val-D-Leu) -NH2; H- (D-Leu-D-Lys-D-Lys-D-Val-D) -Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D-Cha-D-Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D- [p-F] Phe-D-Leu) -NH2; N-methyl- (D-Leu-D-Val-D-Phe-D- [F5] Phe-D-Leu) -NH2; H-D-Leu-D-Val-D-Phe-NH- (H-D-Leu-D-Val-D-Phe-) NH; H-D-Leu-D-Val-D-Phe-NH-NH-COCH3; and H-D-Leu-D-Val-D-Phe-NH-NH2.
5. 5. A compound having the structure: H- (D-Leu-D-Phe- [p-F] D-Phe-D-Val-D-Leu) -NH2.
6. 6. A compound having the structure: N-methyl- (D-Leu-D-Val-D-Phe-D-Phe-D-Leu) -NH2.
7. A pharmaceutical composition comprising a therapeutically effective amount of the compound of any one of claims 1, 2, 3, 4, 5, or 6 and a pharmaceutically acceptable carrier.
8. 8. A method for inhibiting the aggregation of natural β-amyloid peptides, comprising contacting the natural β-amyloid peptides with the compound of any one of claims 1, 2, 3, 4, 5 or 6 of such that the aggregation of the natural β-amyloid peptides is inhibited.
9. 9. A method for detecting the presence or absence of natural β-amyloid peptides in a biological sample, comprising: contacting a biological sample with the compound of any of claims 1, 2, 3, 4, 5 or 6, wherein the compound is labeled with a detectable substance; and detecting the compound bound to natural β-amyloid peptides to thereby detect the presence or absence of natural β-amyloid peptides in the biological sample.
10. 10. The method according to claim 9, wherein the β-amyloid modulator compound and the biological sample are in in vitro contact.
11. The method according to claim 9, wherein the β-amyloid modulator compound is in contact with the biological sample by administration of the β-amyloid modulator compound to a subject.
12. 12. The method according to claim 9, wherein the compound is labeled with radioactive tecnetium or radioactive iodine.
13. A method for treating a subject for a disorder associated with β-amyloidosis, comprising: administering to the subject a therapeutically effective amount of the compound of any one of claims 1, 2, 3, 4, 5 or 6 such that the subject is treated for a disorder associated with β-amyloidosis.
14. 14. The method according to claim 13, wherein the disorder is Alzheimer's disease.