Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1996-03-28
1999-11-02
Celsa, Bennett
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514357, 546145, 546170, 546335, 546337, 560 27, 564157, 564158, 564165, 549 44, 544162, 544168, A61K 3805, C07K 100
Patent
active
059770740
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to compounds and pharmaceutical compositions, and methods for inhibiting or preventing the amyloid protein deposits in the brain. More particularly, the present invention relates to the treatment of Alzheimer's disease.
BACKGROUND ART
It is estimated that over 5% of the U.S. population over 65 and over 15% of the U.S. population over 85 are affected by Alzheimer's disease. (Cross, A. J., Eur. J. Pharmacol. (1982) 82: 77 -80; Terry, R. D., et al., Ann. Neurol. (1983) 14: 497-506). It is believed that the principal cause of confinement of the elderly in long term care facilities is due to this disease, and approximately 65% of those dying in skilled nursing homes suffer from it.
Certain facts about the biochemical and metabolic phenomena associated with the presence of Alzheimer's disease are known. Two morphological and histopathological changes noted in Alzheimer's disease brains are neuro-fibrillary tangles (NFT) and amyloid deposits. Intraneuronal neurofibrillary tangles are present in other degenerative diseases as well, but the presence of amyloid deposits both in the intraneuronal spaces (neuritic plaques) and in the surrounding microvasculature (vascular plaques) seems to be characteristic of Alzheimer's. Of these, the neuritic plaques seem to be the most prevalent (Price, D. L., et al., Drug Development Research (1985) 5: 59-68). Plaques are also seen in the brains of aged Down's Syndrome patients who develop Alzheimer's disease.
Plaque-rich brains of Alzheimer's patients have been used as a source to extract an approximately 4.2 kd "core" polypeptide, amyloid plaque core protein (APCP). This peptide was designated .beta.-protein by (Glenner, G., et al., Biochem. Biophys. Res. Commun. (1984) 120: 885-890). The amino acid sequence of the amino-terminus was determined (Glenner, G., et al., Biochem. Biophys. Res. Commun. (1984) 122: 1131-1135; Masters, C. L., et al., Proc. Natl. Acad. Sci USA (1985) 82: 4245-42259). The amino acid sequences reported by the two groups were identical, except that Glenner et al. reported a glutamine residue at position 11 for Alzheimer's disease cerebral vascular amyloid whereas Master et al. reported glutamic acid at position 11. Also, the former authors reported that the cerebral vascular amyloid has a homogeneous amino-terminus, while the latter authors reported heterogeneous amino-termini. Both groups showed that the same peptide is found in the amyloid plaque cores and vascular amyloid of adult Down's syndrome-afflicted individuals and report glutamic acid at position 11. Wong, C. W., et al. (Proc. Natl. Acad. Sci. USA (1985) 82: 8729-8732) showed that a synthetic peptide which was homologous to the first ten amino acids of the .beta.-amyloid core protein described by Masters (supra) was able to raise antibodies in mice and that these antibodies could be used to stain not only amyloid-laden cerebral vessels, but also neuritic plaques. These results were confirmed by Allsop, D. et al., Neuroscience Letters (1986) 68: 252-256 using antibodies directed against a synthetic peptide corresponding to amino acids 8-17. Thus, in general, the plaque protein found in various locations of the brain of Alzheimer's patients appears to be similar in immuno-reactivity. It is highly insoluble, as shown by the inability to achieve solubilization in many commonly used denaturants, such as detergents and chaotropic agents (Masters, supra, Allsop, D., et al. (supra)).
There are six known instances of disease-associated amyloid deposits in which the amyloid is produced from a precursor protein: for primary amyloidosis, the precursor is an immunoglobulin light chain; for secondary amyloidosis, the precursor is amyloid A protein; for amyloidosis, prealbumin or a variant thereof; for medullary carcinoma of thyroid, a procalcitonin fragment; and for hereditary cerebral hemorrhage, gamma-trace fragment (See, e.g., Glenner, G. New England Journal of Medicine (1980.) 302: 1283; Sletton, K., et al. Biochem J (1981) 195: 561; Benditt, et al. FEBS Lett(197
REFERENCES:
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Angelastro Michael R.
Cordell Barbara
Dorsselaer Viviane Van
Higaki Jeffrey N.
Peet Norton P.
Celsa Bennett
Gupta Balaram
Merrell Pharmaceuticals Inc.
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