Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2001-05-30
2003-05-13
Shah, Mukund J. (Department: 1624)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S085000, C530S331000, C544S337000
Reexamination Certificate
active
06562783
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to phosphinylmethyl or phosphorylmethyl succinic and glutaric acid analogs designed to inhibit &bgr;-secretase in the metabolic processing of the amyloid precursor protein (APP). The invention also provides methods for the synthesis of phosphinylmethyl or phosphorylmethyl succinic and glutaric acid analogs, and further provides therapeutic methods for administration of the compounds for the treatment of plaque formation, especially in Alzheimer's disease.
BACKGROUND OF THE INVENTION
Alzheimer's disease (AD) affects approximately 5-15% of the U.S. population over age 65. This disease is frequently associated with individuals over the age of 60. Alzheimer's disease is the most frequent cause of institutionalization for long-term care. It is now estimated that 4.1 million Americans suffer from AD incurring $100 billion in U.S. health care costs per year.
Alzheimer's disease is characterized by the deposition of &bgr;-amyloid (A&bgr;) peptide in the extracellular compartment of the brain in the form of cognophilic amyloid angiopathy and amyloid plaques. (Small, D. H., Mclean, C. A, Alzheimer's disease and the amyloid &bgr; protein: what is the role of amyloid?, 73
J. Neurochem
443-49, 1999; Masliah, E., Role of amyloid precursor protein in the mechanisms of Neurodegeneration in Alzheimer's disease, 77
Lab. Investig.
197-209, 1997). Recent research on cellular and molecular aspects of Alzheimer's disease over the last two decades suggested that the metabolic fate of the amyloid precursor protein (APP) is one of the key factors in the pathogenesis of AD. (Lins, L., et al., Molecular determinants of the interaction between the C-terminal domain of Alzheimer's &bgr;-amyloid peptide and apolipoprotein E &agr;-Helices, 73
J. Neurochem.
758-69, 1999; Selkoe, D. J., Normal and abnormal biology of the &bgr;-amyloid precursor protein, 17
Annu. Rev. Neurosci.,
489-517, 1994; Tanzi, R. E., et al., The gene defects responsible for familial Alzheimer's disease, 3
Neurobiology of Disease
159-68, 1996; Selkoe, D. J., Alzheimer's disease: genotypes, phenotype and treatments, 275
Science
630-31, 1997; Hardy, J. Amyloid, the presenilins and Alzheimer's disease, 20
TINS
154-159, 1997; Lendon, C. L., et al., Exploring the etiology of Alzheimer disease using molecular genetics, 277
JAMA
825-31, 1997).
Amyloid precursor protein is a 695-770 amino acid membrane spanning glycoprotein, widely and constitutively expressed in the neurons and glial cells in peripheral tissues. A&bgr;, a 39-42 amino acid peptide, constitutes part of the ectodomain of APP and extends partly to the transmembrane domain. There are three secretory pathways involved in the APP processing. &agr;-Secretase cleaves Lys16 and Leu17 of A&bgr; sequence giving rise to soluble APP (sAPP) (see FIG.
1
). (Small, D. H., Mclean, C. A., Alzheimer's disease and the amyloid &bgr; protein: what is the role of amyloid?, 73
J. Neurochem
443-49, 1999; Masliah, E., Role of amyloid precursor protein in the mechanisms of Neurodegeneration in Alzheimer's disease, 77
Lab. Investig.
197-209, 1997). This pathway is non-amyloidogenic and to date, the products P3 and C83 are considered non-participants in AD pathology. Cleavage of APP by &agr;-secretase produces a large soluble NH2-terminal fragment, sAPP&agr;, and a 10-KD membrane-bound COOH terminal fragment C83. C83 can be further cleaved by one or more &ggr;-secretases to release the nonpathogenic p3 peptide. (Skovronsky, D. M., et al., Protein kinase C-dependent &agr;-secretase competes with &bgr;-secretase for cleavge of amyloid-&bgr; precursor protein in the trans-Golgi network, 274(4)
J. Biol. Chem.
2568 -75, 2000; Jolly-Tornetta, C., Wolf, B. A., Regulation of amyloid protein (APP) secretion by protein kinase C&agr; in human Ntera 2 neurons (NT2N), 39
Biochemistry
7428-35, 2000).
Through the &bgr;-secretory pathway, A&bgr; is produced from the cleavage of APP at the N terminus of A&bgr; by &bgr;-secretase and cleavage at the C terminus of A&bgr; by &ggr;-secretase. The extended forms of A&bgr; aggregate more readily and may seed amyloid fibril polymerization during the early stages of plaque formation. The A&bgr; accumulation is critical to AD as suggested by findings that mutations in several genes associated with familial AD (FAD) increase amyloidogenic A&bgr; production. (Selkoe, D. J., Alzheimer's disease: genotypes, phenotype, and treatments, 275
Science
630-31, 1997; Price, D. L., Sisodia, S. S., Mutant genes in familial Alzheimer's disease and transgenic models, 21
Annu. Rev. Neurosci.
479-505, 1998).
A growing list of evidence has demonstrated that enhanced sAPP secretion is associated with diminished A&bgr; production, suggesting that the secretory processing of APP to sAPP&agr; reduces the formation of potentially amyloidogenic derivatives. Most of the experimental evidence suggests that &agr; and &bgr; secretases compete for the same pool of APP. (Skovronsky, D. M., et al., Protein kinase C-dependent &agr;-secretase competes with &bgr;-secretase for cleavage of amyloid-&bgr; precursor protein in the trans-Golgi network, 275(4) J. Biol. Chem. 2568-75, 2000; Jolly-Tornetta, C., Wolf, B. A., Regulation of amyloid protein (APP) secretion by protein kinase C&agr; in human Ntera 2 neurons (NT2N), 39
Biochemistry
7428-35, 2000). Therefore, the relative ratio of amyloidogenic vs. non-amyloidogenic products could be altered by regulating the activity of either secretase.
Additionally, presenilin 1 was also identified recently to control the hydrolysis at the intramembrane &ggr;-secretase site and has been postulated to be itself the responsible protease. (Wolfe, M. S. et al., Are presenilins intramembrane-cleaving proteases? Implication for the molecular mechanism of Alzheimer's Disease, 38
Biochemistry
11223-30, 1999; Selkoe, D. J., Wolfe, M. S., In search of &ggr;-secretase; Presenilin at the cutting edge, 97
Proc. Natl. Acad. Sci.
5690-92, 2000; Li, Y-M. et al., Presenilin 1 is linked with &ggr;-secretase activity in the detergent solubilized state, 97
Proc. Natl. Acad. Sci.
6138-43, 2000; De Strooper, B. et al., Deficiency of presenilin-1 inhibits the normal cleavage of amyloid precursor protein, 391
Nature
387-90, 1998; Wolfe, M. S. et al., Two transmembrane aspartates in presenilin-1 required for presenilin endoproteolysis and &ggr;-secretase activity, 398
Nature
513-17, 1999; De Strooper, B. et al., A presenilin-1-dependent &ggr;-secretase-like protease mediates release of Notch intracellular domain, 398
Nature
518-22, 1999; Kimberly, W. T. et al., The transmembrane aspartates in presenilin 1 and 2 are obligatory for &ggr;-secretase activity and amyloid &ggr;-protein generation, 275
J. Biol. Chem.
3173-78, 2000). Although several &ggr;-secretase inhibitors have been reported, (Rishton, G. M. et al., Fenchylamine sulfonamide inhibitors of amyloid &bgr; peptide production by the &ggr;-secretase proteolytic pathway: Potential small-molecule therapeutic agents for the treatment of Alzheimer's disease, 43
J. Med. Chem.
2297-99, 2000; Seiffert, D. et al., Presenilin-1 and 2 are molecular targets for &ggr;-secretase inhibitors,
J. Biol. Chem. (in press); Li, Y.-M. et al., Photoactivated &ggr;-secretase inhibitors directed to the active site covalently label presenilin
1, 405
Nature
689-94, 2000; Wolfe, M. S. et al., Peptidomimetic probes and molecular modeling suggest that Alzheimer's &ggr;-secretase is an intramembrane-cleaving aspartyl protease, 38
Biochem.
4720-27, 1999; Wolfe, M. S. et al., A substrate-based difluoro ketone selectively inhibits Alzheimer's &ggr;-secretase activity, 41
J. Med Chem.
6-9, 1998) the processing of APP by &bgr;-secretase is thought to be the rate-determining step in A&bgr; production. Therefore, &bgr;-secretase inhibitor emerges as a preferred therapeutic target in the treatment of Alzheimer's disease.
More recently, significant efforts have been devot
Etcheberrigaray Rene
Qiao Lixin
Hunton & Williams
McKenzie Thomas
Neurologic, Inc.
Shah Mukund J.
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