Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
1999-05-27
2002-08-27
Lambkin, Deborah C. (Department: 1626)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C564S428000, C564S429000
Reexamination Certificate
active
06441049
ABSTRACT:
FIELD OF THE INVENTION
The present invention provides a method for treating neurodegenerative disorders. More particularly, a method for treating neurodegenerative disorders (e.g., Alzheimer's disease) by inhibiting the interaction of amyloid beta with alpha-7 nicotinic acetylcholine receptors.
BACKGROUND OF THE INVENTION
Neurodegenerative disorders such as Alzheimer's disease (AD) and Parkinson's disease (PD) afflict humanity with great suffering and financial loss. AD is characterized by neurofibrillary tangles, neuritic plaques, and neuronal cell death. AD appears as either the familial, early onset (<60 yrs) or late-onset (>60 yrs) forms, with the latter being more prevalent. AD is the major cause of age-related dementia and cognitive impairment (Wisniewski, T.; Ghiso, J.; Frangione, B.
Neurobiol. of Disease
1997, 4, 313-328). The amyloid precursor protein (APP), &bgr;-amyloid
1-40
(A&bgr;
1-40
), and &bgr;-amyloid
1-42
(A&bgr;
1-42
) are keenly involved in the pathology of AD. The A&bgr; peptides are derived from APP by proteolytic processing. Dramatic evidence implicating the A&bgr; peptides, particularly A&bgr;
1-42
, in AD comes from various recently identified mutations accounting for certain types of inherited AD. Such mutations in the presenilin (PS1 and PS2) genes are probably the cause of the most frequent form of familial, early-onset AD (Rogaev, E. I.
Molecular Biology
1998, 32, 58). In these cases, as with APP mutations, more A&bgr;
1-42
is observed relative to A&bgr;
1-40
. Extensive studies have shown that A&bgr;
1-42
has a greater ability than A&bgr;
1-40
to aggregate into the amyloid fibrils that constitute the plaques characteristic of AD (Lansbury, P. T., Jr.
Accts. Chem. Res.
1996, 29, 317). Even though A&bgr;
1-40
is generally present to a much larger degree in the cerebrospinal fluid than A&bgr;
1-42
, it is A&bgr;
1-42
which is the major A&bgr; peptide found in AD plaques.
The A&bgr; peptides can inhibit cholinergic neurotransmitter function independent of neurotoxicity (Auld, D. S.; Kar, S.; Quirion, R.
Trends Neurosci.
1998, 21, 43). A&bgr; peptides bind to a number of natural substances such as apoE3, apoE4, apoJ, transthyretin, and albumin. In addition, A&bgr; has been reported to interact with a membrane-bound receptor for advanced glycation end products and to the class A scavenger receptor (SR) associated with the production of reactive oxygen species. Stimulation of the alpha-7 subtype of the nicotinic acetylcholine receptors (nAChRs) can protect neurons against A&bgr; cytotoxicity (Kihara, T. et al.
Ann. Neurol.
1997, 42, 159). Also, a set of compounds that activate nAChRs, especially of the alpha-7 subtype, have been found to have in vivo activity in models of cognition enhancement (U.S. Pat. No. 5,741,802, issued Apr. 21, 1998).
We now describe specific binding of A&bgr;
1-40
and A&bgr;
1-42
to the alpha-7 subtype of nAChRs. This new finding has broad ramifications for the etiology and treatment of AD. nAChRs are members of the ligand-gated ion channel family and appear to be formed from five protein subunits associating together around a central pore (Lindstrom,
J. Molecular Neurobiology
1997, 15, 193). These subunits include &agr;1-&agr;9, &bgr;1-&bgr;4, &ggr;, &dgr;, and &egr;. The &agr;7 subtype forms functional homomers which bind to &agr;-bungarotoxin, a 75-amino acid peptide, with high affinity (0.65-1.7 nM K
d
) and nicotine with relatively low affinity (ca. micromolar K
d
) (Holladay, M. W.; Dart, M. J.; Lynch, J. K.
J. Med. Chem.
1997, 40, 4169).
Compounds which block the aggregation of A&bgr; peptides are potentially useful drugs for the treatment of AD. For example, rifampicin inhibits A&bgr; aggregation and neurotoxicity and may show an effect in vivo in diminishing plaque burden when compared with age-matched controls (Tomiyama, T. et al.
J. Biol. Chem.
1996, 271, 6839). In order to block the interaction of the A&bgr; peptides with &agr;7 nAChRs, compounds can be found to either bind to &agr;7 nAChRs, to A&bgr; itself, or to both. Any of these mechanisms of action would be expected to provide significant protection against A&bgr;-mediated neurotoxicity and inhibition of cholinergic functioning mediated by nAChRs and be extremely useful for the treatment of AD. The binding of A&bgr;
1-42
to alpha-7 nAChRs provides a seed for crystallization or deposition of A&bgr; into insoluble deposits, which have the potential to grow into the fibrillar amyloid deposits characteristic of AD. Therefore, blocking the interaction of A&bgr;
1-42
with alpha-7 nAChRs should reduce the amount of insoluble aggregated A&bgr; that is formed, and thus prevent the neurotoxicity and pathology associated with such aggregated amyloid deposits.
Accordingly, it is an object of the invention to provide a method for treating neurodegenerative disorders by inhibiting the binding of amyloid beta peptides to alpha-7 nicotinic acetylcholine receptors. It is a further object of the invention to provide a method for treating Alzheimer's disease and/or for slowing the progression of Alzheimer's disease by inhibiting the binding of amyloid beta peptides to alpha-7 nicotinic acetylcholine receptors. Another object of the invention is to provide a predictive method, a method for diagnosis, a method to monitor prognosis, a method to monitor the progression, and a method to monitor the therapeutic efficacy for any therapeutic intervention used in Alzheimer's disease. Still another object of the invention is to provide a method for identifying compounds which inhibit the binding of A&bgr; peptides with &agr;7 nAChRs, either by binding to A&bgr; peptides or to &agr;7 nAChRs.
SUMMARY OF THE INVENTION
The present invention is directed to a method of treating a neurodegenerative disorder in a subject (preferably, a human) in need thereof which comprises administering to the subject an amount of a compound effective to inhibit the binding of an amyloid beta peptide, preferably A&bgr;
1-42
, to alpha-7 nAChRs, preferably, human alpha-7 nAChRs. Since alpha-8 and alpha-9 nAChRs are similar with respect to structure and function to alpha-7 nAChRs, it is possible that blocking the interaction of &bgr;-amyloid with alpha-8 and alpha-9 nAChRs would have therapeutic benefit as well.
Neurodegenerative disorders included within the methods of the present invention include, but are not limited to, Alzheimer's disease, Pick's disease, diffuse Lewy body disease, progressive supranuclear palsy (Steel-Richardson syndrome), multisystem degeneration (Shy-Drager syndrome), motor neuron diseases including amyotrophic lateral sclerosis, degenerative ataxias, cortical basal degeneration, ALS-Parkinson's-Dementia complex of Guam, subacute sclerosing panencephalitis, Huntington's disease, Parkinson's disease, synucleinopathies, primary progressive aphasia, striatonigral degeneration, Machado-Joseph disease/spinocerebellar ataxia type 3 and olivopontocerebellar degenerations, Gilles De La Tourette's disease, bulbar and pseudobulbar palsy, spinal and spinobulbar muscular atrophy (Kennedy's disease), primary lateral sclerosis, familial spastic paraplegia, Werdnig-Hoffmann disease, Kugelberg-Welander disease, Tay-Sach's disease, Sandhoff disease, familial spastic disease, Wohifart-Kugelberg-Welander disease, spastic paraparesis, progressive multifocal leukoencephalopathy, and prion diseases (including Creutzfeldt-Jakob, Gerstmann-Sträussler-Scheinker disease, Kuru and fatal familial insomnia).
Other conditions also included within the methods of the present invention include age-related dementia and other dementias and conditions with memory loss including vascular dementia, diffuse white matter disease (Binswanger's disease), dementia of endocrine or metabolic origin, dementia of head trauma and diffuse brain damage, dementia pugilistica and frontal lobe dementia. Also other neurodegenerative disorders resulting from cerebral ischemia or infaction including embolic occlusion and thrombotic occlus
Chen Robert H.
Demeter David A.
Lee Daniel H. S.
Plata-Salaman Carlos R.
Reitz Allen B.
Appollina Mary A.
Lambkin Deborah C.
Ortho-McNeil Pharmaceutical , Inc.
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