Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Reexamination Certificate
2000-12-22
2003-12-30
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
C424S001650, C424S009100, C514S002600, C514S114000, C514S120000, C514S126000, C514S553000
Reexamination Certificate
active
06670399
ABSTRACT:
BACKGROUND OF THE INVENTION
Cerebral amyloid angiopathy (CAA) remains a largely untreatable disease often not diagnosed until autopsy. It ranges in severity from asymptomatic amyloid deposition in otherwise normal cerebral vessels to complete replacement and breakdown of the cerebrovascular wall. Severe CAA can cause lobar cerebral hemorrhage, transient neurologic symptoms, and dementia with leukoencephalopathy. (see Greenberg,
Neurology
1998, 51: 690-694).
Amyloid-&bgr; (A&bgr;) is a toxic peptide which is implicated in the pathogenesis of CAA. A&bgr; peptide is derived from a normal proteolytic cleavage of the precursor protein, the Amyloid-&bgr; precursor protein (&bgr;APP). Advanced cases of CAA demonstrate structural changes to the walls of the amyloid-laden vessel such as cracking between layers, smooth muscle cell toxicity, microaneuryism formation, and fibrinoid necrosis.
The exact mechanisms involved in the genesis of cerebral amyloid angiopathy (CAA) have not been completely established, but it appears that a preponderance of the form of the 39-40 amino acid A&bgr; peptide (A&bgr;40) is responsible for the deposits on blood vessel wall cells which lead to CAA, in comparison to the 42-43 amino acid A&bgr; peptides (A&bgr;42 and A&bgr;43), which are implicated in other amyloid-related conditions such as Alzheimer's Disease (AD).
SUMMARY OF THE INVENTION
The present invention provides methods for modulating, e.g., inhibiting and/or preventing, cerebral amyloid angiopathy. The present invention is based, at least in part, on the discovery that compounds which interfere with the deposition of A&bgr; peptide, e.g., the A&bgr;40 peptide, in blood vessel wall cells, prevent the structural changes to cerebral blood vessels like capillaries, that lead to CAA. It is believed, without intending to limit the invention as claimed herein, that the compounds of the invention interfere with the association of the A&bgr;40 peptide, e.g., the association of the A&bgr;40 peptide to the sulfate GAGs present at the smooth muscle cell surface, and thus prevent intracellular and extracellular amyloid deposition. However, while it is believed that inhibition of A&bgr;40 is a significant factor in inhibiting CAA, the A&bgr;40 inhibitors of the invention may well work in other ways to inhibit or prevent CAA, and these are intended to be part of the present invention.
Accordingly, this invention pertains to a method of modulating, e.g., inhibiting and/or preventing, cerebral amyloid angiopathy. The method includes contacting a blood vessel wall cell with an A&bgr;40 inhibitor, such that the compound inhibits or prevents cerebral amyloid angiopathy. The A&bgr;40 inhibitor is believed to at least interfere with the ability of the A&bgr;40 peptide to form amyloid fibrils and/or with the ability of the A&bgr;40 peptide to bind to a cell (e.g., blood vessel wall smooth muscle cells, pericytes or endothelial cells) surface molecule or structure, forming deposits on the walls of the blood vessel and thus prevent A&bgr;-induced cell death and/or the structural changes to cerebral blood vessels, e.g., capillaries, medium sized arteries, or arterioles, that lead to CAA. The A&bgr;40 peptide can be either in a soluble form or in a fibril form.
In one embodiment, the A&bgr;40 inhibitor may be ethanesulfonic acid, 1,2-ethanedisulfonic acid, 1-propanesulfonic acid, 1,3-propanedisulfonic acid, 1,4-butanedisulfonic acid, 1,5-pentanedisulfonic acid, 2-aminoethanesulfonic acid, or 4-hydroxy-1-butanesulfonic acid, and pharmaceutically acceptable salts thereof. In other preferred embodiments, the A&bgr;40 inhibitor may be 1-butanesulfonic acid, 1-decanesulfonic acid, 2-propanesulfonic acid, 3-pentanesulfonic acid, or 4-heptanesulfonic acid, and pharmaceutically acceptable salts thereof. In yet further preferred embodiments, the A&bgr;40 inhibitor may be 1,7-dihydroxy-4-heptanesulfonic acid, 3-amino-1-propanesulfonic acid, or a pharmaceutically acceptable salt thereof. In another embodiment the A&bgr;40 inhibitor is a peptide or a peptidomimetic which interacts with specific regions of the A&bgr; peptide such as the regions responsible for cellular adherence (aa 10-16), GAG binding site region (13-16) or the region responsible for the &bgr;-sheet formation (16-21). These peptides are the d-stereoisomers of the A&bgr; or complementary image of the A&bgr; peptide.
In one embodiment, the A&bgr;40 inhibitor is administered in a pharmaceutically acceptable formulation. The pharmaceutically acceptable formulation can be a dispersion system like a lipid-based formulation, a liposome formulation, or a multivesicular liposome formulation. The pharmaceutically acceptable formulation can also comprise a polymeric matrix, e.g., synthetic polymers such as polyesters (PLA, PLGA), polyethylene glycol, poloxomers, polyanhydrides, and pluronics; or naturally derived polymers, such as albumin, alginate, cellulose derivatives, collagen, fibrin, gelatin, and polysaccharides. In other preferred embodiments, the pharmaceutically acceptable formulation provides sustained delivery of the A&bgr;40 inhibitor to the target site.
Yet another aspect of the invention pertains to a method of treating a disease state characterized by cerebral amyloid angiopathy in a subject. The method includes administering an A&bgr;40 inhibitor to the subject, such that the disease state characterized by cerebral amyloid angiopathy is treated, e.g., inhibited or prevented.
Another aspect of the invention pertains to a method of modulating, e.g., inhibiting and/or preventing, cerebral amyloid angiopathy, including contacting a blood vessel wall cell with an A&bgr;40 inhibitor having the structure:
Q-[—Y
−
X
+
]
n
wherein Y
−
is an anionic group at physiological pH; Q is a carrier group; X
+
is a cationic group; and n is an integer selected such that the biodistribution of the A&bgr;40 inhibitor for an intended target site is not prevented while maintaining activity of the A&bgr;40 inhibitor, provided that the A&bgr;40 inhibitor is not chondroitin sulfate A, such that cerebral amyloid angiopathy is inhibited or prevented.
In yet another aspect, the invention features a method of modulating, e.g., inhibiting and/or preventing, cerebral amyloid angiopathy, including contacting a blood vessel wall cell with an A&bgr;40 inhibitor having the structure:
wherein Z is XR
2
or R
4
, R
1
and R
2
are each independently hydrogen, a substituted or unsubstituted aliphatic group (preferably a branched or straight-chain aliphatic moiety having from 1 to 24 carbon atoms in the chain; or an unsubstituted or substituted cyclic aliphatic moiety having from 4 to 7 carbon atoms in the aliphatic ring; preferred aliphatic and cyclic aliphatic groups are alkyl groups, more preferably lower alkyl), an aryl group, a heterocyclic group, or a salt-forming cation; R
3
is hydrogen, lower alkyl, aryl, or a salt-forming cation; R
4
is hydrogen, lower alkyl, aryl or amino (including alkylamino, dialkylamino (including cyclic amino moieties), arylamino, diarylamino, and alkylarylamino); X is, independently for each occurrence, O or S; Y
1
and Y
2
are each independently hydrogen, halogen (e.g., F, Cl, Br, or I), alkyl (preferably lower alkyl), amino, hydroxy, alkoxy, or aryloxy; and n is an integer from 0 to 12 (more preferably 0 to 6, more preferably 0 or 1), such that cerebral amyloid angiopathy is inhibited or prevented.
Other features and advantages of the invention will be apparent from the following detailed description, and from the claims.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is based, at least in part, on the discovery that compounds which interfere with the ability of the A&bgr;40 peptide to form deposits in cerebral blood vessels, e.g., on the smooth muscle cells thereof, and thus prevent the structural changes to cerebral blood vessels that lead to CAA.
As used herein, the language “contacting” is intended to include both in vivo, in vitro, or ex vivo methods of bringing an A&bgr;40 inhibitor into proximity with a
Gervais Francine
Green Allan M.
Hanley Elizabeth A.
Lahive & Cockfield LLP
Neurochem (International) Limited
Russel Jeffrey E.
West Theodore R.
LandOfFree
Compounds and methods for modulating cerebral amyloid... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Compounds and methods for modulating cerebral amyloid..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Compounds and methods for modulating cerebral amyloid... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3114467