Methods and compounds for inhibiting amyloid deposits

Details Methods and compounds for inhibiting amyloid deposits Methods and compounds for inhibiting amyloid deposits

2000-05-23

2003-05-13

Fay, Zohreh (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S308000, C514S311000, C514S313000, C514S314000

Reexamination Certificate

active

06562836

ABSTRACT:

BACKGROUND OF THE INVENTION
Amyloidosis refers to a pathological condition characterized by the presence of amyloid. Amyloid is a generic term referring to a group of diverse but specific intra- and extracellular protein deposits which are associated with a number of different diseases. Though diverse in their occurrence, all amyloid deposits have common morphologic properties, including that they stain with specific dyes (e.g., Congo red), and have a characteristic birefringent appearance (sometimes characterized as “red-green”) in polarized light after staining. They also share common ultrastructural features and common x-ray diffraction and infrared spectra.
Amyloidosis can be classified clinically as primary, secondary, familial and/or isolated. Isolated forms of amyloidosis are those that tend to involve a single organ system. Different amyloids are also characterized by the type of protein present in the deposit. For example, neurodegenerative diseases such as scrapie, bovine spongiform encephalitis, Creutzfeldt-Jakob disease and the like are characterized by the appearance and accumulation of a protease-resistant form of a prion protein (referred to as AScr or PrP-27) in the central nervous system. Similarly, Alzheimer's disease, another neurodegenerative disorder, is characterized by congophilic angiopathy, neuritic plaques and neurofibrillary tangles, all of which have the characteristics of amyloids. In this case, the plaque and blood vessel amyloid is formed by the beta protein. Other diseases, such as juvenile and adult-onset diabetes, complications of long-term hemodialysis and sequelae of long-standing inflammation or plasma cell dyscrasias are characterized by the accumulation of amyloids systemically. In each of these cases, a different amyloidogenic protein is involved in amyloid deposition.
Islet amyloid polypeptide (IAPP) is known to be capable of forming fibrils which are deposited in the pancreas of patients with Type II diabetes, forming deposits. Once these amyloid deposits have formed, there is no known therapy or treatment which significantly reduces or clears the deposits in situ.
SUMMARY OF THE INVENTION
This invention provides methods and compositions which are useful in the treatment of amyloidosis. In particular, methods and compositions are disclosed for inhibiting, preventing and treating amyloid deposition, e.g., in pancreatic islets wherein the amyloidotic deposits to be treated are, e.g., islet amyloid polypeptide (IAPP)-associated amyloid deposits having at least some &bgr;-sheet structure. The methods of the invention involve administering to a subject a therapeutic compound which inhibits, reduces or disrupts amyloid deposits, e.g., IAPP-associated amyloid deposits. Accordingly, the compositions and methods of the invention are useful for inhibiting amyloidosis in disorders in which such amyloid deposition occurs, such as diabetes.
In one embodiment, a method for inhibiting amyloid deposition, particularly IAPP-associated amyloid deposition, in a subject is provided, wherein an effective amount of an IAPP-inhibiting compound, or a pharmaceutically acceptable salt thereof, is administered to the subject such that said IAPP-associated amyloid deposition is inhibited. Such compounds include those of the following general formula
wherein C is carbon, N is nitrogen, l, m, o, p and q are independently 0 or 1; n is an integer from 0 to 3; W is hydrogen or an anionic group at physiological pH; Y is an anionic group at physiological pH; R
1
and R
2
are independently hydrogen, alkyl, an anionic group at physiological pH, or R
1
and R
2
, taken together with the nitrogen to which they are attached, may form an unsubstituted or substituted heterocycle having from 3 to 7 atoms in the heterocyclic ring; R
3
is hydrogen, halogen, thiol or hydroxyl; R
4
, R
5
, and R
6
are independently hydrogen or halogen; and A is hydrogen or C
1
to C
6
alkyl; or a pharmaceutically acceptable ester, acid or salt thereof.
Preferred therapeutic compounds include 3-(3-hydroxy-1-propyl)amino-1-propanesulfonic acid; 2-amino-5-phosphovaleric acid; 4-phenyl-1-(3′-sulfopropyl)-1,2,3,6-tetrahydropyridine; cyclohexylsulfamic acid; O-phospho-L-serine; hexafluoroglutaric acid; 3-amino-2-hydroxy-1-propanesulfonic acid; 8-methoxy-5-quinolinesulfonic acid; and 3-dimethylamino-1-propanesulfonic acid, the compounds depicted in
FIGS. 10-14
, and pharmaceutically acceptable esters, acids or salts thereof.
In another embodiment a method for inhibiting amyloid deposition, particularly IAPP-associated amyloid deposition, in a subject is provided, wherein an effective amount of an IAPP-inhibiting compound, or a pharmaceutically acceptable ester, acid or salt thereof, is administered to the subject such that said IAPP-associated amyloid deposition is inhibited. Such compounds include those of the following general formula
wherein A
1
, A
2
, A
3
, A
4
, A
5
and A
6
are independently alkyl, O, S, or —NH; m and n (for each individual A group) are independently 0 or 1; l, p and q are independently 0, 1, or 2; R
7
, R
8
, R
9
, R
10
, R
11
, R
12
, R
13
, and R
14
are independently hydrogen, alkyl, alicyclyl, heterocyclyl or aryl, and adjacent R groups (e.g., R
7
and R
8
) may form an unsubstituted or substituted cyclic or heterocyclic ring. In an embodiment, R
13
may be anionic.
Preferred therapeutic compounds include 1,2,3,4-tetrahydroisoquinoline, and the compounds depicted in
FIGS. 1-9
.
In another embodiment the invention relates to a method for reducing IAPP-associated amyloid deposits in a subject having IAPP-associated amyloid deposits, the method comprising administering to a subject an effective amount of an IAPP inhibiting compound, or a pharmaceutically acceptable ester, acid or salt thereof, such that IAPP-associated amyloid deposits are reduced.
The therapeutic compounds of the invention are administered to a subject by a route which is effective for inhibiting IAPP-associated amyloid deposition. Suitable routes of administration include oral, transdermal, subcutaneous, sublingual, buccal, intravenous and intraperitoneal injection. The therapeutic compounds can be administered with a pharmaceutically acceptable vehicle.
The invention further provides pharmaceutical compositions for treating amyloidosis. The pharmaceutical compositions include a therapeutic compound of the invention in an amount effective to inhibit IAPP-associated amyloid deposition, and a pharmaceutically acceptable vehicle.


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