Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – C-o-group doai
Reexamination Certificate
2000-07-17
2002-10-29
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
C-o-group doai
C514S453000, C514S456000
Reexamination Certificate
active
06472436
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to methods for the treatment and prevention of various amyloidosic disease conditions using one or more of defined classes of polycyclic compounds. In a particular aspect, the invention relates to methods of inhibiting production of amyloid beta peptides, methods of inhibiting aggregation of amyloid fibrils and inhibiting amyloid-induced toxicity.
BACKGROUND OF THE INVENTION
The amyloidoses are a group of pathological conditions in which normally soluble proteins polymerize to form insoluble amyloid fibrils and amyloid deposits. More than 15 proteins form amyloid fibrils resulting in diverse clinical conditions. Amyloidoses are usually classified into systemic amyloidoses and localized amyloidoses. Major systemic amyloidoses include AL amyloidosis, amyloid A amyloidosis, and familial transthyretin amyloidosis; the corresponding amyloid proteins in these amyloidoses are AL amyloid, amyloid A protein, and transthyretin, respectively. Prominent localized amyloidoses include Alzheimer's disease, prion diseases, and type II diabetes; the corresponding amyloid proteins in these diseases are amyloid &bgr; peptide, scrapie prion protein, and human amylin, respectively (Sipe (1992)
Annu. Rev. Biochem.
61:947-975).
Amyloid or amyloid proteins refer to a group of diverse extracellular proteins that form amyloid deposits with common morphological, ultrastructural and physicochemical properties. For example, amyloid deposits have similar affinities for certain dyes and a characteristic appearance under polarized light. Although they vary in amino acid sequence, all amyloid proteins found in amyloid deposits consist of aggregations containing interlacing bundles of parallel arrays of fibrils where the protein in the fibrils is organized in a &bgr;-pleated sheet structure.
Amyloidoses share several common features, indeed all are related to amyloid deposits formed by amyloid proteins having different amino acid sequences. For example, many of the amyloid proteins in amyloid deposits are rich in &bgr;-pleated sheet conformation, which is responsible for the intensely increased birefingence of amyloid fibrils following Congo red staining (Glenner et al., (1974)
J. Histochem. Cytochem
22:1141-1158; Glenner and Page (1976)
Int. Rev. Exp. Pathol.
15:1-92; Glenner (1980)
N. Engl. J. Med.
302:1283-1292 (Pt. 1) and 133-1343 (Pt. 2)).
Amyloid fibrils, regardless of the amyloid protein from which they are formed, have a cytotoxic effect on various cell types including primary cultured hippocampal neurons,(Yankner et al. (1990)
Science
250:279-282), pancreatic islet &bgr; cells (Lorenzo et al. (1994)
Nature
368:756-760) and clonal cell lines (Behl et al. (1992)
Biochem Biophys. Res. Commun.
186:944-952; O'Brien et al., (1995)
Am. J. Pathol.
147:609-616). In fact, only amyloid proteins in fibrillar form are cytotoxic (Pike et al. (1991)
Brain Res.
563:311-314; Lorenzo and Yankner (1994)
Proc. Natl. Acad. Sci.
91:12243-12247). It is likely that the cytotoxic effect of fibrils is mediated by a common mechanism (Lorenzo and Yankner (1994) id.; Schubert et al. (1995)
Proc. Natl. Acad. Sci. USA
92:1989-1993).
Modulation of amyloid protein aggregation is one means of blocking or reducing amyloid toxicity. A detailed description of such modulatory methods can be found in U.S. Pat. No. 5,854,204 (issued Dec. 29, 1998) which is incorporated herein by reference in its entirety.
There is thus a need for additional methods for blocking amyloid protein production and for blocking amyloid toxicity. In particular there is a need for blocking amyloid beta peptide toxicity in neurons, inhibiting the production of amyloid beta peptide, and blocking the production of various other cytotoxic amyloid proteins that result in disease conditions.
SUMMARY OF THE INVENTION
The present invention provides methods of blocking amyloid protein toxicity in cells using one or more of defined classes of polycyclic compounds. Also provided are methods of decreasing amyloid protein production in cells. Invention methods can be used to prevent and treat a diverse class of disease conditions, known as amyloidoses, which are all the result of amyloid protein deposits. In accordance with another embodiment of the invention, there are provided methods of identifying compounds that can block amyloid toxicity or block the amyloid protein induced inhibition of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) reduction.
DETAILED DESCRIPTION OF THE INVENTION
In accordance with the present invention, there are provided methods of blocking amyloid toxicity in cells, said methods comprising contacting said cells with an effective amount of at least one polycyclic compound selected from biphenyl compounds of Structure I or phenyl benzopyranone compounds of Structure II, wherein said structures are:
or enantiomers, diasteriomeric isomers or mixtures of any two or more thereof, or pharmaceutically acceptable salts thereof, wherein:
L is C
1
-C
12
alkylene, substituted alkylene, cycloalkylene, substituted cycloalkylene or substituted lactone radical;
S, T, U and V are independently H, OH, halogen, alkyl or substituted alkyl;
each X is independently OH, SH or NH
2
;
X′ is H, SH, NH
2
or OR, wherein R is H, lower alkyl, alkenyl, or alkynyl;
Y′ is H, OH, SH, or NH
2
; and
Z is H, OH, SH or NH
2
;
provided, however, that at least one of Z and Y′ is H; or Z is absent when ring 3 is attached at the 3-position of ring 2 of Structure II.
Compounds contemplated for use in the practice of the present invention are those having the structure of Structure I and/or Structure II as set forth herein. In each of these structures, “alkyl” refers to straight or branched chain alkyl radicals having in the range of about 1 up to 12 carbon atoms; “substituted alkyl” refers to alkyl radicals further bearing one or more substituents such as hydroxyl, alkoxy, mercapto, aryl, heterocycle, halogen, trifluoromethyl, pentafluoroethyl, cyano, cyanomethyl, nitro, amino, amide, amidine, amido, carboxyl, carboxamide, carbamate, ester, sulfonyl, sulfonamide, and the like.
As used herein, “C
1
-C
12
alkylene” refers to divalent straight or branched chain alkyl moieties having in the range of about 1 up to 12 carbon atoms wherein said moiety serves to link two structures together; “substituted alkylene” refers to alkylene moieties further bearing one or more substituents as set forth above.
As used herein, “cycloalkylene” refers to divalent ring-containing alkyl radicals containing in the range of about 3 up to 20 carbon atoms; “substituted cycloalkylene” refers to cyloalkylene moieties further bearing one or more substituents as set forth above.
As used herein, “halogen” refers to fluoride, chloride, bromide or iodide radicals.
As used herein, “lactone” refers to compounds that are derived by intramolecular elimination of water from a hydroxyl and a carboxyl group of a hydroxyl-substituted carboxylic acid, leading to formation of a cyclic ester; “substituted lactone radical” refers to lactone moieties further bearing one or more substituents as set forth above.
In presently preferred embodiments of the present invention, compounds of Structure I are employed wherein:
L is a substituted lactone radical, alkylene or cycloalkylene;
each X is hydroxyl; and
S, T, U, and V are hydrogen.
In especially preferred embodiments, compounds of Structure I are employed wherein:
L is dimethylmethylene,
each X is hydroxyl, and
S, T, U and V are hydrogen, (i.e., bisphenol A) or
L is 1,4-cyclohexylene,
each X is hydroxyl, and
S, T, U and V are hydrogen (i.e., 4,4-cyclohexylidenebisphenol) or
L is 2,3-dimethylbutylene,
each X is hydroxyl,
U and T are hydroxyl and
S and V are hydrogen (i.e., nordihydroguaiaretic acid) or
L is 5,5-benzofuranonylene;
each X is hydroxyl;
S, T, U and V are hydrogen (i.e. phenolphthalein).
In additional presently preferred embodiments of the present invention, compounds of Structure II are employed, wherein:
each X is hydroxyl,
X′ is hydroxyl,
Y&prime
Liu Yuanbin
Schubert David R.
Fay Zohreh
Foley & Lardner
Kwon Brian
Reiter Stephen E.
The Salk Institute for Biological Studies
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