Inhibitors of amyloid formation

Details Inhibitors of amyloid formation Inhibitors of amyloid formation

2001-03-07

2003-10-14

Raymond, Richard L. (Department: 1624)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Heterocyclic carbon compounds containing a hetero ring...

C514S410000, C540S122000, C540S145000

Reexamination Certificate

active

06632808

ABSTRACT:

FIELD OF THE INVENTION
This invention concerns pharmaceutical compositions that are useful for inhibiting formation of amyloid deposits in amyloidogenic disorders, such as those deposits associated with protease resistant prion proteins in transmissible spongiform encephalopathies.
BACKGROUND OF THE INVENTION
Amyloid formation is found in a number of disorders, such as diabetes, Alzheimer's Disease (AD), scrapie, Gerstmann-Staussler-Scheinker (GSS) Syndrome, bovine spongiform encephalopathy (BSE), Creutzfeldt-Jakob disease (CJD), chronic wasting disease (CWD), and related transmissible spongiform encephalopathies (TSEs). These and other diseases in which amyloid plaques or amyloid deposits are formed in the body are referred to as amyloidogenic diseases.
Transmissible spongiform encephalopathies are fatal neurodegenerative diseases that include such human disorders as CJD, kuru, fatal familial insomnia, and GSS. Animal forms of TSE include scrapie in sheep, CWD in deer and elk, and bovine spongiform encephalopathy in cattle. These diseases are characterized by the formation and accumulation in the brain of an abnormal proteinase K resistant isoform (PrP-res) of a normal protease-sensitive host-encoded prion protein (PrP-sen). PrP-res is formed from PrP-sen by a post-translational process involving conformational changes that convert the PrP-sen into a PrP-res molecular aggregate having a higher &bgr;-sheet content. The formation of these macromolecular aggregates of PrP-res is closely associated with TSE-mediated brain pathology in which amyloid deposits of PrP-res are formed in the brain, which eventually becomes “spongiform” (filled with holes).
In the past, the TSE diseases were a medical curiosity because the transmissible agent was difficult to inactivate with heat, radiation or chemicals that would be expected to inactivate infectious living organisms such as bacteria and viruses. Instead, this class of diseases appeared to be transmitted by exposure to an unusual agent, for example by ritual cannibalism in the Foret people of New Guinea, or feeding of animal parts to cattle in bovine spongiform encephalopathy (BSE), latrogenic CJD has also been caused by administration of human growth hormone derived from cadaveric pituitaries, transplanted dura mater and corneal grafts, as well as exposure of surgeons to affected tissue during neurological procedures. The TSE diseases took on new urgency, however, when it appeared that cross-species infection of humans in Europe may have occurred, perhaps from the ingestion of beef from affected cows. That development has further stimulated an international search for a better understanding of the pathophysiological mechanism of the disease, and possible treatments.
The presence of a native prion protein (PrP) has been shown to be essential to pathogenesis of TSE. The cellular protein PrP-sen is a sialoglycoprotein encoded by a gene that in humans is located on chromosome 20. The PrP gene is expressed in neural and non-neural tissues, with the highest concentration of its mRNA being in neurons. The translation product of the PrP gene consists of 253 amino acids in humans, 254 in hamsters and mice, 264 amino acids in cows, and 256 amino acids in sheep (all of these sequences are disclosed in U.S. Pat. No. 5,565,186, which describes methods of making transgenic mice that express species specific PrP). In prion protein related encephalopathies, the cellular PrP-sen is converted into the altered PrP-res that is distinguishable from PrP-sen in that PrP-res aggregates (Caughey and Chesebro, 1997
, Trends Cell Biol
. 7, 56-62); is proteinase K resistant in that only approximately the N-terminal 67 amino acids are removed by proteinase K digestion under conditions in which PrP-sen is completely degraded (Prusiner et al., 1996, Sem. Virol. 7, 159-173); and has an alteration in protein conformation in which the amount of &agr;-helical conformation for PrP-sen is reduced, and the amount of &bgr;-sheet conformation for PrP-res is increased (Pan et al., 1993
, Proc. Natl. Acad. Sci. USA
90, 10962-10966).
If PrP-sen is not expressed in the brain tissue of animal recipients of scrapie-infected neurografts, no pathology occurs outside the graft, demonstrating that PrP-res and PrP-sen are both required for the pathology (Brander et al.,
Nature
379:339-343, 1996). The long latency period between infection and the appearance of disease (months to decades depending on species) has prompted the development of a cell-free in vitro test, in which PrP-res induces the conversion of PrP-sen to PrP-res (Kocisko et al.,
Nature
370:471474, 1994). See also Prusiner et al., WO 97/16728 published May 9, 1997. The in vitro interaction between PrP-res and PrP-sen occurs with species and strain specificities that mimic TSE species barrier effects and strain differences in vivo (Kocisko et al., 1995
, Proc Natl Acad Sci USA
92, 3923-3927; Bessen et al., 1995
, Nature
375 , 698-700; Bossers et al., 1997
, Proc. Natl. Acad. Sci. USA
94, 49314936; Raymond et al., 1997
, Nature
388, 285-288), hence in vitro cell free culture techniques are considered to accurately predict pathological developments in the brains of infected animals. These in vivo and in vitro observations indicate that direct interactions between PrP-res and PrP-sen form PrP-res and promote TSE pathogenesis.
Small synthetic peptides containing certain PrP sequences have previously been shown to spontaneously aggregate to form fibrils with a high degree of &bgr;-sheet secondary structure of the type seen in the insoluble deposits in TSE afflicted brains (Gasset et al. , 1992
, Proc. Natl. Acad. Sci. USA
89, 10940-10944; Come et al., 1993
, Proc. Natl. Acad. Sci. USA
90, 5959-5963; Forloni et al., 1993
, Nature
362, 543-546; Hope et al., 1996
, Neurodegeneration
5, 1-11). Moreover, other synthetic PrP peptides have been shown to interact with PrP-sen molecules to form an aggregated complex with increased protease-resistance (Kaneko et al.,
Proc. Natl. Acad. Sci. USA
92, 11160-11164, 1995; Kaneko et al.,
J. Mol. Biol
. 270, 574-586, 1997).
The bovine spongiform encephalopathy epidemic and the appearance of the new variant of CJD in humans has heightened the urgency to develop therapies for the transmissible spongiform encephalopathies (TSE) or prion diseases. U.S. Pat. No. 5,134,121 disclosed the use of a nerve growth blocking peptide to treat prion associated diseases by inhibiting PrP-res formation in the infected host. Sulfated glycans and the sulfonated amyloid stain Congo Red are known inhibitors of PrP-res formation and scrapie agent replication in scrapie-infected neuroblastoma (ScNB) cells (Caughey and Chesebro, 1997
, Trends Cell Biol
. 7, 56-62; Caughey et al., 1992
, J. Neurochem
. 59, 768-771; Caughey et al., 1993
, J. Virol
. 67, 643-650; Caughey et al., 1993
, J. Virol
. 67, 6270-6272). These polyanions are also protective against scrapie in rodents if administered near the time of infection, but have less therapeutic benefit after the infection has reached the central nervous system (Ehlers and Diringer, 1984
, J. Gen. Virol
. 65, 1325-1330; Farquhar and Dickinson, 1986
, J. Gen. Virol
. 67, 463-473; Kimberlin and Walker, 1986
, Antimicrob. Agents Chemother
. 30, 409-413; Ingrosso et al., 1995
, J. Virol
. 69, 506-508). This problem, and/or inherent toxicity, also limit the utility of other classes of potential drugs, such as the polyene antibiotics (Demaimay et al., 1997
J. Virol
. 71, 9685-9689) and anthracycline (Tagliavini et al., 1998
, Science
276, 1119-1122).
Protohemin has been reported to inhibit a protein kinase that phosphorylates filament proteins in patients with Alzheimer' disease. (Vincent and Davies, 1992
, PNAS USA
89:2878-82). Porphyrins and other tetrapyrroles have previously been used therapeutically against cancers and against viral infections (Schuitmaker et al., 1996
, J. Photobiol
. 34 (1): 3-12; Petho, 1995
, Acta Physiol. Hung
. 83(2): 113-119). A major therapeutic use has exploited the light absorbing qualities of these molecules to perform

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