Compounds and methods for diagnosing and treating...

Details Compounds and methods for diagnosing and treating... Compounds and methods for diagnosing and treating...

2000-09-22

2003-07-08

Padmanabhan, Sreeni (Department: 1617)

Drug, bio-affecting and body treating compositions

Radionuclide or intended radionuclide containing; adjuvant...

In an organic compound

C424S001850, C424S001810, C424S009100

Reexamination Certificate

active

06589504

ABSTRACT:

BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention provides methods for diagnosing and treating amyloid-related conditions and compounds useful for the same. The invention allows for detecting, imaging, monitoring, diagnosing, and treating conditions characterized by the binding or aggregation of amyloid fibrils. More particularly, the invention relates to the use of quinolinehydrazone compounds for diagnosing and treating amyloidotic conditions.
The invention also encompasses a method for using quinolinehydrazone compounds as an antioxidant.
2. Description of the Related Technology
Disease-causing agents once were believed to be limited to pathogens containing nucleic acids, for example viruses and bacteria. More recently, however, considerable evidence suggests that irregular peptides or proteinaceous infective agents can induce or transmit infectious disease.
Currently, it is widely recognized that some proteins can contain irregular protein sequences which cause living tissue or organs to assemble into insoluble aggregates of partially unfolded proteins, known as amyloid fibrils. All types of amyloid are structurally related by containing A&bgr; peptides. The A&bgr; peptides aggregate to form fibrils, which typically have a &bgr;-sheet secondary structure. The fibril deposits, or plaque, are believed to be at the root of the pathology for a number of neurodegenerative diseases, or amyloidosis.
In general, the term “amyloidosis” refers to diseases characterized by the tendency of particular proteins to aggregate and precipitate as insoluble fibrils. The fibrils collect in the extracellular space of the surrounding organs or tissues causing structural and functional damage. Common attributes of amyloidosis include, for example, cell toxicity and cell degeneration. For instance, the clinical course of the amyloidotic condition, Alzheimer's disease, is neurodegeneration. Neurodegeneration can be identified, for example, by the progressive loss of mental capacity, loss of motor control, and dementia. Portmortem deposits of amyloid plaque have been identified in patients suffering from Alzheimer's disease, Down syndrome, Type 2 diabetes mellitus, and other amyloid-related conditions.
Infectious protein particles, or prions, also contain irregular protein sequences. These particles typically can be characterized by a single irregular sequence in the protein peptide. The expression of the irregular sequence favors a protein conformation that, like amyloid protein, tends to aggregate. The aggregation of the protein into a plaque has been identified in many patients inflicted with prion disease, such as, for example, Crutzfeld-Jacob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), fatal familial insomnia (FFI), kuru, Alper's syndrome, scrapie, transmissible mink encepthalopathy (TME), chronic wasting disease (CWD), and bovine spongiform encephalopathy (BSE). In some cases, amyloid plaque has been detected in patients having prion-initiated disease, for example patients diagnosed with CJD. However, prion plaque generally has not been definitively linked to cell impairment. Instead, considerable evidence suggests that the prions propagate by changing the conformation of naturally-existing, non-infectious counterpart proteins into proteins having a harmful secondary structure.
Few methods are known for identifying, treating, or inhibiting the aggregation of amyloid proteins or prions. The target proteins or plaque often exhibit similar properties as healthy, unaffected tissue. As a result, it is difficult to develop an imaging agent selective for only harmful plaque or protein.
Moreover, the harmful plaque often resides in the brain, for example in the case of Alzheimer's disease. To provide a method that is useful for associating with brain plaque, the compound will have useful properties both for binding to amyloid or prion plaque and for crossing the blood-brain barrier. Compounds useful for staining or imaging the plaque in vitro often can not cross the highly discriminant blood-brain barrier to provide a useful in vivo diagnostic or therapeutic tool. Consequently, successful compounds and methods for detecting plaque in vitro can fail as a tool for in vivo imaging.
One compound useful for selectively identifying plaque in vitro is the commercially available diazo dye, Congo red, having the scientific name 3,3′-[[1,1′-biphenyl]-4,4′-diylbis(azo)]bis[4-amino-1-naphthalenesulfonic acid] disodium salt. Congo red has demonstrated binding to amyloid-like proteins with a beta-pleated sheet conformation. See, W. E. Klunk, et al., Quantitative Evaluation of Congo Red Binding to Amyloid-like Proteins with a Beta-Pleated Sheet Conformation,
J. Histochem. Cytochem
., 37:1273-1281 (1989). However, Congo red lacks the necessary properties to cross the blood-brain barrier as shown by P. D. Griffiths, et al.,
Receptor Changes in the Neocortex of Postmortem Tissue in Parkinson's Disease and Alzheimer's Disease, Dementia
, 3:239-246 (1992). As such, the compound provides useful properties for postmortem staining of brain plaque in vitro, but is unsuitable for in vivo use.
Chrysamine G (CG) compounds are a class of compounds derived from Congo red. The predominant structural difference is replacement of sulphonic acid groups in Congo red with carboxylic acid groups. See, for example, International Publication Nos. WO 98/47969, published Oct. 29, 1998; WO 96/34853, published November 7, 1996; and WO 99/24394, published May 20, 1999. In addition, organometallic ligands of Congo red and Chrysamine G compounds have been investigated for use as a diagnostic tool. See, for example, International Publication No. WO 97/41856, published Nov. 13, 1997.
The replacement of sulphonic acid groups with carboxylic acid groups potentially would effect better blood-brain barrier entry of the compound. However, in vivo biodistribution of Chrysamine G compounds has shown that technetium-99m-labeled conjugates of 2-(acetamido)-CG with bis-S-trityl protected monoamide-monoaminedithiol were rapidly cleared from the blood, causing low uptake of the conjugate in the brain. See, for example, N. A. Dezutter,
European Journal of Nuclear Medicine
, Vol. 26,. No. 11, pp. 1392-1399 (1999); W. E. Klunk, et al.,
Life Sciences
, Vol. 63, No. 20, pp. 1807-1814 (1998); and W. E. Klunk, et al., Neurobiology of Aging, Vol. 16, No. 4, pp. 541-548 (1995).
Derivatives of 9-acridinone also have been reported as inhibiting amyloid aggregation. International Publication No. WO 97/16191, published May 9, 1997, describes that 9-acridinone compounds inhibit amyloid aggregation in vitro. In vivo diagnostic or therapeutic activity of the compounds is not described.
Commonly-assigned U.S. Pat. Nos. U.S. 5,731,313, and 5,998,615, issued Mar. 24, 1998, and Dec. 7, 1999, respectively, identify fluoroanthracyclinone compounds as useful anti-infective agents and also as a diagnostic agent for imaging amyloid plaque. The in vitro binding of A&bgr;25-35 peptides is described in International Publication No. WO 97/49433, published Dec. 31, 1997.
More recently, naphthylazo derivatives have been prepared for inhibitinglamyloid aggregation. The in vitro binding activity of naphthylazo compounds is described in International Publication No. 97/16194, published May 9, 1997. However, no in vivo data is described in the publication.
Radiolabeled hydrazine and ethylene derivatives of benzenethiazole compounds also have been reported for binding insulin amyloid. See, International Publication WO 97/26919, published Jul. 31, 1997. These compounds show inhibitory activity in vitro, however, to the best of our knowledge, no in vivo activity has been shown.
Of the methods known, the only conclusive test is staining for plaque postmortem. Some compounds have been investigated for in vivo administration and imaging, but it remains beneficial to provide a compound for demonstrating in vitro imaging of compounds.
Accordingly, it remains beneficial to provide a c

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