WO2004045552A2 - Compositions for treating and/or preventing diseases characterized by the presence of metal ions - Google Patents
Compositions for treating and/or preventing diseases characterized by the presence of metal ions Download PDFInfo
- Publication number
- WO2004045552A2 WO2004045552A2 PCT/US2003/037037 US0337037W WO2004045552A2 WO 2004045552 A2 WO2004045552 A2 WO 2004045552A2 US 0337037 W US0337037 W US 0337037W WO 2004045552 A2 WO2004045552 A2 WO 2004045552A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- compound
- atom
- independently
- composition
- ofclaim
- Prior art date
Links
- 0 CC*PC(C*)[Cn+](N)N Chemical compound CC*PC(C*)[Cn+](N)N 0.000 description 6
- HIHKGSJYMJOEHV-UHFFFAOYSA-N CC(C)[Si+](C(C)C)(Cl)Cl Chemical compound CC(C)[Si+](C(C)C)(Cl)Cl HIHKGSJYMJOEHV-UHFFFAOYSA-N 0.000 description 1
- RVTZRNZPXMUOJI-UHFFFAOYSA-N CCCCCCCC[Si+](Cl)(Cl)Cl Chemical compound CCCCCCCC[Si+](Cl)(Cl)Cl RVTZRNZPXMUOJI-UHFFFAOYSA-N 0.000 description 1
- UIFBMBZYGZSWQE-UHFFFAOYSA-N C[Si](CCCC#N)(Cl)Cl Chemical compound C[Si](CCCC#N)(Cl)Cl UIFBMBZYGZSWQE-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/695—Silicon compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/04—Chelating agents
Definitions
- This invention generally relates to the treatment and/or prevention of diseases characterized by the presence of metal ions, such as Alzheimer's disease and, in particular, to the treatment and/or prevention of such diseases using certain compositions comprising chelating agents and/or silicon compounds.
- Many diseases can be characterized by an excess or an imbalance of metal ions within the body, for example, within an organ or a tissue.
- An excess of metal ions may, in some cases, affect protein structure or function, or lead to or facilitate certain diseases, such as Alzheimer's disease, Parkinson's disease, various homeostatic diseases, cardiac arrhythmia, various central nervous system (CNS) disorders, blood plasma imbalances, dermatitis, Gerstmann-Staussler-Scheinker disorder, familial insomnia, Menkes's syndrome, lead poisoning and other heavy metal toxicities, or various prion diseases such as transmissible spongiform encephalopathy or Creutzfeld- akob disease.
- an excess of metal ions may also interfere with ion channel function, protein structure or folding, or enzyme function, which can lead to disease states. For example, many proteins and enzymes use metal ions to stabilize their conformation at or as a reactive site.
- Physiological removal or sequestration of metal ions may be useful in treating such diseases.
- biocompatible agents able to bind ions that can be delivered to a target site are known to exist.
- One example of a compound able to bind ions within the body is ethylenediaminetetraacetic acid ("EDTA").
- EDTA ethylenediaminetetraacetic acid
- the half-life of EDTA in the body is relatively short. Typical doses of EDTA last for only about 1 hour in the body, limiting the effectiveness of this form of treatment.
- Alzheimer's disease is a common form of senile dementia. Some studies have suggested that 25-50% of all people in their eighties may have Alzheimer's disease. Symptoms of Alzheimer's disease include memory loss, loss of language or cognitive ability, declines in reasoning ability, and reduced use of speech. Behavioral disorders may also be present. Changes in brain physiology may also occur, for example, enlarged ventricles, narrow cortical gyri, or widened sulci. These changes have been attributed to neuronal loss. The deterioration in mental abilities and brain function appears to be irreversible, and may eventually lead to death.
- Alzheimer's disease is actually a family of related neurodegenerative diseases.
- One feature of Alzheimer's disease and other such neurodegenerative diseases is the appearance and accumulation of fibrous proteinaceous structures, commonly known as neurofibrillary tangles or senile plaques.
- Neurofilament (NF) protein is one constituent of neurofibrillary tangles. NF proteins may form filaments that can give rise to neurofibrillary tangles, for example, when the NF protein is hyperphosphorylated.
- Beta- amyloid a protein containing about 42 amino acids, is one important component of certain senile plaques.
- Alzheimer's disease causes, genetic factors (for instance, certain genes on chromosomes 1, 14, 19, and 21 have been implicated in increased susceptibility to Alzheimer's disease), or environmental factors, especially greater than normal aluminum concentrations. Some studies have shown that increased aluminum concentrations within the brain may be associated with neurofibrillary tangles or senile plaques. Aluminum may appear, for example, complexed with beta-amyloid or neurofilament protein. Certain studies have suggested a link between the aluminum found in water supplies and the incidence of Alzheimer's disease. Aluminum may also arise from pharmaceuticals or other compounds, such as antacid tablets.
- Aluminum may be found in the body complexed to other species such as organic species, or dissolved in solution (e.g., within the blood or the cerebrospinal fluid).
- the aluminum may be present as Al 3+ , Al(OH) 3 , Al 2 O 3 , or A1 2 (S0 4 ) 3 , etc.
- the invention generally relates to the treatment and/or prevention of diseases characterized by the presence of metal ions, such as Alzheimer's disease.
- the subject matter of this invention involves, in some cases, interrelated products, alternative solutions to a particular problem and/or a plurality of different uses of one or more systems and/or articles.
- the invention includes a composition.
- the composition, or at least a portion thereof is able to enter an organ, e.g., the brain through transport across the blood-brain barrier.
- the composition also includes a pharmaceutically acceptable carrier.
- the composition includes at least one of a silanol, a silandiol, a silantriol, and/or a compound able to form at least one of a silanol, silandiol, or a silantriol, e.g., upon exposure to physiological conditions.
- a silanol e.g., silanol, silandiol, or a silantriol
- Such compounds may include, for example, a halogenated organosilicon compound or a cyclic organosilicon compound.
- the compound is unable to significantly polymerize in solution.
- at least 50%, at least 75%, at least 90%, at least 95%o, at least 97%, or at least 99%> of the compound is able to retain a monorneric structure in vivo.
- the composition includes a compound having a structure:
- each of Z 1 and Z 2 independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- Each of Y 1 and Y 2 is an moiety interconnecting Si and an N (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.).
- Each of J 10 , J 11 , J 12 , and J 13 independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- each of J 10 , J 11 , J 12 , and J 13 is independently hydrogen, an alkyl, or an aryl.
- at least one of J 10 , S n , J 12 , and J 13 is an alkyl having no more than three or four carbon atoms.
- at least one of Y 1 and Y 2 has a structure:
- Y may include a hydrogen or a non-hydrogen atom.
- Y 3 comprises a hydrophobic moiety.
- the two 5 symbols indicate where the above structure respectively attaches to N and Si in the parent chemical structure immediately preceding the above structure.
- the composition includes a silicon compound comprising an aminoalkyl moiety.
- the compound has a structure:
- each of Z 1 , Z 2 , and Z 3 is independently one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, and R 1 comprising at least one carbon atom.
- Each J independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom
- Y is a moiety interconnecting Si and N (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.).
- composition of the invention includes a compound having a structure:
- each of Z 1 , Z 2 , Z 3 , and Z 4 independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the compound may include at least one carbon atom, i.e., at least one of Z 1 , Z 2 , Z 3 , and Z 4 comprises at least one carbon atom.
- each of Z 1 and Z 2 independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprismg at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- A is a moiety including at least one of a carbon atom and a silicon atom.
- Each of E 1 and E 2 independently is either (a) one of O and NJ 3 , or (b) absent such that Si is covalently bonded to moiety A.
- J 3 is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom. In certain instances, E 1 and E 2 (where applicable) are not both absent.
- a composition of the invention includes cyclic organosilicon compound, i.e., a cyclic organic compound containing at least one silicon atom.
- cyclic organosilicon compound may have a structure such as:
- each A independently is a moiety having at least one of a carbon atom and a silicon atom
- each Z independently is one of H, X, R, OH, OR 1 , or NJ ! J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the composition may include a salt of any of the above-described structures.
- a composition of the invention comprises a compound having at least two silicon atoms.
- the compound has a structure: or a salt thereof, where each of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 independently is one of H, X, R,
- the composition includes a polymer having a repeat unit comprising at least one silicon atom.
- the compound may have a structure such as:
- each of Y, Y 1 and Y 2 independently is an interconnecting moiety comprising at least one carbon atom (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.), and each of Z ! , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 independently is one of H, X, R, OH, OR 1 , or J 1 !
- R comprising at least one carbon atom
- X being a halogen or a pseudohalogen
- R 1 comprising at least one carbon atom
- J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- E 1 , E 2 , E 3 , and E 4 independently is either (a) one of O and NJ 3 , or (b) absent such that a Si is covalently bonded to a Y moiety.
- J 3 can be H or comprise at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- at least one E moiety is present within the structure.
- Y is a structure able to facilitate transport of the compound (or a portion thereof) across the blood brain-barrier
- the structure X ⁇ X comprises at least one chemical bond
- the structure — is a moiety that can be hydrolyzed under physiological conditions, e.g., within the brain or within the bloodstream, for example, to OH.
- the chelating agent may be any agent able to bind or otherwise immobilize an ion, for example, so that it becomes complexed or otherwise bound to the chelating agent instead of remaining free in solution.
- the invention is a method.
- the method includes administering, to a subject, a therapeutically effective amount of a composition comprising at least one of a silanol compound, a silandiol compound, a silantriol compound, a cyclic organosilicon compound, and/or a compound able to be hydrolyzed within the subject to at least one of a silanol compound, a silandiol compound, or a silantriol compound.
- the method includes administering, to a subject, one or more of the compounds described above. In some cases, the subject is susceptible to or exhibits symptoms of Alzheimer's disease.
- the subject is susceptible to or exhibits symptoms of a disease characterized by an excess of an ion such as a metal ion.
- the subject is not otherwise indicated for treatment with the composition.
- the subject may not be indicated as having a disease treatable by the inhibition of leukocyte elastase.
- a compound of the invention is able to bind to (or otherwise interact with) aluminum and/or other metal ions such as divalent or trivalent metal ions, and/or is able to be hydrolyzed within the subject to form a compound able to bind to aluminum and/or other metal ions.
- the organosilicon compound, or at least a portion thereof is able to enter an organ, e.g., the brain through transport across the blood-brain barrier. In other embodiments, however, the organosilicon compound is not able to enter an organ such as the brain, but instead, remains in circulation in the bloodstream, for example, to remove or sequester aluminum or other ions within the blood before they enter the brain or other organs.
- the composition may also include a pharmaceutically acceptable carrier in certain cases.
- the method includes administering, to a subject, a therapeutically effective amount of a composition comprising a compound having a structure:
- the structure v_ indicates a portion of the compound that can be positively charged when the compound is located within the subject, for example, in an active site. In one embodiment, the subject is not otherwise indicated for treatment with the composition. In another
- the structure Xx is a portion of the compound that has a structure that allows the compound, or at least a portion thereof, to enter into an organ, or cross the blood-brain barrier.
- the method includes administering to a subject a composition that includes a compound able to be converted, within the subject, into a form able to bind aluminum and/or other metal ions such as divalent or trivalent metal ions, e.g., through hydrolysis.
- the method includes administering, to a subject, a therapeutically effective amount of a composition including a compound able to cross the blood-brain barrier and/or bind aluminum and/or other metal ions.
- the method includes administering, to a subject, a therapeutically effective amount of a composition comprising a compound comprising, within the molecular structure of the compound, at least two silicon atoms.
- the compound can have a molecular weight of at least about 100 g/mol, at least about 200 g/mol, at least about 300 g/mol, at least about 400 g/mol, at least about 500 g/mol, at least about 600 g/mol, at least about 700 g/mol, at least about 800 g/mol, at least about 900 g/mol, at least about 1000 g/mol, or more in some cases.
- the compound is a salt.
- the method includes administering, to a subject, a therapeutically effective amount of a composition comprising a compound having, within the molecular structure of the compound, a silicon atom and a nitrogen atom.
- the method is a method of facilitating the reversion of a protein having a non-functional or a dysfunctional conformation (i.e., functioning at a less than physiologically normal level) to a functional conformation.
- the method includes the step of introducing a compound comprising silicon into a subject, where the subject has, or is suspected of having, a disease or condition characterized by having a protein, a lipid, or a sugar bound to one or more metal atoms.
- the protein, lipid, or sugar may have a non-functional or a dysfunctional conformation when so bound to the one or more metal atoms.
- the method can also include allowing at least some of the metal atoms to be transferred from the protein, lipid, or sugar to the silicon compound.
- the silicon polymer may be hydroxylated and/or halogenated.
- the method includes administering, to a neurological system of a subject susceptible to or exhibiting symptoms of Alzheimer's disease, a therapeutically effective amount of a composition comprising a compound having a silicon atom.
- the composition includes a compound having a structure:
- each of Z 1 , Z 2 , Z 3 , and Z 4 independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- one, two, three, or four of Z 1 , Z 2 , Z 3 , and Z 4 may each be OH and/or acetate.
- the composition includes a silicate, such as sodium silicate, and/or a metasilicate, such as sodium metasilicate, or the like.
- the composition includes a silicon salt.
- the invention includes the use of a composition in the manufacture of a medicament for treatment of diseases such as Alzheimer's disease characterized by the presence of metal ions.
- the composition comprises one or more of the compounds described above. It should be understood that everywhere a method of treating a subject with a composition is described herein, the invention also involves, in another aspect, the use of that composition in the manufacture of a medicament for the treatment of the subject.
- the invention is directed to a method of making any of the embodiments described herein.
- the invention is directed to a method of using any of the embodiments described herein.
- the invention is directed to a method of promoting any of the embodiments described herein.
- Fig. 1 illustrates a neurofilament sequence (SEQ ID NO: 1);
- Figs. 2A-2U illustrate various chemical structures useful in the invention
- Figs. 3 A-3D illustrate the effect of sodium metasilicate hydrate on the neurofilament of Fig. 1, as indicated by circular dichroism (CD) data plotted as ellipticity vs. wavelength
- Figs. 4A-4E illustrate the effect of sodium orthosilicate on the neurofilament of Fig. 1, as indicated by CD data;
- Figs. 5A-5F illustrate the effect of 3-aminopropylsilantriol on the neurofilament of Fig. 1, as indicated by CD data;
- Figs. 6A-6D illustrate comparative CD data for sodium orthosilicate versus 3- aminopropylsilantriol;
- Figs. 7A-7D illustrate the effect of 3-cyanopropyltrichlorosilane on the neurofilament of Fig. 1, as indicated by CD data;
- Figs. 8A-8D illustrate the effect of hexylmethyldichlorosilane on the neurofilament of Fig. 1, as indicated by CD data;
- Figs. 9A-9D illustrate the effect of methylphenyldichlorosilane on the neurofilament of Fig., 1, as indicated by CD data;
- Figs. 10A-10D illustrate the effect of dichlorodiethylsilane on the neurofilament of Fig. 1, as indicated by CD data
- Figs. 11 A-l IE illustrate the effect of dichlorodiisopropylsilane on the neurofilament of Fig. 1, as indicated by CD data;
- Figs. 12A-12E illustrate the effect of (dichloro)methylsilylbutyiOi ⁇ itrile on the neurofilament of Fig. 1, as indicated by CD data;
- Fig. 13 illustrates the effect of aluminum on human amyloid beta-protein, as illustrated by CD data
- Fig. 14 illustrates the effect of 3-cyanopropyltrichlorosilane on the amyloid protein, as illustrated by CD data;
- Fig. 15 illustrates the effect of dichlorodiethylsilane on the amyloid protein, as illustrated by CD data
- Fig. 16 illustrates the effect of dichlorodiisopropylsilane on the amyloid protein, as illustrated by CD data
- Fig. 17 illustrates the effect of (dichloro)ethylmethylsilane on the amyloid protein, as illustrated by CD data;
- Fig. 18 illustrates the effect of hexylmethyldichlorosilane on the amyloid protein, as illustrated by CD data
- Fig. 19 illustrates the effect of (dichloro)methylsilylbutyronitrile on the amyloid protein, as illustrated by CD data
- Fig. 20 illustrates the effect of dichlorosilacyclobutane on the amyloid protein, as illustrated by CD data;
- Fig. 21 illustrates the effect of l,7-dioxa-6-sila-spiro[5.5]undecane on the amyloid protein, as illustrated by CD data;
- Fig. 22 illustrates the effect of sodium orthosilicate on the amyloid protein, as illustrated by CD data;
- Fig. 23 illustrates the effect of triethoxysilylbutyronitrile on the amyloid protein, as illustrated by CD data
- Fig. 24 illustrates the effect of triethoxysilylpropionitrile on the amyloid protein, as illustrated by CD data
- Fig. 26 illustrates the effect of triethylsilanol on the amyloid protein, as illustrated by CD data
- Fig. 27 illustrates the effect of tetrakis(dimethylamino)silane on the amyloid protein, as illustrated by CD data;
- Fig. 28 illustrates the effect of tetraacetooxysilane on the amyloid protein, as illustrated by CD data
- Figs. 29A-29B illustrate fransport of certain organosilicon compounds of the invention across Caco-2 cells.
- Fig. 30 illustrates molecular transport of certain organosilicon compounds of the invention across bMNEC cells.
- the present invention generally relates to the treatment and/or prevention of
- a composition of the invention may be administered to a mammal, such as a human.
- the composition may include a silanol, a silandiol, a silantriol, or a cyclic organosilane, and/or be able to form a silanol, a silandiol, or a silantriol upon exposure to physiological conditions such as are found in the blood, in the stomach and/or gastrointestinal tract, or in the brain or other organ.
- the organosilicon compound may be bound to a moiety able to be transported across the blood-brain barrier into the brain, for example, an amino acid, a peptide, a protein, a virus, etc.
- the organosilicon compound may also be labeled (e.g., fiuorescently or radioactively) in certain instances.
- the composition, or a portion thereof may sequester aluminum or other ions, for example, by electrostatically binding to aluminum ions.
- composition may also include other functionalities such as amines, certain alkyl and/or aryl moieties (including substituted alkyls and/or aryls), or hydrophobic moieties, for example, to facilitate transport of the organosilicon compound through the blood-brain barrier.
- functionalities such as amines, certain alkyl and/or aryl moieties (including substituted alkyls and/or aryls), or hydrophobic moieties, for example, to facilitate transport of the organosilicon compound through the blood-brain barrier.
- determining generally refers to the analysis of a species, for example, quantitatively or qualitatively, and/or the detection of the presence or absence of the species. “Determining” may also refer to the analysis of an interaction between two or more species, for example, quantitatively or qualitatively, and/or by detecting the presence or absence of the interaction.
- a material is "able to cross the blood-brain barrier” if it is capable of being transported (passively or actively) from the blood to the brain or central nervous system in vivo under physiological conditions using endogenously available transport processes such as diffusion or certain endogenous transport systems.
- a composition of the invention (or a portion thereof) may include a sugar or a peptide, and/or be able to be substituted as a substrate (i.e., a mimic) in a sugar and/or a peptide transport system of the blood-brain barrier (e.g., endogenous transport proteins), thus allowing transport of the composition across the blood-brain barrier to occur.
- the "blood-brain barrier” is given its ordinary meaning as used in the art, i.e., the cellular barrier separating the bloodstream from the "neurological system,” i.e., the brain and central nervous system, including the spinal cord.
- Treatment of Alzheimer's disease includes preventing, arresting, altering, and/or reversing formation of neurofibrillary tangles and/or senile plaques within the brain, and may be performed on subjects "in need of such treatment," i.e., a subject that exhibits symptoms of Alzheimer's disease, a subject susceptible to or otherwise at increased risk for Alzheimer's disease, or a subject not exhibiting symptoms of Alzheimer' s disease, but for whom it is desired to decrease the risk of Alzheimer' s disease (e.g., a vaccination or a prophylactic treatment).
- patient or “subject” as used herein includes mammals such as humans, as well as non-human mammals such as non-human primates, cows, horses, pigs, sheep, goats, dogs, cats, rabbits, or rodents such as mice or rats. It should be understood that any of the compositions or methods described herein in reference to Alzheimer's disease can also be used, in some cases, to treat other diseases characterized by an excess of metal ions. As used herein, a disease "characterized by an excess of an ion” includes any disease where an excess of an ion (e.g., a metal ion) within an organ or a system of the body may lead to health-related problems.
- an ion e.g., a metal ion
- ions include, but are not limited to, iron, lead, aluminum, magnesium, calcium, mercury, strontium, beryllium, cobalt, zinc, nickel, arsenic, etc.
- the ions may be divalent or trivalent (i.e., having a net charge of ⁇ 2 or ⁇ 3, respectively) in certain instances.
- the disease may result in misfolded proteins, due to the presence of excess ions.
- Alzheimer's disease can be characterized by an excess of aluminum ions in the brain.
- Other brain diseases which may be characterized by an excess of ions include, for example, certain prion diseases such as transmissible spongiform encephalopathy or Creutzfeldt- Jakob disease.
- diseases where an excess of ions such as metal ions has been implicated include Parkinson's disease, various homeostatic diseases, cardiac arrhythmia, various central nervous system (CNS) disorders, blood plasma imbalances, dermatitis, Gerstmann-Staussler- Scheinker disorder, familial insomnia, Menkes's syndrome, or heavy metal toxicity or poisoning.
- the disease may be created by environmental factors, for example, an excess of ions such as aluminum, lead or iron from the environment.
- the disease ions may be created through diet, drinking water, on the like.
- the organ or system may be any organ or system in the body, for example, within the bloodstream, within the brain, liver, kidneys, skin, fatty tissue, etc.
- Other diseases characterized by an excess of ions may be readily identified by those of ordinary skill in the relevant art.
- amino acid is given its ordinary meaning as used in the field of biochemistry.
- An amino acid typically has a structure:
- R may be any suitable moiety; for example, R may be a hydrogen atom, a methyl, or an isopropyl.
- a series of amino acids can be connected to form a peptide or a protein, by reaction of the NH 2 of one amino acid with the COOH of the next amino acid to form a peptide (-NH-C(O)) bond.
- the amino acid may be a natural amino acid or an unnatural amino acid.
- the "natural amino acids” are the 20 amino acids commonly found in nature, i.e., alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalaine, proline, serine, threonine, tryptophan, tyrosine, and valine.
- an "unnatural amino acid” is an amino acid corresponding to the above structure, where the R moiety does not correspond to one of the 20 natural amino acids.
- the amino acid may also be derivatized in some fashion.
- the amino acid may be amidated, esterified, side moieties may be attached to the amino acid, etc. Other amino acid derivatization reactions will be known to those of ordinary skill in the art.
- alkyl is given its ordinary meaning as used in the field of organic chemistry.
- Alkyl or aliphatic moieties may contain a number of carbon atoms.
- the moieties may include, for example, between 1 and 15 carbon atoms, between 1 and 10 carbon atoms, or between 1 and 5 carbon atoms.
- the alkyl moiety will have less than 10 carbon atoms, less than 6 carbon atoms, less than 5 carbon atoms, less than 4 carbon atoms, or less than 3 carbon atoms.
- alkyl chains having a certain size may be used to control the hydrophobicity of the composition.
- the carbon atoms may be arranged in an appropriate configuration within the alkyl moiety, for example, as a straight chain (i.e., an rc-alkyl such as methyl "(Me”), ethyl (“Et”), propyl (“Pr”), butyl (“Bu”), pentyl (“Pe”), or hexyl (“Hx”)) or a branched chain (e.g., a tert-butyl moiety, or an isoalkyl moiety such as an isopropyl moiety).
- an rc-alkyl such as methyl "(Me), ethyl (“Et"), propyl (“Pr”), butyl (“Bu”), pentyl (“Pe”), or hexyl (“Hx”)
- a branched chain e.g., a tert-butyl moiety, or an isoalkyl moiety such as an isopropyl moiety.
- the alkyl moiety may contain a halogen, an alkoxy (e.g., methoxy, ethoxy, or propoxy), an amine (e.g., a primary, secondary, tertiary, or quaternary amine), an ether, a carbonyl (e.g., an acetyl ("Ac”) moiety) or a hydroxide as a substituent (i.e., a "substituted alkyl"). If more than one substituent is present, then the substituents may each be the same or different.
- an alkoxy e.g., methoxy, ethoxy, or propoxy
- an amine e.g., a primary, secondary, tertiary, or quaternary amine
- an ether e.g., a carbonyl (e.g., an acetyl ("Ac”) moiety) or a hydroxide as a substituent (i.e., a
- the alkyl moiety includes only carbon and hydrogen atoms; however, in other cases, the atoms within the alkyl moiety may also include nitrogen atoms, oxygen atoms, sulfur atoms, silicon atoms, or any other suitable atom.
- a "cyclic" moiety is given its ordinary definition as used in the field of organic chemistry, i.e., a moiety that contains at least one ring of atoms, and may contain more than one ring of atoms. That is, a cyclic moiety has at least one chain of atoms that does not have a terminal end.
- the chain may have, for example, three, four, five, six, seven, eight, nine, or ten or more atoms arranged in a ring.
- the cyclic moiety has a maximum size of at most ten atoms, at most eight atoms, or at most seven atoms.
- the cyclic moiety includes only carbon atoms within the ring of the cyclic moiety; however, in other cases, the atoms within the ring may also include nitrogen atoms, oxygen atoms, sulfur atoms, silicon atoms, or any other atom able to covalently bond to at least two different atoms (i.e., a "heterocyclic" moiety).
- the rings may be arranged in any orientation with respect to each other, e.g., the rings may be fused (i.e., at least two rings have more than one atom in common, for example, as in bicyclic moieties, tricyclic moieties, etc.), spiro (i.e., two rings have only one atom in common), a ring may be a substituent on another ring, two or more rings may be connected through an alkyl moiety, etc.
- the cyclic moiety may contain zero or one or more double or triple bonds within its structure, for example, as in a cycloalkene, a cycloalkyne, a cycloalkadiene, an aromatic moiety, or the like.
- aromatic or “aryl” moieties are given their ordinary meaning as used in the art, e.g., where at least two or more atoms of the moiety participate in delocalized pi bonding.
- Aryl moieties which include one or more non- carbon atoms (e.g., nitrogen) participating in delocalized pi bonding are “heteroaryl” moieties.
- a "silicon compound,” as used herein, includes any chemical compound that contains at least one silicon atom.
- the silicon compound may be water-soluble, lipid- soluble, or exhibit amphiphillic properties, e.g., when located within a subject.
- An "organosilicon compound,” as used herein, is a compound that includes at least one silicon atom bonded to an organic moiety, such as an alkyl, an aryl, an alkoxy, a cycloalkyl, an amine (primary, secondary, tertiary, or quaternary), etc.
- organosilicon composition includes at least one organosilicon compound and may include other compounds as well, for example, other physiologically active compounds and/or pharmaceutically acceptable carriers such as those further described below.
- the silicon atom within the organosilicon compound may be hypercoordinated (i.e., the silicon atom may have a valency of 5 or 6).
- the silicon compound includes one or more "hydrolyzable" moieties (for example, a moiety that can by hydrolyzed under physiological conditions, spontaneously and/or through metabolic processes, e.g., to a hydroxide moiety), such as halogens, hydroxides, alkoxides, esters, ethers, etc.
- “hydrolyzable” moieties for example, a moiety that can by hydrolyzed under physiological conditions, spontaneously and/or through metabolic processes, e.g., to a hydroxide moiety
- examples include, but are not limited to, a halosilane, a dihalosilane, a trihalosilane, a silanol, a dihalosilanol, a halosilandiol, a silantriol, a halosilanol, etc.
- silanol is a compound which includes two hydroxide moieties covalently bonded to a silicon atom
- a “silantriol” is a compound which includes three hydroxide moieties covalently bonded to a silicon atom.
- a "dihalosilane” e.g., dichlorosilane or bromochlorosilane
- a “halosilanol” is a compound that includes a halogen and a hydroxide moiety each bonded to a silicon atom within the compound. Terms such as “trihalosilane,” “dihalosilanol,” and “halodisilanol” are similarly defined.
- halogen includes halogen- group atoms as ordinarily used in the field of chemistry (e.g., fluorine, chlorine, bromine, or iodine).
- pseudohalogens are moieties that are not halogen atoms, but have properties similar to halogen compounds. Examples of pseudohalogens include CN, SCN, NCO, etc., and other hydrolyzable moieties that can form labile bonds with silicon (e.g., imidazoles, triazoles, tetrazoles, etc).
- a pseudohalogen moiety can be substituted for a halogen atom in any of the structures described herein.
- the organosilicon compounds of the present invention may inhibit and/or reverse interaction between ions such as aluminum ions and physiological (or neurological) components of the brain or other organs, such as beta-amyloid or other amyloid compounds, neurofilament proteins, etc.
- ions such as aluminum ions
- physiological (or neurological) components of the brain or other organs such as beta-amyloid or other amyloid compounds, neurofilament proteins, etc.
- certain types of amyloid proteins may be found in the liver or in muscle tissue.
- the compounds may inhibit and/or reverse such interactions anywhere within the body, e.g., within the brain or other organ, within the blood-brain barrier, within the bloodstream, etc.
- inhibitor includes inhibition which occurs before and/or after the aluminum (or other metal ion) complexes with the component.
- the inhibition may be partial or complete inhibition.
- One simple test to illustrate the efficacy of the compositions of the invention is to add the composition to a solution containing a a component such as a suitable disease marker, and determine if the added composition is able to prevent or reduce changes in the structure and/or conformation of the component or marker when the solution is exposed to aluminum.
- a suitable marker for the disease may be a beta-amyloid or a neurofilament protein (or a cell able to produce beta-amyloid or a neurofilament protein) that is sensitive to aluminum, i.e., where the structure and/or conformation of the marker is altered upon exposure to aluminum).
- the composition may be added before or after the marker is exposed to aluminum or other ions. An example of this process is discussed in Example 1.
- aluminum refers to any form of aluminum that may appear in the body, for example, as aluminum particles, aluminum oxide particles, aluminum ions (Al 3+ ), Al(OH) 3 , Al 2 O 3 , Al 2 (SO ) 3 , etc.
- the aluminum may arise from any environmental source, for example, dissolved within drinking water; from aluminum pots, pans, pipes, utensils, or tools; from dust; from components of medical devices; from medications; from jewelry; from aerosols; from deodorants and other products applied to the skin; from aluminum cans, etc.
- the organosilicon compounds of the invention are not able to enter the brain or other organ.
- the organosilicon compounds may remain where they were introduced into the body, or the organosilicon compounds may remain in circulation in the bloodstream.
- a compound if a compound is injected directly into the brain (e.g., as further described below), the compound may be unable to cross the blood-brain barrier and hence is able to remain within the brain.
- a compound of the invention may be introduced into systemic circulation, to remove or sequester aluminum or other ions within the blood before they enter the brain or other organs.
- compositions of the invention may be administered to a subject so as to treat (e.g., reverse), prevent, and/or reduce the formation and/or growth of neurofibrillary tangles or senile plaques within the brain.
- the beta-amyloid and/or neurofilament proteins found in senile plaques and neurofibrillary tangles may become, in some cases, phosphorylated and/or complexed in the presence of metal ions such as aluminum and/or assume a dysfunctional or a nonfunctional conformation (e.g., a structure that lacks proper activity, or a structure indicative of a diseased state) such as a beta-sheet.
- a composition of the present invention may bind to or otherwise sequester ions such as metal ions within the body.
- the ion is divalent or trivalent.
- the ion may be present within the body, or within an organ or system within the body, in an excess concentration (e.g., significantly above a concentration that is physiologically desirable).
- the composition may sequester the ion by interaction of the ion with a charged portion of the composition, e.g., of the opposite charge.
- the composition may allow a molecule or structure affected by an excess of metal ions to revert back to its original conformation, or the composition may prevent the formation of nonfunctional or deformed structures, for example, as in a protein that has been denatured, or improperly folded or configured, due to the presence of an excess of metal ions.
- compositions of the invention may be determined by their ability to allow a molecule or structure to revert back to its original conformation, etc.
- the composition may bind and/or sequester the excess ion, which may prevent, inhibit, and/or reduce interaction of the ion with the molecule or structure.
- the presence of the compositions of the invention in the brain may allow certain neurofilament proteins to revert back to their original functional structures, and/or prevent the formation of the beta-sheet conformation or other nonfunctional or dysfunctional structures within the neurofilament proteins.
- the organosilicon compound may also bind any aluminum (or other metal ions) present within the brain or other organ, which may cause at least some sequestering of aluminum or other metal ions, preventing and/or reducing interaction of aluminum with other components of the brain or other organ, for example, with beta-amyloid or neurofilament proteins.
- the interaction of the composition with aluminum or other metal ions may be, for instance, via an ionic interaction, a hydrogen bond interaction, a van der Waals interaction, a metal ligand interaction, a dative interaction, a hydrophobic interaction, and/or a combination of these.
- an organosilicon composition of the invention may be mixed with a solution containing a known concentration of aluminum ions or other metal ions, and the resulting decrease in the concentration of free aluminum or other metal ions in solution (if any) may be determined or calculated using known techniques for detecting the dissolved ions in solution, for example, using circular dichroism (CD) techniques, atomic absorption spectroscopy, mass spectroscopy, radioactive tracer measurements, or the like.
- CD circular dichroism
- an ion such as aluminum may be sequestered within the body or the brain or other organ by the organosilicon compositions of the invention, for instance, by sequestering the aluminum ions with a negatively charged portion of an organosilicon compound.
- the organosilicon compound may include one or more hydroxide moieties that can become negatively charged under physiological conditions (i.e., deprotonated), enabling electrostatic attraction or binding of aluminum or other metal ions to the compound.
- the organosilicon compound may be a silanol, a silandiol, or a silantriol.
- the organosilicon compound may be a silicon compound able to form a silanol, a silandiol, or a silantriol upon hydrolysis of the compound, for example, within the body under physiological conditions (e.g., at a temperature of 37 °C and/or within a generally aqueous environment).
- the complex after formation of the aluminum- organosilicon complex (or other ionic-organosilicon complex), the complex may also be removed from the brain or other organ, e.g., physically removed, or otherwise deactivated.
- the composition includes a compound containing silicon.
- Silicon compounds include, e.g., acids, salts, bases, oxides, etc., for example, silicic acid (H 4 Si0 ), silicon tetraacetate, sodium silicate, sodium metasilicate, etc. Additional examples are described below.
- the silicon compound may be capable of binding to or otherwise interacting with aluminum or other metal ions, e.g., within the central nervous system or other organ, or within the bloodstream, as further described below.
- the invention provides a composition comprising one or more of the compounds shown below (numbered 1-35), optionally with a pharmaceutically acceptable carrier:
- the composition includes a silicon compound or an organosilicon compound, i.e., a compound including at least one silicon atom bonded to an organic moiety.
- the compound may have a structure such as:
- each of Z 1 , Z 2 , Z 3 , and Z 4 independently is one of H, X, R, OH,
- R comprising at least one carbon atom
- X being a halogen or a pseudohalogen (for example, a nitrile)
- R 1 comprising at least one carbon atom
- J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the compound in this instance, includes at least one carbon atom, i.e., at least one of Z 1 , Z 2 , Z 3 , and Z 4 comprises at least one carbon atom.
- Z 1 , Z 2 , Z 3 , and Z 4 are not all, simultaneously, one of H or R; and Z 1 , Z 2 , Z 3 , and Z 4 are not all simultaneously acetate.
- the composition includes a compound having a structure:
- each of Z 1 , Z 2 , Z 3 , and Z 4 independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- one, two, three, or four of Z 1 , Z 2 , Z 3 , and Z 4 may each be OH and/or acetate.
- the composition includes a silicate, such as sodium silicate, and/or metasilicate, such as sodium metasilicate, or the like.
- the compound may have a structure such as: / 1 / z1
- A is a moiety having at least one of a carbon atom and a silicon atom.
- Each of E 1 and E 2 (where applicable) mdependently is either (a) one of O and NJ 3 , or (b) absent such that Si is covalently bonded to moiety A.
- J 3 is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- E 1 and E 2 (where applicable) are not both absent, and Si may be bonded to A as well as to E 1 or E 2 , which is not absent.
- the compound may be a cyclic organosilicon compound.
- more than one ring may be present within the compound, for example, as in a bicyclic or a spiro ring system (i.e., where the rings share one, two, three, or more atoms).
- the two rings of the bicyclic or spiro structure may each comprise alkyl moieties.
- the compound in one embodiment, has a structure such as:
- each A 1 , A 2 , and A 3 independently is a moiety having at least one of a carbon atom and a silicon atom
- each of E 1 and E 2 (where applicable) mdependently is either (a) one of O and NJ 3 , or (b) absent such that Si is covalently bonded to moiety A 1
- Z is one of H, X, R, OH, OR 1 , or NJ ! J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, and R 1 comprismg at least one carbon atom.
- E 1 and E 2 are not both absent.
- E 3 and E 4 may independently be either (a) one of O and NJ 4 , or (b) absent such that Si is covalently bonded to moiety A 2 .
- Each J independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the composition of the invention may include a salt of any of the above-described chemical structures.
- the cyclic organosilicon compound may include one or more hydrolyzable structures, for example, a compound of the invention may be hydrolyzed to form a silanol, a silandiol, or a silantriol, e.g., upon exposure to physiological conditions.
- the cyclic organosilicon compound may include an ester or an amine moiety that is hydrolyzable to form a hydroxide, which may thus cause one or more rings of the cyclic organosilicon compound to open.
- the compound may be a structure having at least two silicon atoms.
- the compound may be a polymer, for example, a polymer having a repeat unit comprising at least one silicon atom, as further discussed below.
- the compound has a structure such as:
- each of Y, Y 1 and Y 2 independently is an interconnecting moiety comprising at least one carbon atom (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.), and each of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or
- R comprising at least one carbon atom
- J and J each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- E 1 , E 2 , E 3 , and E 4 independently is either (a) one of O and NJ 3 , or (b) absent such that a Si is covalently bonded to a Y moiety.
- J 3 can be H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- at least one E moiety is present within the structure.
- any one, two, three, four, five, or six of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 may each independently be a halogen (X), for example, F, Cl, Br, I, etc., or a pseudohalogen.
- X halogen
- the halogen or pseudohalogen may be hydrolyzable under physiological conditions to OH.
- any one, two, three, four, five, or six of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 may each independently be a hydroxide (OH), or an alkoxy (OR 1 , where R 1 comprises at least one carbon atom).
- the hydroxide in some instances, can be deprotonated under physiological conditions (i.e., to O " ).
- the alkoxy may be hydrolyzable (e.g., within a subject) to form a hydroxide.
- Non- limiting examples of alkoxy moieties include methoxy (OMe), ethoxy (OEt), propoxy (OPr), isopropoxy, butoxy (OBu), tert-butoxy, .sec-butoxy, acetoxy (OAc), etc.
- the alkoxy moieties may be substituted alkoxy moieties in some cases, for example, a chloromethoxy or a bromochloromethoxy moiety. Any one, two, three, four, five, or six of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 (where applicable) may each independently be a moiety comprising at least one carbon atom in any of the above-described embodiments.
- R can be an alkyl (e.g., methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, isoheptyl, octyl, isooctyl, etc.), a cycloalkyl, an aromatic moiety (e.g., phenyl, benzyl, a substituted phenyl or benzyl, etc.), an aminoalkyl, a hydroxyalkyl (e.g., hydroxymethyl, 1 -hydroxyethyl, 2-hydroxyethyl, 3-hydroxpropyl, etc.), a cyanoalkyl (i.e., an alkyl comprising at least one CN, such as cyanoethyl, cyanopropyl, cyan
- nitriles may be particularly useful in some cases.
- Nitrile moieties may allow the compound to bind to metal ions such as aluminum.
- the nitrile moiety may facilitate transport or penetration of the compound across the blood-brain barrier, e.g., as further described below.
- the alkyl moieties may further include one or more side moieties.
- the side moiety may be any non-hydrogen atom or moiety, for example, an alkyl moiety such as a methyl moiety or a cycloalkyl moiety.
- the side moiety may be chosen, for example, to allow for detection of the compound, to allow the compound to have a certain degree of hydrophobicity or other physical properties, to allow the compound to have certain metabolic functions, to allow the compound to have certain immunological properties, etc.
- a hydrophobic side chain is attached to the compound, for example, an alkyl moiety, a cyclic moiety, or an aryl moiety.
- the cyclic moiety may be an unsaturated structure, such as a cyclohexyl structure.
- the compound can include a phosphono moiety, i.e., a moiety having a structure:
- any one, two, three, four, five, or six of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 may each independently comprise a nitrogen-containing moiety, for example, an amine, a hydroxylamine, an oxime, a nitro moiety, etc.
- the nitrogen-containing moiety may contain a sulfur atom, which may be bonded to a nitrogen atom, such as in a sulfonamide, i.e., as in the structure N-S0 2 -Ar, where Ar is an aryl (including a heteroaryl) moiety (bonds removed for clarity).
- the nitrogen-containing moiety may contain an oxygen atom, which may be bonded to the nitrogen atom, such as in a hydoxylamine (N-OH), an oxime (N-OR, R comprising at least one carbon atom), or a nitro moiety (NO 2 ).
- the nitrogen-containing moiety may contain two nitrogen atoms, which may be bonded to each other, such as in a hydrazide (N-NH 2 ), a substituted hydrazide (N-NHJ or N-NHJ 1 ! 2 , each J comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom, such as acyl, sulfonyl, etc.), or the like.
- N-NH 2 hydrazide
- N-NHJ or N-NHJ 1 ! 2 each J comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom, such as acyl, sulfonyl, etc.
- any one, two, three, four, five, or six of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 may each independently have a formula NJ 1 J 2 , where J 1 and J 2 each independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom. J 1 and J 2 each may contain atoms other than carbon and hydrogen atoms, for example, sulfur, nitrogen, or oxygen. As one example, NJ ! J 2 may be an amine. In some cases, the N of the amine may be covalently bonded to Si.
- the N of the amine may not be covalently bonded to Si, and one or more carbon atoms may connect the N of the amine to Si (i.e., a aminocycloalkyl moiety such as an aminoaryl moiety, or an aminoalkyl moiety such as an aminopropyl, an aminobutyl, an aminopentyl, etc).
- the amine may be a primary amine, a secondary amine, a tertiary amine, or a quaternary amine.
- At least one aminoalkyl and/or aminoaryl moiety is chosen such that the amine moiety is able to interact with one or more hydroxide moieties covalently bonded to a silicon atom of the compound.
- the interaction of the aminoalkyl and/or aminoaryl moiety with the hydroxide moiety may stabilize the compound, for example, against degradation or polymerization in solution (e.g., spontaneous polymerization in water) in certain instances.
- Significant or detectable degradation or polymerization in solution may be prevented, for example, by self-interaction within the compound, which may prevent or inhibit substantial and/or stable polymerization of the compound to neighboring molecules.
- the compound may have a structure, or may be hydrolyzed or protonated within the body to form a structure such as:
- A is any alkyl and/or aryl moiety that allows substantial interaction between the nitrogen atom and the hydroxide to occur (indicated by ), and each of J 1 , J 2 , and J 3 independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- suitable alkyls include those previously described. In the above structures, not all of the atoms bonded to silicon are drawn for reasons of clarity.
- the aminoalkyl moiety may include 2, 3, 4, 5, or 6 carbon atoms between the nitrogen atom and the silicon atom. In some cases the aminoalkyl moiety may be aminopropyl, aminobutyl, or aminoisobutyl, etc.
- Non-limiting examples of compounds having aminoalkyl moieties include the following:
- the aminoalkyl moiety may include more than one amino moiety, for example, as in a bis(aminoalkyl)alkyl moiety or a tris(aminoalkyl)alkyl moiety.
- Examples of compounds having such structures include, but are not limited to:
- each of Z 1 and Z 2 independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- Each of J 10 , J 11 , J 12 , and J 13 is independently H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- Z 1 and Z 2 may each independently be a halogen or a pseudohalogen, such as chlorine or CN, or an alkoxy, such as methoxy.
- each of J 10 , J 11 , J 12 , and J 13 may independently be an alkyl, for example, methyl, ethyl, propyl, butyl, pentyl, etc.
- an aminoalkyl moiety of the compound may include a cyclic structure (i.e., an aminocycloalkyl moiety), e.g., an aryl moiety, a saturated or unsaturated cyclic moiety, a heteroaryl moiety, etc.
- the aminocycloalkyl moiety may optionally include one or more alkyl moieties, for example, between an aryl moiety or a cycloalkyl moiety and the silicon atom.
- Non-limiting examples of aminocycloalkyl compounds include: Ar Si Ar Ak— Si Ak 2 — Ar— A 1 — Si
- each Ak independently comprises an alkyl
- each Ar independently comprises an aryl (for example, an aminoaryl)
- J independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the silicon composition may include both aminoalkyl and aminocycloalkyl moieties, including the amines previously discussed.
- the compound is an aminosilicon compound, or a salt thereof, i.e., a compound in which a nitrogen atom is covalently bonded to a silicon atom.
- the compound may be, for example, a silanol, a silandiol, or a silantriol, or a compound able to form a silanol, a silandiol, or a silantriol upon hydrolysis, for example, under physiological conditions.
- the aminosilicon compound is cyclic in some cases. Non-limiting examples of cyclic aminosilicon compounds include:
- A is a moiety having at least one of a carbon atom and a silicon atom (for example, an alkyl, a cycloalkyl, an aryl, etc.), and each J independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- cyclic aminosilicon compounds include:
- each Z is independently one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom.
- Each J is independently H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- Each Y moiety independently comprises at least one atom (for example, hydrogen, a halogen, a pseudohalogen, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.).
- any one, two, three, four, five, or six of Z 1 , Z 2 , Z 3 , Z , Z 5 , and Z 6 may each mdependently comprise a silicon atom.
- the compound may have at least two, at least three, at least four, at least five, etc. silicon atoms within its structure.
- the compound is a polymer.
- An example of a compound having two silicon atoms within its structure is:
- each of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 independently is one of H, X, R, OH, OR 1 , or NJ J , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each mdependently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the compound may have a structure that allows, or can be hydrolyzed under physiological conditions to form a structure that allows, multiple silicon hydroxide moieties to simultaneously interact with aluminum or another metal ion.
- M indicates the position of a metal ion
- each R moiety in the illustrated structures independently comprises at least one atom interconnecting the silicon atoms (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, an amine, etc.).
- Z 1 and Z 2 each independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- R comprising at least one carbon atom
- X being a halogen or a pseudohalogen
- R 1 comprising at least one carbon atom
- J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the (noncovalent) interaction of SiO " with the metal ion is indicated by — :
- Non-limiting examples of such structures include:
- Y comprises at least one atom (for example, hydrogen, a halogen, a pseudohalogen, an alkyl moiety, an aiyl moiety, a cyclic moiety, etc.).
- the compound is a polymer having a repeat unit comprising at least one silicon atom.
- the silicon may be functionalized as described above (e.g., the silicon atom of the repeat unit may be covalently bonded to one or more of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom).
- the compound is a polymer comprising a repeat unit having silanol, silandiol, or silantriol functionality, or the polymer comprises a repeat unit that can by hydrolyzed to form silanol, silandiol, or silantriol functionality.
- Non-limiting examples include:
- Y comprises at least one atom (for example, hydrogen, a halogen, a pseudohalogen, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.), R comprises at least one carbon atom, and n and m are positive integers.
- the polymer is a copolymer (e.g., as shown above), the copolymer may be, for example, a block copolymer, a random copolymer, an alternating copolymer, a graft copolymer, etc.
- a compound of the invention is a cyclic organosilicon compound having at least one ester moiety, or a salt thereof.
- Non-limiting examples of such compounds include:
- each A independently is a moiety having at least one of a carbon atom and a silicon atom
- each Z independently is one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1
- each A may be chosen to render the compound more hydrophobic or less hydrophobic, and/or to facilitate passage of the compound across the blood-brain barrier.
- cyclic organosilicon esters of the invention include:
- Z and Z is each independently one of H, X, R, OH, OR , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- R comprising at least one carbon atom
- X being a halogen or a pseudohalogen
- R 1 comprising at least one carbon atom
- J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the compound has a structure:
- each of A 1 , A 2 , A 3 , A 4 , A 5 , A 6 , A 7 , A 8 , A 9 , A 10 , A 11 , and A 12 independently is H or comprises at least one carbon atom. Not all of the atoms bonded to silicon are drawn for reasons of clarity. In some cases, each of the A's may be chosen such that two A moieties joined by a common carbon atom of an oxasilinane ring are the same. In certain cases, each of the A's may be chosen such that the compound is symmetrical or nonchiral, or such that the compound is asymmetrical or chiral. In one embodiment, each A is either H or an alkyl moiety, such as methyl, ethyl, propyl, etc.
- the compound may have more than one silicon atom in some embodiments. Additional non-limiting examples include:
- each of Z 1 , Z 2 , Z 3 , Z 4 , Z 5 , and Z 6 is independently one of H, X, R, OH, OR 1 , or NJ ! J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- a compound of the invention may have a portion that
- the compound becomes positively charged (represented schematically herein by the symbol Xx) under physiological conditions within the body, which may thereby cause the molecule to become less charged or zwitterionic in some cases (i.e., the molecule has a positively charged portion and a negatively charged portion, or the molecule has a net dipole moment).
- a less charged compound may facilitate transport of the compound into the brain in some cases, for example, across the blood-brain barrier or across a cell membrane.
- the compound may be represented by:
- each of Z 1 and Z 2 mdependently is one of H, X, R, OH, OR 1 , or NJ 1 ! 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- the compound may be present as a salt.
- V_ is an amine moiety.
- the nitrogen atom of the amine moiety may be located on one portion of the compound, which may give that portion of the compound a positive charge when exposed to certain physiological solutions or conditions.
- suitable amines include those described above.
- the amine may be a primary amine, a secondary amine, a tertiary amine, or a quaternary amine.
- the amine may be a dimethylamine, an ethylmethylamine, a propylmethylamine, a diethylamine, etc.
- amines may each be the same or different.
- Other moieties that can provide positive charge include, for example, amidines, guanidines, aryl amines, heteroaryl amines, pyridines, imidazoles, etc.
- Combinations of one or more moieties that can be positively charged under physiological conditions within a compound of the invention are also envisioned, for example, a compound having an amine moiety and a guanidine moiety, a guanidine moiety and a pyridine, etc.
- one or more counterions may also be present or associated with the compound, for example, an organic or an inorganic anion, such as chloride, fluoride, bromide, sulfate, carbonate, acetate, etc. if the compound is positively charged.
- an organic or an inorganic anion such as chloride, fluoride, bromide, sulfate, carbonate, acetate, etc.
- the compound may have a structure that facilitates transport of the compound into an organ or across the blood-brain barrier.
- the compound may be designed so as to optimize the hydrophobicity of the composition to facilitate transport of the compound into the organ or across the blood-brain barrier (e.g., via diffusion, or using a transport system such as transport proteins or ion channels).
- the compound's ability to move into the organ or across the blood-brain barrier may be lost when the compound binds to a metal ion such as aluminum, or when the compound enters the brain or other organ, or in transit (i.e., within the cells that form the blood-brain barrier, etc).
- the compound may retain or improve its ability to move into an organ or cross the blood- brain barrier when bound to a metal ion.
- positive, negative, and/or hydrophobic moieties may be attached to the compound so as to achieve a selected hydrophobicity and/or a selected electric dipole moment of the compound.
- the hydrophobicity of the compound may be determined by those of ordinary skill in the art using any suitable test, for example, by partitioning the compound in a two-phase liquid system, such as a water-octanol system, or other suitable systems known to those of ordinary skill in the art.
- the hydrophobicity of a compound may be determined by allowing the compound to partition in a water-octanol system, and determining the percentage of the compound in the octanol phase relative to the water phase (e.g., on a per mass basis or other quantitative measurement).
- the water-octanol partition coefficient may be chosen such to optimize penetration of the blood-brain barrier in certain instances, and may depend on actual physiological conditions. See, e.g., Lohmann, et al, "Predicting Blood-Brain Barrier Permeability of Drugs: Evaluation of Different In Vitro Assays," J. Drug Targeting, 10(4): 263-276, 2002.
- the octanol/water partition ratio for a hydrophobic compound is at least about 1.25:1 (octanokwater), at least about 1.5:1, at least about 1.75:1, at least about 2:1, at least about 5:1, at least about 10:1, at least about 20:1, at least about 50:1, at least about 100:1, at least about 300:1, or at least about 1000:1 or greater.
- a hydrophobic compound may more readily cross the blood-brain barrier or other similar barrier or membrane to enter into the brain or other organ.
- the compound includes one or more hydrophobic or lipophilic moieties, for example, an alkyl moiety, a cycloalkyl moiety, an aryl moiety, or the like.
- a compound of the invention includes a chelating agent able to bind to aluminum or another metal ion (or is able to form a chelating agent able to bond to aluminum or another metal ion).
- a compound of the invention has a structure: — Y or x — Y, where X is a chelating agent able to bond to aluminum or another metal ion, or is able to form a chelating agent able to bond to aluminum or another metal ion.
- Y is a structure able to facilitate transport of the compound (or a portion thereof) across the blood brain-barrier
- the structure X ⁇ ⁇ comprises at least one chemical bond
- the structure — is a moiety that can be hydrolyzed under physiological conditions, e.g., within the brain, the blood-brain barrier, or within the bloodstream.
- the structure ⁇ includes at least one atom that connects structure X and structure Y (e.g., the structure X ⁇ ⁇ may include two atoms bridging between X and Y, three atoms bridging between X and Y, four atoms bridging between X and Y, five atoms bridging between X and Y, etc.).
- Suitable hydrolyzable structures interconnecting X and Y include, for example, alkoxide moieties, ester moieties, or ether moieties, e.g., as previously described. Other suitable hydrolyzable structures will be l ⁇ iown to those of ordinary skill in the art.
- the hydrolyzable structures may be chosen to control the degradation rate of the compound within the brain (for example, if the release of Y activates X in the above structure).
- a compound having a Si-F bond may hydrolyze at a relatively slow rate
- a compound having a Si-Cl or Si-Br bond may hydrolyze at a relatively faster rate. Slow rates of degradation may be desirable in some cases, for example, when slow or controlled release of the compound is desired.
- Different compounds having different halogens may also be administered together to provide short and long term activity in certain cases.
- Y is a targeting moiety able to target a component of the blood-brain barrier to facilitate transport, such as via an endogenous transport pathway, for example, by mimicking proteins or other substrates naturally transported by the targeted endogenous transport protein.
- the composition may be selected to mimic a substrate for a hexose transporter, a monocarboxylate transporter, an amino acid transporter, a glucose transporter, a peptide transporter (for example, transporters for enkephalins, vasopressin, apamins, etc.), a protein transporter (e.g., transferrin), or the like.
- a compound of the invention targeted towards transport across the blood-brain barrier using a carbohydrate transporter may have a structure such as:
- each of Z 1 , Z 2 , and Z 3 independently is one of H, X, R, OH, OR 1 , or NJ 1 ! 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, and R 1 comprising at least one carbon atom.
- Each J independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom
- Y is an interconnecting moiety (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.)
- Cb comprises a carbohydrate moiety (or a portion thereof).
- Cb is an entity that substantially derives from a carbohydrate or a portion thereof.
- a reaction of a carbohydrate with an aminosilicon composition or an amidated silicon compound may be used to produce a composition of the compound.
- the carbohydrate may be an aldehyde sugar ("aldocarbose”) (e.g., aldohexose or aldopentose) or a ketone sugar (“ketocarbose”) (e.g., ketohexose or ketopentose), or a moiety derived from an aldocarbose or a ketocarbose.
- the carbohydrate may be amidated, animated, esterif ⁇ ed, etc. Other carbohydrate derivitization reactions will be known to those of ordinary skill in the art.
- at least a portion of the carbohydrate may be an aldehyde sugar or a ketone sugar.
- the composition may have a structure such as:
- each of Z 1 , Z 2 , and Z 3 independently is one of a H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, and R 1 comprising at least one carbon atom.
- each J independently is H or comprises at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom
- Y is an interconnecting moiety (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.)
- Aa comprises one or more amino acids (i.e., n may be 1, 2, 3, a peptide, a protein, etc.) and/or one or more amino acid derivatives. In some cases, n may be a positive integer less than about 50, less than about 20, or less than about 10.
- Such compounds may be prepared, for example, by reacting a suitable aminosilicon compound with a carbohydrate, an amino acid, a peptide, a protein, a hormone, a neurotransmitter, etc. using coupling reactions known to those to ordinary skill in the art.
- a compound of the invention may be packaged or included in a virus, for example, a virus that is targeted towards the brain or other organ.
- a virus may be loaded with a silanol, a silandiol, or a silantriol, and/or a compound able to form a silanol, a silandiol, or a silantriol upon hydrolysis and/or release from the virus.
- the viruses may be prepared by assembling the viral envelope of the virus in the presence of one or more compounds of the invention, thus facilitating internal loading of the virus with the compounds of the invention.
- the compound may have a detectable moiety, i.e., a moiety that facilitates external detection, e.g., in vivo or in vitro.
- a portion of the compound may be radioactively and/or fluorescently labeled.
- Such compounds can be prepared using coupling reactions known to those of ordinaiy skill in the art.
- a compound having a structure :
- a compound having a structure may be reacted with an acyl, isocyanate, or an isothiocyanate moiety on, or attached to, a fluorescent moiety, thereby producing a detectable compound.
- an acyl, isocyanate, or an isothiocyanate moiety on, or attached to, a fluorescent moiety thereby producing a detectable compound.
- a compound having a structure may be reacted with an acyl, isocyanate, or an isothiocyanate moiety on, or attached to, a fluorescent moiety, thereby producing a detectable compound.
- each Z is independently one of H, X, R, OH, OR 1 , or NJ 1 J 2 , with R comprising at least one carbon atom, X being a halogen or a pseudohalogen, R 1 comprising at least one carbon atom, and J 1 and J 2 each independently being H, or comprising at least one of a carbon atom, a nitrogen atom, an oxygen atom, or a sulfur atom.
- Y is a moiety interconnecting Si and N (for example, an alkyl moiety, an aryl moiety, a cyclic moiety, etc.).
- the fluorescent label may be FITC or a FITC derivative, fluorescein, GFP, etc.
- the detectable moiety in another set of embodiments, includes a radioactive atom, for example, 3 H, 14 C, 33 P, 32 P, 125 1, 131 1, 35 S, etc.
- suitable ways to incorporate a radioactive label into a compound of the invention will be any suitable fluorescent label for use in the above structures.
- the fluorescent label may be FITC or a FITC derivative, fluorescein, GFP, etc.
- the detectable moiety in another set of embodiments, includes a radioactive atom, for example, 3 H, 14 C, 33 P, 32 P, 125 1, 131 1, 35 S, etc.
- tritium can be incorporated into the compound using a reducing reaction.
- a tritiated lithium aluminum hydride e.g., LiAlT 4 , LiAlHT 3 , LiAlH 2 T 2 , and/or LiAlH 3 T
- LiAlT 4 , LiAlHT 3 , LiAlH 2 T 2 , and/or LiAlH 3 T may be reacted with a functional moiety, resulting in reduction of the functional moiety and incorporation of a tritium label into the compound.
- useful reducing reactions include: ⁇ 2 R CN -c- -NH,
- each R (or, for structures with R 1 and R 2 , at least one of R 1 and R 2 ) comprises at least one silicon atom. It should be understood that, for any T in the above structure, the actual reaction products will include a mixture of labeled (tritiated) and unlabeled hydrogen atoms.
- compositions of the invention may be assayed for transport across subject cells.
- the cells are cells that can be used to model the blood-brain barrier, for example, Caco-2 cells or bMNEC cells
- a composition of the invention may be used to determine or predict the transport or uptake rate of the composition (or a portion thereof) across the blood-brain barrier.
- Transport of the composition may be determined, for example, using CD or similar techniques, such as atomic absorption, spectroscopy, mass spectroscopy, radioactive tracer measurements, or the like.
- a composition of the invention may be determined by its transport behavior across a monolayer of cells, i.e., a composition of the invention may be transported across the cell monolayer at a substantial rate.
- a composition "able to cross" the blood-brain barrier may be determined, in some cases, by the compound's ability to cross a monolayer of cells, such as Caco-2 cells or bMNEC cells.
- suitable cell models are described in Lohmann, et al, "Predicting Blood-Brain Barrier Permeability of Drugs: Evaluation of Different In Vitro Assays," J. Drug Targeting, 10(4): 263-276, 2002.
- the toxicity of a test compound against cells such as human cells is determined.
- a step of selecting test compounds that are substantially non-toxic to subject cells is provided.
- Substantially non-toxic means that the test compound can be administered to a subject with an acceptable amount of damage (preferably, no detectable damage) to the subject cells.
- the damage to the cells may be indicated by altered cell metabolism, cell morphology, cell mitosis, necrosis, apoptosis, etc.
- An acceptable amount of damage can be determined by one of skill in the art with no more than routine experimentation. Acceptable amounts of damage may depend on route of administration, risk of side effects versus benefit of administration, etc.
- the compositions and methods of the invention may be used in diagnostic or assay techniques.
- a composition of the invention may be used in an assay such as an aluminum detection assay or a metal ion detection assay.
- a sample having a known or unknown concentration of aluminum or other metal ion may be added to a solution containing a composition of the invention, and the amount or degree of binding of the composition (or a portion thereof) to the aluminum or other metal ion may be determined, using techniques known by those of ordinary skill in the art, for example, using circular dichroism or mass spectroscopy.
- the invention may be used in a cell culture system, for example, in a cell culture that includes neural and/or other types of cells, such as a cell able to produce beta-amyloid and/or a neurofilament protein.
- a composition of the invention is added to a cell culture, optionally with a known or unknown concentration of aluminum or other metal ion, and the net effect on cell function of the combination of the aluminum or other metal ion and the organosilicon composition of the invention is determined using techniques known to those of ordinary skill in the art.
- a cell culture is used to detect and/or determine the concentration of aluminum (or other metal ion) in a sample using the methods and compositions of the invention, which may be a sample of biological origin in some cases.
- a cell culture, a diagnostic, or an assay may be used to determine proper dosing to achieve a certain specified result (e.g., a certain concentration of free aluminum ions) when the composition is applied to a subject.
- compositions of the invention are applied in a therapeutically effective, pharmaceutically acceptable amount as a pharmaceutically acceptable formulation.
- pharmaceutically acceptable is given its ordinary meaning as used in the art.
- Pharmaceutically acceptable compounds are generally compatible with other materials of the formulation and are not generally deleterious to the subject.
- a composition of the invention (or prodrug form of the composition) may be administered to the subject in any therapeutically effective dose or treatment.
- a "therapeutically effective" dose or amount is capable of at least partially preventing or reversing symptoms related to the adverse effects of metal ions as previously discussed, for example, neurofibrillary tangles or senile plaque formation in the brain.
- a therapeutically effective amount may be determined by those of ordinary skill in the art, for instance, employing factors such as those further described below and using no more than routine experimentation.
- the subject being so treated is not mdicated as having a disease or condition treatable by the inhibition of leukocyte elastase.
- dosing amounts, dosing schedules, routes of administration, and the like may be selected so as to affect l ⁇ iown activities of the compositions of the invention. Dosages may be estimated based on the results of experimental models, optionally in combination with the results of assays of compositions of the present invention. Dosage may be adjusted appropriately to achieve desired drug levels, local or systemic, depending upon the mode of administration. The doses may be given in one or several administrations per day. In some cases, parenteral administration of the composition may be from one to several orders of magnitude lower dose per day, as compared to oral doses.
- the dose of the composition to the subject may be such that a therapeutically effective amount of the composition (or a portion thereof, such as an organosilicon compound) reaches or enters the brain or other active site.
- the dosage may be given in some cases at the maximum amount while avoiding or minimizing any potentially detrimental side effects to the subject.
- the dose of the organosilicon composition may be about 0.1 mcmol/kg ("micromoles'Vkg) to about 50 mcmol/kg, or about 0.5 mcmol/kg to about 5.0 mcmol/kg.
- the dosage of the composition that is actually administered is dependent upon factors such as the final concentration desired at the active site, the method of administration to the subject, the efficacy of the composition, the longevity (i.e., half-life) within the subject of the composition, the timing of administration relative to the formation of the tangles and/or plaques the frequency of treatment, the effect of concurrent treatments, etc.
- the dose delivered may also depend on conditions associated with the subject, and can vary from subject to subject in some cases. For example, the age, sex, weight, size, environment, physical conditions, or current state of health of the subject may also influence the dose required and/or the concentration of the composition (or portion thereof) at the active site. Nariations in dosing may occur between different individuals or even within the same individual on different days.
- a maximum dose that is, the highest safe dose according to sound medical judgment.
- the dosage form is such that it does not substantially deleteriously affect the subject.
- the specific dosage(s) given to the subject can thus be determined by those of ordinary skill in the art, using no more than routine experimentation.
- compositions of the invention may be accomplished by any medically acceptable method which allows the composition (or portion thereof) to reach its target.
- the particular mode selected will depend, of course, upon factors such as the particular composition, the severity of the state of the subject being treated, or the dosage required for therapeutic efficacy.
- a "medically acceptable" mode of treatment is a mode able to produce effective levels of the composition (or portion thereof) within the subject, without causing clinically unacceptable adverse effects.
- a “target” or “active site” is the location where a composition (or portion thereof) of the invention is able to bind to a metal ion and/or inhibit interaction between the metal ion and components of the body adversely affected by the presence of the metal ion, such as with beta-amyloid or neurofilament proteins.
- the inhibition of the metal ion may occur before or after the metal ion complexes or otherwise inactivates such components adversely affected.
- targets include the bloodstream or the brain.
- any medically acceptable method may be used to administer the composition to the subject.
- the administration may be localized (i.e., to a particular region, physiological system, tissue, organ, or cell type) or systemic, depending on the condition to be treated.
- the composition may be administered orally, vaginally, rectally, buccally, pulmonary, topically, nasally, transdermally through parenteral injection or implantation, via surgical administration, or any other method of administration where access to the target by the composition of the invention is achieved.
- any of the compositions described herein may be injected directly into the brain, spinal cord, or other organ, or the composition may be injected in a region such that it will be transported into the brain, spinal cord, or other organ, for example, injected into the cerebrospinal fluid.
- parenteral modalities that can be used with the invention include intravenous, intradermal, subcutaneous, intracavity, intramuscular, intraperitoneal, epidural, or intrathecal.
- implantation modalities include any implantable or injectable drug delivery system.
- the implantable delivery system is a subdural article containing the organosilicon composition, placed in direct contact with the brain, for example, through surgery.
- the article may have any suitable form for implantation within the brain, for example, a sponge, a film, a blanket, a pad, a wafer, a disc, etc.
- the article may be removed (and optionally replaced with a new article) after a suitable period of time has passed, for example, after a fixed time, such as a day, a week, or a month.
- the article may be removed when a certain condition is reached, for example, once a certain amount or percentage of the composition has diffused out of the article and/or when a certain amount of aluminum has been bound to the article.
- the article may be allowed to remain within the subject indefinitely.
- a sponge may include one or more compositions of the invention, which may be released from the sponge upon implantation, or which may remain mobilized within the sponge.
- compositions suitable for oral administration may be presented as discrete units such as hard or soft capsules, pills, cachettes, tablets, troches, or lozenges, each containing a predetermined amount of the active compound of the composition.
- Other oral compositions suitable for use with the invention include solutions or suspensions in aqueous or non-aqueous liquids such as a syrup, an elixir, or an emulsion.
- the composition may be used to fortify a food or a beverage.
- the administration of the composition of the invention may be designed so as to result in sequential exposures to the composition over a certain time period, for example, hours, days, weeks, months or years. This may be accomplished by repeated administrations of the composition by one of the methods described above, or by a sustained or controlled release delivery system in which the composition is delivered over a prolonged period without repeated administrations. Administration of the composition using such a delivery system may be, for example, by oral dosage forms, bolus injections, transdermal patches or subcutaneous implants.
- Maintaining a substantially constant concentration of the composition may be preferred in some cases, for example, to allow for scavenging of metal ions such as aluminum throughout the body, and promoting excretion of the metal ions via the kidney and bowel, or to allow for reaction with components of the body adversely affected by the metal ions, such as neurofibrillary tangles or senile plaque.
- avoidance of short- term elevated levels of compositions within the body may be desired in some cases, for instance, to minimize the precipitation of silicate kidney stones in the presence of non- physiological levels of silicon and silicon-containing compounds.
- Other delivery systems suitable for use with the present invention include time-release, delayed release, sustained release, or controlled release delivery systems. Such systems may avoid repeated administrations of the composition in many cases, increasing convenience to the subject. Many types of release delivery systems are available and known to those of ordinary skill in the art.
- polymer-based systems such as polylactic and/or polyglycolic acids, polyanhydrides, polycaprolactones and/or combinations of these; nonpolymer systems that are lipid-based including sterols such as cholesterol, cholesterol esters, and fatty acids or neutral fats such as mono-, di- and triglycerides; hydrogel release systems; liposome-based systems; phospholipid based- systems; silastic systems; peptide based systems; wax coatings; compressed tablets using conventional binders and excipients; or partially fused implants.
- Specific examples include, but are not limited to, erosional systems in which the composition is contained in a form within a matrix (for example, as described in U.S. Patent Nos.
- the formulation may be as, for example, microspheres, hydrogels, polymeric reservoirs, cholesterol matrices, or polymeric systems.
- the system may allow sustained or controlled release of the composition to occur, for example, through control of the diffusion or erosion/degradation rate of the formulation containing the composition.
- a pump-based hardware delivery system may be used to deliver one or more embodiments of the invention. Use of a long-term release implant may be particularly suitable in some embodiments of the invention.
- Long-term release means that the implant containing the composition is constructed and arranged to deliver therapeutically effective levels of the composition for at least 30 or 45 days, and preferably at least 60 or 90 days, or even longer in some cases. Long-term release implants are well l ⁇ iown to those of ordinary skill in the art, and include some of the release systems described above.
- the composition of the invention is administered to subjects who have a family history of Alzheimer's disease or other disease that is characterized by an excess of metal ions, or to subjects who have a genetic predisposition for the disease. In other embodiments, the composition is administered to subjects who have reached a particular age, or to subjects more likely to get the disease.
- the composition may be administered to subjects who exhibit symptoms of the disease (e.g., early or advanced). In still other embodiments, the composition may be administered to subjects as a preventive measure. In some embodiments, the composition is administered to subjects based on demographics or epidemiological studies, for example, to persons living in a certain geographic area, such as areas where a high concentration of metal ions such as aluminum are present in the groundwater; or to persons in a particular field, for example, workers in the aluminum or lead industry, or workers who use aluminum compounds or materials.
- Alzheimer's disease may be characterized in a subject by those of ordinary skill in the art prior to treatment with the compositions of the invention.
- a biological sample for the subject such as a blood test, a urine test, a biopsy, a spinal tap, etc.
- a concentration of ions e.g. metal ions such as aluminum
- an ion concentration may be determined by NMR, mass spectrometry, ICP, emission spectroscopy, fluorescence spectrometry, ELISA, a chemical stain or indicator, etc.
- a subject may be directly tested to determine if a disease exists or may exist (i.e., the subject is susceptible to the disease), for example, using MRI, CAT scans, X-rays, etc.
- a subject may be diagnosed as having or being at risk for Alzheimer's disease by a medical professional using routine practice.
- Alzheimer's disease may be diagnosed, for example, by considering the medical history, including such information as the person's general health, past medical problems, and/or any difficulties the subject has in performing carrying out daily activities; medical tests such as tests of blood, urine, or spinal fluid; neuropsychological tests such as memory, problem solving, attention, counting, and language tests; and/or brain scans, for example, using electroencephalograms, MRI, CAT, or PET scans; and behavioral indicators such as memory loss, personality change, dementia, speech problems, cognitive or reasoning problems, eating problems, incontinence, motor control problems, etc. Research studies have also indicated a general decrease in cerebrospinal fluid (CSF) beta-amyloid levels with an increase in tau protein may be indicative of a subject having or at risk for disease. 1 An improvement or arresting of at least some of the above indications may be related to the effectiveness of the inventive compositions. Of course, effectiveness may be measured by any of the techniques known to those skilled in the art, including, but not limited to, those listed above.
- CSF cerebros
- compositions of the invention can be alone, or in combination with other therapeutic agents and/or compositions (e.g., other agents or compositions that can be used to treat Alzheimer's disease or other disease that is characterized by an excess of metal ions).
- the compositions of the invention can be combined with a suitable pharmaceutically acceptable carrier, for example, as incorporated into a liposome, incorporated into a polymer release system, or suspended in a liquid, e.g., in a dissolved form or a colloidal form.
- the carrier may be either soluble or insoluble, depending on the application.
- compositions of the invention that may be pharmaceutically acceptable include not only the active compound, but also formulation ingredients such as salts, carriers, buffering agents, emulsifiers, diluents, excipients, chelating agents, drying agents, antioxidants, antimicrobials, preservatives, binding agents, bulking agents, solubilizers, or stabilizers that may be used with the active compound.
- formulation ingredients such as salts, carriers, buffering agents, emulsifiers, diluents, excipients, chelating agents, drying agents, antioxidants, antimicrobials, preservatives, binding agents, bulking agents, solubilizers, or stabilizers that may be used with the active compound.
- the carrier may be a solvent, partial solvent, or non-solvent, and may be aqueous or organically based.
- suitable formulation ingredients include diluents such as calcium carbonate, sodium carbonate, lactose, kaolin, calcium phosphate, or sodium phosphate; granulating and disintegrating agents such as corn starch or algenic acid; binding agents such as starch, gelatin or acacia; lubricating agents such as magnesium stearate, stearic acid, or talc; time-delay materials such as glycerol
- suspending agents such as sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone; dispersing or wetting agents such as lecithin or other naturally-occurring phosphatides; thickening agents such as cetyl alcohol or beeswax; buffering agents such as acetic acid and salts thereof, citric acid and salts thereof, boric acid and salts thereof, or phosphoric acid and salts thereof; or preservatives such as benzalkonium chloride, chlorobutanol, parabens, or thimerosal.
- compositions of the invention may be formulated into preparations in solid, semi-solid, liquid or gaseous forms such as tablets, capsules, elixirs, powders, granules, ointments, solutions, depositories, inhalants or injectables.
- suitable formulation ingredients or will be able to ascertain such, using only routine experimentation.
- pharmaceutically acceptable carriers suitable for use in the invention are well-known to those of ordinary skill in the art.
- a “pharmaceutically acceptable carrier” refers to a non-toxic material that does not significantly interfere with the effectiveness of the biological activity of the active compound(s) to be administered, but is used as a formulation ingredient, for example, to stabilize or protect the active compound(s) within the composition before use.
- carrier denotes an organic or inorganic ingredient, which may be natural or synthetic, with which one or more active compounds of the invention are combined to facilitate the application of the composition.
- the carrier may be co-mingled or otherwise mixed with one or more active compounds of the present invention, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficacy.
- Pharmaceutically acceptable carriers include, for example, diluents, emulsifiers, fillers, salts, buffers, excipients, drying agents, antioxidants, preservatives, binding agents, bulking agents, chelating agents, stabilizers, solubilizers, silicas, and other materials well-known in the art.
- Preparations include sterile aqueous or nonaqueous solutions, suspensions and emulsions, which can be isotonic with the blood of the subject in certain embodiments.
- nonaqueous solvents are polypropylene glycol, polyethylene glycol, vegetable oil such as olive oil, sesame oil, coconut oil, peanut oil, injectable organic esters such as ethyl oleate, or fixed oils including synthetic mono or di-glycerides.
- Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, mcluding saline and buffered media.
- Parenteral vehicles include sodium chloride solution, 1,3-butandiol, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or fixed oils.
- Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and/or other additives may also be present such as, for example, antimicrobials, antioxidants, chelating agents and inert gases and the like. Those of skill in the art can readily determine the various parameters for preparing and formulating the compositions of the invention without resort to undue experimentation.
- the present invention includes a step of bringing a composition or compound of the invention into association or contact with a suitable carrier, which may constitute one or more accessory ingredients.
- a suitable carrier which may constitute one or more accessory ingredients.
- the final compositions may be prepared by any suitable technique, for example, by uniformly and intimately bringing the composition into association with a liquid carrier, a finely divided solid carrier or both, optionally with one or more formulation ingredients as previously described, and then, if necessary, shaping the product.
- a compound of the present invention may be present as a pharmaceutically acceptable salt.
- pharmaceutically acceptable salts includes salts of the compound, prepared in combination with, for example, acids or bases, depending on the particular compounds found within the composition and the treatment modality desired.
- Pharmaceutically acceptable salts can be prepared as alkaline metal salts, such as lithium, sodium, or potassium salts; or as alkaline earth salts, such as beryllium, magnesium or calcium salts.
- suitable bases that may be used to form salts include ammonium, or mineral bases such as sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, and the like.
- acids examples include inorganic or mineral acids such as hydrochloric, hydrobromic, hydroiodic, hydrofluoric, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, phosphorous acids and the like.
- Suitable acids include organic acids, for example, acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, /j-tolylsulfonic, citric, tartaric, methanesulfonic, glucuronic, galacturonic, salicylic, formic, naphthalene- 2-sulfonic, and the like.
- Still other suitable acids include amino acids such as arginate, aspartate, glutamate, and the like.
- the composition comprises homologs, analogs, derivatives, enantiomers and/or functionally equivalent compositions thereof of the compounds of the invention, such as any of the above-described compounds.
- homologs, analogs, derivatives, enantiomers and functionally equivalent compositions thereof of the compounds may be used in any of the assays, methods, or compositions described above that are able to detect or treat Alzheimer's disease or other diseases characterized by the presence of metal ions.
- “Functionally equivalent” generally refers to a composition capable of treatment of a subject that exhibits symptoms of Alzheimer's disease or other diseases characterized by the presence of metal ions, a subject susceptible to or otherwise at increased risk for such diseases, or a subject not exhibiting symptoms of such diseases, but for whom it is desired to decrease the risk of such diseases (e.g., a vaccination or a prophylactic treatment). It will be understood one of ordinary skill in the art will be able to manipulate the conditions in a manner to prepare such homologs, analogs, derivatives, enantiomers and functionally equivalent compositions.
- compositions which are about as effective or more effective than the parent compound are also intended for use in the methods of the invention. Synthesis of such compositions may be accomplished through typical chemical modification methods such as those routinely practiced in the art.
- Another aspect of the present invention involves a method comprising providing any of the compositions of the present invention (or portions thereof), and performing a combinatorial synthesis on the composition, preferably to obtain homologs, analogs, derivatives, enantiomers and functionally equivalent compositions thereof of the composition.
- An assay may be performed with the homolog, analog, derivative, enantiomer or functionally equivalent composition to determine its effectiveness in treating, preventing, or inhibiting Alzheimer's disease or other diseases characterized by the presence of metal ions.
- the combinatorial synthesis can involve subjecting a plurality of the compositions described herein to combinatorial synthesis, using techniques l ⁇ iown to those of ordinary skill in the art.
- the present invention also provides any of the above-mentioned compositions useful for the treatment of Alzheimer's disease or other diseases characterized by the presence of metal ions packaged in kits, optionally including instructions for use of the composition for the treatment of such diseases.
- the kit can include a description of use of the composition for participation in any biological or chemical mechanism disclosed herein associated with Alzheimer's disease or other diseases characterized by the presence of metal ions.
- the kit can include a description of use of the compositions as discussed herein.
- the kit also can include instructions for use of a combination of two or more compositions of the invention. Instructions also may be provided for administering the drug by any suitable technique, as described above.
- the invention also involves, in some embodiments, the promotion of the treatment of Alzheimer's disease or other diseases characterized by the presence of metal ions according to any of the techniques and compositions described herein.
- promoted includes all methods of doing business including, but not limited to, methods of selling, advertising, assigning, licensing, contacting, instructing, educating, researching, importing, exporting, negotiating, financing, loaning, trading, vending, reselling, distributing, replacing, or the like that can be associated with the methods and compositions of the invention, e.g., as discussed herein. Promoting may also include, in some cases, seeking approval from a government agency to sell a composition of the invention for medicinal purposes.
- Methods of promotion can be performed by any party including, but not limited to, businesses (public or private), contractual or sub- contractual agencies, educational institutions such as colleges and universities, research institutions, hospitals or other clinical institutions, governmental agencies, etc.
- Promotional activities may include instructions or communications of any form (e.g., written, oral, and/or electronic communications, such as, but not limited to, e-mail, telephonic, facsimile, Internet, Web-based, etc.) that are clearly associated with the invention.
- instructions can define a component of instructional utility (e.g., directions, guides, warnings, labels, notes, FAQs ("frequently asked questions"), etc., and typically involve written instructions on or associated with the composition and/or with the packaging of the composition, for example, use or administration of the composition, e.g., in the treatment or prevention of Alzheimer's disease or other diseases characterized by the presence of metal ions.
- Instructions can also include instructional communications in any form (e.g., oral, electronic, digital, optical, visual, etc.), pt led in any manner such that a user will clearly recognize that the instructions are to be associated with the composition, e.g., as discussed herein.
- kits defines a package including any one or a combination of the compositions of the invention, and/or homologs, analogs, derivatives, enantiomers and functionally equivalent compositions thereof, and the instructions, but can also include the composition of the invention and instructions of any form that are provided in connection with the composition in a manner such that a clinical professional will clearly recognize that the instructions are to be associated with the specific composition, for example, as described above.
- the kits described herein may also contain, in some cases, one or more containers, which can contain compositions such as those described above.
- the kits also may contain instructions for mixing, diluting, and/or administrating the composition.
- kits also can include other containers with one or more solvents, surfactants, preservative and/or diluents (e.g., normal saline (0.9% NaCl), or 5% dextrose) as well as containers for mixing, diluting or administering the composition to the subject.
- solvents e.g., normal saline (0.9% NaCl), or 5% dextrose
- preservative and/or diluents e.g., normal saline (0.9% NaCl), or 5% dextrose
- compositions of the kit may be provided as any suitable form, for example, as liquid solutions or as dried powders.
- the composition may be reconstituted by the addition of a suitable solvent, which may also be provided.
- a suitable solvent which may also be provided.
- the liquid form may be concentrated or ready to use.
- the solvent will depend on the formulation of the composition and the mode of use or administration. Suitable solvents for drug compositions are well known and are available in the literature.
- the kit in one set of embodiments, may comprise a carrier that is compartmentalized to receive in close confinement one or more container means such as vials, tubes, and the like, each of the compartments comprismg one of the separate elements to be used in the method.
- one of the compartments may comprise a positive control for an assay.
- the kit may include containers for other components of the compositions, for example, buffers useful in the assay.
- EXAMPLE 1 circular dichroism (CD) was used to monitor changes in conformation of model peptides from human neurofilament, NF-M17 (glu-glu-lys-gly- lys-ser-pro-val-pro-lys-ser-pro-val-glu-glu-lys-gly) (SEQ ID NO: 1) (Fig. 1) when exposed to certain compounds of the present invention.
- NF-M17 glu-glu-lys-gly- lys-ser-pro-val-pro-lys-ser-pro-val-glu-glu-lys-gly
- SEQ ID NO: 1 glu-glu-lys-gly- lys-ser-pro-val-pro-glu-glu-lys-gly
- Fig. 1 circular dichroism
- the experiments were performed as follows. Peptides containing a seventeen amino acid region of the human neurofilament mid-sized subunit protein, NF-M17 were synthesized at greater than 95% purity.
- the peptides were dissolved in 2,2,2-trifluoroethanol (TFE) to a concentration of 0.4 mg/ml (0.2 mM).
- TFE 2,2,2-trifluoroethanol
- the aluminum solution (20 mM) was also prepared in TFE.
- Sodium metasilicate and the orthosilicate were dissolved in water.
- the sodium metasilicate solution was acidified to pH 6.0.
- the initial CD spectra collected contained primarily only information about the peptide.
- APST 3-(trihydroxysilyl) ⁇ ropylmethylphosphonate sodium salt
- TSPMP 3-(trihydroxysilyl) ⁇ ropylmethylphosphonate sodium salt
- OTCS n- octyltrichlorosilane
- CPTCS 3-cyanopropyltrichlorosilane
- silandiols or their precursors were also tested in this example: diphenylsilandiol (DPSD), hexylmethyldichlorosilane (HMDS), methylphenyldichlorosilane (MPDS), dichlorodiethylsilane (DCDES), dichlorodiisopropylsilane (DCDIPS), and (dichloro)methylsilylbutyronitrile (DCMSBN).
- DPSD diphenylsilandiol
- HMDS hexylmethyldichlorosilane
- MPDS methylphenyldichlorosilane
- DCDES dichlorodiethylsilane
- DCDIPS dichlorodiisopropylsilane
- DCMSBN dichloromethylsilylbutyronitrile
- silanols or their precursors were also tested: potassium trimethylsilanolate (PTMS), tert-butyldimethylsilanol (TBDMS), triethylsilanol (TES), and benzyldiethylsilanol (BDS).
- APST, DPSD, and APTES were obtained from Gelest, Inc. (Tullytown, PA).
- TFE, TSPMP, PTMS, TBDMS, TES, TPS, DCDIPS, DCDES, DCMSBN, and BDS were obtained from Sigma-Aldrich (St. Louis, MO).
- OCS and CPTCS were obtained from Lancaster Synthesis (Windham, NH). These structures are shown in Fig. 2.
- APST (Fig.2A), TSPMP (Fig. 2B), PTMS (Fig. 2K), TBDMS (Fig. 2L), TES (Fig. 2M), and BDS (Fig. 2N) were each dissolved to a final concentration of 20 mM in TFE.
- OTCS (Fig. 2C), CPTCS (Fig. 2D), HMDS (Fig. 2F), DCDES (Fig. 2H), DCDIPS (Fig. 21), and DCMSBN (Fig. 2J) were each hydrolyzed in water and diluted to a final concentration of 20 mM.
- MPDS was first dissolved in 50% TFE in water and then made up to a final concentration of 20 mM.
- MPDS (Fig. 2G) was first dissolved in 50% TFE in water and diluted to final concentration of 20 mM.
- DPSD (Fig. 2E) was first dissolved in dimethyl sulfoxide (DMSO) and then made up to a final concentration of 20 mM in TFE.
- DMSO blanks (containing no peptide) were collected for each dilution (0.04% to 1%).
- Figs. 3 and 4 show control experiments using sodium metasilicate nonahydrate and sodium orthosilicate, respectively, as a source of the silicate ion.
- the CD curve showed some return to its original shape at about 32 equivalents (Fig. 3D).
- Sodium orthosilicate showed a return to the original shape beginning at 4 equivalents (Fig. 4C).
- the CD spectrum with sodium orthosilicate is similar in shape to the original NF-M17 spectra (Fig. 4D).
- the APST solution used was a 22-25% by weight solution in water.
- the APST solution was able to restore the CD spectrum of NF-M17/aluminum to its original shape, with better recovery at higher equivalents (Fig. 5).
- the APST solution also showed improved chelation of aluminum compared to sodium orthosilicate (Fig. 6).
- TSPMP solution used was a 42% by weight solution in water. This triol did not successfully restore the original spectra of NF-M17. The incremental addition of TSPMP solution precipitated the peptide out of solution (data not shown).
- the OTCS solution used was a 100% solution. With the addition of water, the organochlorosilane solution underwent gelation and did not restore the original spectra of the NF-M17 peptide (data not shown).
- the CPTCS solution used was as a 100% solution. The CPTCS solution did not gel on addition of water, and the solution restored the CD spectrum of NF- M17/aluminum to its original shape at around 32 equivalents (Fig. 7).
- DPSD did not restore the original spectra of NF-M17.
- the incremental addition of DPSD solution precipitated the peptide out of solution (data not shown).
- solutions of HMDS Fig. 8
- MPDS Fig. 9
- DCDES Fig. 10
- DCDIPS Fig. 11
- DCMSBN Fig. 12
- the organosilanes, the diols and triols restored the original CD spectra of NF-M17, thus indicating the restoration of the original conformation of NF- M17.
- the diols and triols may form polyvalent crosslinked entities that may favorably bind and strip aluminum from NF-M.
- EXAMPLE 2 This prophetic example illustrates a method for treating Alzheimer's disease in a human subject with a composition of the invention comprising an organosilicon compound that inhibits interaction between aluminum and beta-amyloid.
- the subject is given the composition orally, in the form of a pill, once a day.
- the dose concentration per day is 4.0 mcmol/kg.
- Administration is carried out for a period of about six months. This treatment interferes with further development of neurofibrillary tangles and senile plaques.
- Amyloid peptide in TFE is believed to have a large degree of alpha-helical structure that is changed to a beta-sheet structure by the presence of aluminum ions. That transformation can be seen in a CD spectrum as a flattening of the signal. Reagents that partially or fully restore the initial beta-amyloid signal can thus be interpreted as the binding of aluminum to the reagent, allowing the peptide to regain its native alpha-helix character.
- Amyloid peptide human amyloid beta-protein 1-42, SynPep
- TFE trifluoroethanol
- the stock solution was diluted to 0.45 nm/ml to 0.50 nm/ml in TFE for use in these experiments.
- the molecular weight of the peptide was 4315 Da; thus, 0.45 mg/ml is equivalent to 100 micromolar.
- Aluminum perchlorate was dissolved in TFE at a concentration of 10 mg/ml.
- the silicate test reagents were typically dissolved and hydrolyzed in water at 60 mM.
- the CD spectrum was determined for each sample as follows. The sample was placed in a JASCO J-810 spectropolarimeter, in a cuvette having a volume of 100 ml, and a path length of 500 mM. The sensitivity of the instrument was approximately 100 millidegrees. Each spectrum was scanned with a wavelength range of between about 180 nm to about 260 nm, or between about 180 nm to about 280 nm. The data pitch was about 0.2 nm. The scan settings were performed under continuous scanning, at about 50 nm/min, with a response of 1 second. The data presented are data from two accumulations.
- HMDS hexylmethyldichlorosilane
- DCMSBN hexylmethyldichlorosilane
- DCSCB dichlorosilacyclobutane
- TSPM trihydroxysilylpropylmethyl phosphonate
- TES triethylsilanol
- Fig. 2M triethylsilanol
- tetrakis(dimethylamino)silane tetrakis
- Fig. 2U tetraacetooxysilane
- TAS tetraacetooxysilane
- Fig. 13 illustrates the effect of aluminum on the amyloid peptide.
- the CD spectrum of amyloid peptide decreases with higher concentrations of aluminum.
- Fig. 14 illustrates the effect of CPTCS on the aluminum-amyloid peptide system.
- the addition of 12 equivalents of aluminum to the solution containing the amyloid peptide causes a major reduction in the CD spectrum.
- the further addition of CPTCS is able to restore the CD spectrum of the peptide.
- Moderate reversal • was seen at 6 equivalents and 12 equivalents, while almost full reversal of the effects of aluminum on the peptide was seen with the addition of 24 equivalents of CTPCS.
- EXAMPLE 4 In this example, the transport of various organosilicon compounds of the invention across cell monolayers that mimic the blood-brain barrier as demonstrated.
- Two different cell lines were used as model blood-brain barrier systems: Caco-2 cells and bMNEC cells.
- Detection of the organosilicon compounds was performed using inductively coupled plasma spectrometry (ICP), per EPA method 200.7, using an ultrasonic nebulizer.
- ICP inductively coupled plasma spectrometry
- Caco-2 is a cell line derived from human intestinal epithelium, commonly used for studies of molecular transport across epithelia with tight junctions.
- the Caco-2 cells used in these experiments were from the laboratory of Dr. Neil Simister at Brandeis University, originating from the ATCC (American Type Culture Collection). The cells were grown in Dulbecco's Modified Eagle's Medium (DMEM), with 5% fetal bovine serum, 50 microgram/ml gentamicin at 5% C0 2 , 37 °C. Cells grown in Isgrove's medium and RPMI-1640 instead of DMEM showed similar times to reach confluence and similar morphology (data not shown). The Caco-2 cells formed electrically tight junctions, as assayed by measuring the electrical resistance with a World Precision Instruments ENOM-G.
- DMEM Dulbecco's Modified Eagle's Medium
- the cells were grown in tissue culture flasks, and split (passaged) when confluence reached about 4:1. Cells were seeded for experiments onto Corning Costar Transwell inserts, polyester or polycarbonate, with 0.4 micrometer pores. Cells on transparent polyester membranes could be directly observed using phase contrast microscopy. The cells were fed fresh medium at intervals of every 2 to 4 days. The cells were used for assays when the electrical resistance of the cell monolayer was at least 400 ohms/cm 2 .
- Bovine microvascular epithelial cells are primary cells from bovine brain, purchased frozen from Cambrex Bio Science. These cells were grown on collagen- coated membrane inserts, overcoated with fibronectin. The medium used was Endothelial Basal Medium 2 (Clonetics) supplemented with bECGF, ascorbic acid, platelet poor horse serum, penicillin, streptomycin and fungizone (provided as a kit by Cambrex). One aliquot of cells was diluted and split to seed 48 6.5 mm membranes (corning Costar polyester, 0.4 micrometer pores). The cells were fed fresh medium every 2-3 days, and used when visually confluent.
- Endothelial Basal Medium 2 (Clonetics) supplemented with bECGF, ascorbic acid, platelet poor horse serum, penicillin, streptomycin and fungizone (provided as a kit by Cambrex).
- One aliquot of cells was diluted and split to seed 48 6.5 mm membranes (corning Costar polyester, 0.4 micro
- Figs. 29A and 29B (Caco-2 cells) and Fig. 30 (bMNEC).
- Figs. 29A and 29B the transport of these organosilicon compounds are plotted as a function of time and hours. The starting concentrations on the apical side for each compound range between 1 mm and 10 mm. In all cases, a significant amount of transport was observed, across the Caco-2 cells, with more transport being observed for TESB, DCMSBN, and DCEMS (Fig. 29B) than TSPM, DCSCB, and SDSU (Fig. 29A).
- Fig. 30 illustrates transport of these compounds across the bMNEC cells.
- data are plotted for transport after 4 h and after 24 h, for two different donor concentrations. In all cases, a significant amount of transport was observed, with more transport occurring for higher concentration apicals. Thus, this example illustrates that various compounds of the invention can successfully be transported across the blood-brain barrier.
- This example illustrates a method of making l,7-dioxa-6-sila-spiro[5.5]undecane (Fig. 2Q) in one embodiment of the invention.
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Neurology (AREA)
- Biomedical Technology (AREA)
- Neurosurgery (AREA)
- Toxicology (AREA)
- Hospice & Palliative Care (AREA)
- Psychiatry (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
Description
Claims
Priority Applications (7)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU2003298673A AU2003298673A1 (en) | 2002-11-18 | 2003-11-18 | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
CA002506231A CA2506231A1 (en) | 2002-11-18 | 2003-11-18 | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
JP2004570636A JP2006526567A (en) | 2002-11-18 | 2003-11-18 | Composition for treating and / or preventing diseases characterized by the presence of metal ions |
MXPA05005286A MXPA05005286A (en) | 2002-11-18 | 2003-11-18 | Compositions for treating and/or preventing diseases characterized by the presence of metal ions. |
EP03796428A EP1583765A4 (en) | 2002-11-18 | 2003-11-18 | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
US11/132,170 US7595308B2 (en) | 2002-11-18 | 2005-05-17 | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
US12/567,678 US8273726B2 (en) | 2002-11-18 | 2009-09-25 | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
Applications Claiming Priority (12)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US42710502P | 2002-11-18 | 2002-11-18 | |
US42720102P | 2002-11-18 | 2002-11-18 | |
US42720302P | 2002-11-18 | 2002-11-18 | |
US42710402P | 2002-11-18 | 2002-11-18 | |
US60/427,203 | 2002-11-18 | ||
US60/427,201 | 2002-11-18 | ||
US60/427,104 | 2002-11-18 | ||
US60/427,105 | 2002-11-18 | ||
US45634503P | 2003-03-20 | 2003-03-20 | |
US60/456,345 | 2003-03-20 | ||
USPCT/US03/36749 | 2003-11-17 | ||
US0336749 | 2003-11-17 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US11/132,170 Continuation-In-Part US7595308B2 (en) | 2002-11-18 | 2005-05-17 | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
Publications (2)
Publication Number | Publication Date |
---|---|
WO2004045552A2 true WO2004045552A2 (en) | 2004-06-03 |
WO2004045552A3 WO2004045552A3 (en) | 2005-08-18 |
Family
ID=34382290
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US2003/037037 WO2004045552A2 (en) | 2002-11-18 | 2003-11-18 | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
Country Status (5)
Country | Link |
---|---|
JP (1) | JP2006526567A (en) |
AU (1) | AU2003298673A1 (en) |
CA (1) | CA2506231A1 (en) |
MX (1) | MXPA05005286A (en) |
WO (1) | WO2004045552A2 (en) |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2006047477A1 (en) * | 2004-10-22 | 2006-05-04 | Grenpharama Llc | Compositions for treating and/or preventing diseases characterized by the presence of the metal ions |
US7347970B2 (en) * | 2004-02-13 | 2008-03-25 | University Of Florida Research Foundation, Inc. | Biocides based on silanol terminated silanes and siloxanes |
US7504456B2 (en) | 2006-02-21 | 2009-03-17 | Momentive Performance Materials Inc. | Rubber composition containing organofunctional silane |
US7510670B2 (en) | 2006-02-21 | 2009-03-31 | Momentive Performance Materials Inc. | Free flowing filler composition based on organofunctional silane |
US7595308B2 (en) | 2002-11-18 | 2009-09-29 | Grenpharma Llc | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
US7718819B2 (en) | 2006-02-21 | 2010-05-18 | Momentive Performance Materials Inc. | Process for making organofunctional silanes and mixtures thereof |
US7816435B2 (en) | 2007-10-31 | 2010-10-19 | Momentive Performance Materials Inc. | Halo-functional silane, process for its preparation, rubber composition containing same and articles manufactured therefrom |
US7919650B2 (en) | 2006-02-21 | 2011-04-05 | Momentive Performance Materials Inc. | Organofunctional silanes and their mixtures |
US7928258B2 (en) | 2004-08-20 | 2011-04-19 | Momentive Performance Materials Inc. | Cyclic diol-derived blocked mercaptofunctional silane compositions |
US7960576B2 (en) * | 2004-08-13 | 2011-06-14 | Momentive Performance Materials Inc. | Diol-derived organofunctional silane and compositions containing same |
US8008519B2 (en) | 2006-08-14 | 2011-08-30 | Momentive Performance Materials Inc. | Process for making mercapto-functional silane |
US8026108B1 (en) * | 2006-10-19 | 2011-09-27 | The University Of Central Florida Research Foundation, Inc. | Detection of biotargets using bioreceptor functionalized nanoparticles |
US8097744B2 (en) | 2006-08-14 | 2012-01-17 | Momentive Performance Materials Inc. | Free flowing filler composition comprising mercapto-functional silane |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5523295A (en) * | 1994-07-06 | 1996-06-04 | Brandeis University | Method for treating and preventing alzheimer's disease |
US5532397A (en) * | 1987-05-08 | 1996-07-02 | Merrell Pharmaceuticals Inc. | Substituted silyl alkylene amines |
US5854215A (en) * | 1995-03-14 | 1998-12-29 | Praecis Pharmaceuticals Incorporated | Modulators of β-amyloid peptide aggregation |
US5859277A (en) * | 1997-06-25 | 1999-01-12 | Wisconsin Alumni Research Foundation | Silicon-containing solid support linker |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4039666A (en) * | 1975-12-15 | 1977-08-02 | Dow Corning Corporation | Anticonvulsant phenylsilanes |
JPH06509103A (en) * | 1991-07-15 | 1994-10-13 | アルベマール・コーポレーシヨン | Preventing and reducing the severity of traumatic injuries |
FR2725208B1 (en) * | 1994-09-30 | 1996-11-29 | Exsymol Sa | PROCESS FOR THE PREPARATION OF BIOLOGICALLY ACTIVE SILICON COMPOUNDS IN CONCENTRATED FORM |
JPH10101569A (en) * | 1996-10-01 | 1998-04-21 | Eisai Co Ltd | Antacid |
-
2003
- 2003-11-18 AU AU2003298673A patent/AU2003298673A1/en not_active Abandoned
- 2003-11-18 WO PCT/US2003/037037 patent/WO2004045552A2/en active Application Filing
- 2003-11-18 MX MXPA05005286A patent/MXPA05005286A/en not_active Application Discontinuation
- 2003-11-18 CA CA002506231A patent/CA2506231A1/en not_active Abandoned
- 2003-11-18 JP JP2004570636A patent/JP2006526567A/en active Pending
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5532397A (en) * | 1987-05-08 | 1996-07-02 | Merrell Pharmaceuticals Inc. | Substituted silyl alkylene amines |
US5523295A (en) * | 1994-07-06 | 1996-06-04 | Brandeis University | Method for treating and preventing alzheimer's disease |
US5854215A (en) * | 1995-03-14 | 1998-12-29 | Praecis Pharmaceuticals Incorporated | Modulators of β-amyloid peptide aggregation |
US5859277A (en) * | 1997-06-25 | 1999-01-12 | Wisconsin Alumni Research Foundation | Silicon-containing solid support linker |
Non-Patent Citations (1)
Title |
---|
See also references of EP1583765A2 * |
Cited By (16)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8273726B2 (en) | 2002-11-18 | 2012-09-25 | Brandeis University | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
US7595308B2 (en) | 2002-11-18 | 2009-09-29 | Grenpharma Llc | Compositions for treating and/or preventing diseases characterized by the presence of metal ions |
US7347970B2 (en) * | 2004-02-13 | 2008-03-25 | University Of Florida Research Foundation, Inc. | Biocides based on silanol terminated silanes and siloxanes |
US7960576B2 (en) * | 2004-08-13 | 2011-06-14 | Momentive Performance Materials Inc. | Diol-derived organofunctional silane and compositions containing same |
US8198472B1 (en) | 2004-08-13 | 2012-06-12 | Momentive Performance Materials Inc. | Diol-derived organofunctional silane and compositions containing same |
US8158812B2 (en) | 2004-08-13 | 2012-04-17 | Momentive Performance Marerials Inc. | Diol-derived organofunctional silane and compositions containing same |
US7928258B2 (en) | 2004-08-20 | 2011-04-19 | Momentive Performance Materials Inc. | Cyclic diol-derived blocked mercaptofunctional silane compositions |
WO2006047477A1 (en) * | 2004-10-22 | 2006-05-04 | Grenpharama Llc | Compositions for treating and/or preventing diseases characterized by the presence of the metal ions |
US7919650B2 (en) | 2006-02-21 | 2011-04-05 | Momentive Performance Materials Inc. | Organofunctional silanes and their mixtures |
US7718819B2 (en) | 2006-02-21 | 2010-05-18 | Momentive Performance Materials Inc. | Process for making organofunctional silanes and mixtures thereof |
US7510670B2 (en) | 2006-02-21 | 2009-03-31 | Momentive Performance Materials Inc. | Free flowing filler composition based on organofunctional silane |
US7504456B2 (en) | 2006-02-21 | 2009-03-17 | Momentive Performance Materials Inc. | Rubber composition containing organofunctional silane |
US8008519B2 (en) | 2006-08-14 | 2011-08-30 | Momentive Performance Materials Inc. | Process for making mercapto-functional silane |
US8097744B2 (en) | 2006-08-14 | 2012-01-17 | Momentive Performance Materials Inc. | Free flowing filler composition comprising mercapto-functional silane |
US8026108B1 (en) * | 2006-10-19 | 2011-09-27 | The University Of Central Florida Research Foundation, Inc. | Detection of biotargets using bioreceptor functionalized nanoparticles |
US7816435B2 (en) | 2007-10-31 | 2010-10-19 | Momentive Performance Materials Inc. | Halo-functional silane, process for its preparation, rubber composition containing same and articles manufactured therefrom |
Also Published As
Publication number | Publication date |
---|---|
MXPA05005286A (en) | 2006-02-22 |
AU2003298673A1 (en) | 2004-06-15 |
WO2004045552A3 (en) | 2005-08-18 |
JP2006526567A (en) | 2006-11-24 |
CA2506231A1 (en) | 2004-06-03 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
Zhang et al. | α-Lipoic acid improves abnormal behavior by mitigation of oxidative stress, inflammation, ferroptosis, and tauopathy in P301S Tau transgenic mice | |
WO2004045552A2 (en) | Compositions for treating and/or preventing diseases characterized by the presence of metal ions | |
Shin et al. | A novel trivalent cation chelator Feralex dissociates binding of aluminum and iron associated with hyperphosphorylated τ of Alzheimer’s disease | |
AU752236B2 (en) | Metal Chelators for Use in the Treatment of Alzheimer's Disease | |
AU748768B2 (en) | Identification of agents for use in the treatment of Alzheimer's disease | |
US8273726B2 (en) | Compositions for treating and/or preventing diseases characterized by the presence of metal ions | |
Kennedy et al. | Cellular lipid metabolism is influenced by the coordination environment of copper | |
WO1998040071A9 (en) | Identification of agents for use in the treatment of alzheimer's disease | |
Kuglstatter et al. | X-ray structure analyses of photosynthetic reaction center variants from Rhodobacter sphaeroides: structural changes induced by point mutations at position L209 modulate electron and proton transfer | |
TW470644B (en) | Pharmaceutical compositions useful for inhibiting amyloid aggregation in a mammal | |
Yatmark et al. | Effects of iron chelators on pulmonary iron overload and oxidative stress in β-thalassemic mice | |
Nelson et al. | Development of novel silyl cyanocinnamic acid derivatives as metabolic plasticity inhibitors for cancer treatment | |
Ding et al. | Oral administration of nanoiron sulfide supernatant for the treatment of gallbladder stones with chronic cholecystitis | |
Raj et al. | New phosphated poly (methyl methacrylate) polymers for the prevention of denture-induced microbial infection: an in vitro study | |
Corneillie et al. | Crystal structures of two complexes of the rare-earth-DOTA-binding antibody 2D12. 5: ligand generality from a chiral system | |
EP1583765A2 (en) | Compositions for treating and/or preventing diseases characterized by the presence of metal ions | |
US20090203644A1 (en) | Compositions for treating and/or preventing diseases characterized by the presence of metal ions | |
ZA200504054B (en) | Compositions for treating and/or preventing diseases characterized by the presence of metal ions | |
Bluhm et al. | Corynebactin and a serine trilactone based analogue: chirality and molecular modeling of ferric complexes | |
US20240181023A1 (en) | Functionalized biocatalytical compositions | |
EP4301350A1 (en) | Treatment of copper disorders | |
Fang et al. | Cobalt protoporphyrin promotes human keratinocyte migration under hyperglycemic conditions | |
Zhao et al. | Reaction with, and fine structural recognition of polyamines by human IgE antibodies | |
Mölzer et al. | Interaction between TNFone and tetrapyrroles may account for their anti-genotoxic effects—a novel mechanism for DNA-protection | |
Wernicke et al. | Antidepressants: The safety of duloxetine in the long-term treatment of diabetic neuropathic pain |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A2 Designated state(s): AE AG AL AM AT AU AZ BA BB BG BR BY BZ CA CH CN CO CR CU CZ DE DK DM DZ EC EE ES FI GB GD GE GH GM HR HU ID IL IN IS JP KE KG KP KR KZ LC LK LR LS LT LU LV MA MD MG MK MN MW MX MZ NI NO NZ OM PG PH PL PT RO RU SC SD SE SG SK SL SY TJ TM TN TR TT TZ UA UG US UZ VC VN YU ZA ZM ZW |
|
AL | Designated countries for regional patents |
Kind code of ref document: A2 Designated state(s): BW GH GM KE LS MW MZ SD SL SZ TZ UG ZM ZW AM AZ BY KG KZ MD RU TJ TM AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LU MC NL PT RO SE SI SK TR BF BJ CF CG CI CM GA GN GQ GW ML MR NE SN TD TG |
|
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 168577 Country of ref document: IL |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2506231 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: PA/a/2005/005286 Country of ref document: MX Ref document number: 11132170 Country of ref document: US Ref document number: 2003298673 Country of ref document: AU |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2004570636 Country of ref document: JP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2005/04054 Country of ref document: ZA Ref document number: 200504054 Country of ref document: ZA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 2003796428 Country of ref document: EP |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1159/KOLNP/2005 Country of ref document: IN |
|
WWE | Wipo information: entry into national phase |
Ref document number: 20038A65997 Country of ref document: CN |
|
WWP | Wipo information: published in national office |
Ref document number: 2003796428 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 11132170 Country of ref document: US |