WO2010114636A1 - Compositions pour le traitement de la maladie d'alzheimer - Google Patents

Compositions pour le traitement de la maladie d'alzheimer Download PDF

Info

Publication number
WO2010114636A1
WO2010114636A1 PCT/US2010/001041 US2010001041W WO2010114636A1 WO 2010114636 A1 WO2010114636 A1 WO 2010114636A1 US 2010001041 W US2010001041 W US 2010001041W WO 2010114636 A1 WO2010114636 A1 WO 2010114636A1
Authority
WO
WIPO (PCT)
Prior art keywords
disease
composition
pharmaceutical composition
alzheimer
beta amyloid
Prior art date
Application number
PCT/US2010/001041
Other languages
English (en)
Inventor
Jorge Galvez
Javier Llompart
David Land
Giulio Pasinetti
Original Assignee
Mount Sinai School Of Medicine Of New York University
Medisyn Technologies, Inc.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mount Sinai School Of Medicine Of New York University, Medisyn Technologies, Inc. filed Critical Mount Sinai School Of Medicine Of New York University
Priority to EP10759174A priority Critical patent/EP2413696A4/fr
Priority to AU2010232923A priority patent/AU2010232923A1/en
Priority to CA2759187A priority patent/CA2759187A1/fr
Publication of WO2010114636A1 publication Critical patent/WO2010114636A1/fr

Links

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/69—Boron 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
    • 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

Definitions

  • the application generally discloses compositions useful for treating Alzheimer's disease (AD). More specifically, the application discloses compositions that inhibit beta amyloid production, deposition and/or formation of high molecular weight A ⁇ 40 and A ⁇ 42 for treatment of Alzheimer's disease.
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • AD Alzheimer's disease
  • AD affects the parts of the brain that control thought, memory and language.
  • the financial costs attributable to Alzheimer's disease are high.
  • AD Alzheimer's Disease Education and Referral
  • the goals of treatment for Alzheimer's disease include improving cognition or, when this is not possible, slowing the loss of memory and cognition, as well as prolonging independent function and controlling co-morbid conditions.
  • AD Alzheimer's disease
  • Neurotransmitter replacement therapy i.e., inhibition of acetylcholine breakdown
  • This strategy provides symptomatic improvement and may delay the need for nursing home placement, but does not affect the underlying causes of the disease.
  • AD is characterized by the presence of extracellular A ⁇ plaques and intracellular neurofibrillary tangles (NFTs) within the afflicted brain, which causes neuronal loss in the neocortex, hippocampus, and basal forebrain, leading to progressive cognitive and behavioral decline.
  • a ⁇ plaques are composed mostly of insoluble A ⁇ peptides, mostly 40 and 42 amino acids in length with A ⁇ 42 being the most prevalent.
  • NFTs are composed mainly of hyperphosphorylated forms of microtubule-associated protein tau.
  • amyloid cascade hypothesis posits that an imbalance in the production or clearance of the A ⁇ peptide results in accumulation of A ⁇ and initiation of events leading to neurodegeneration and dementia.
  • Extracellular cerebral A ⁇ plaques consist of an insoluble aggregated core of A ⁇ surrounded by dystrophic axons, dendrites, activated microglia and reactive astrocytes.
  • Neurofibrillary Tangles (NFTs) made up of hyperphosphorylated tau protein destroy cellular architecture and aggregate into paired helical filaments in the cytoplasm of limbic and cortical neurons.
  • NFTs Neurofibrillary Tangles
  • Amyloidogenic 39-42 (A ⁇ 40 and A ⁇ 42) residue fragments of the amyloid precursor protein (APP) are produced via beta-secretase- and gamma-secretase-mediated cleavage during progression of AD.
  • Deposition and accumulation of the Abeta42 peptide (A ⁇ 42) in the brain constitute one major pathological feature of AD.
  • a small fraction of the total A ⁇ is in a soluble form, levels of which correlate with the severity of AD.
  • Inhibition of APP production, A ⁇ production i.e., through blocking cleavage or production of APP
  • reductions in A ⁇ accumulation and/or increases in A ⁇ degradation, solubilization and clearance from the brain represent potentially effective approaches for the treatment of AD.
  • the Blood-Brain-Barrier (BBB) is made of a dense layer of endothelial cells that create a barrier between the blood and brain parenchyma.
  • Many new therapeutic agents for AD have limited efficacy in vivo because of poor transport across the BBB.
  • Conventional strategies to improve transport across the BBB include extensive modification of drugs at significant cost, possible reduced efficacy, and delayed time to clinic.
  • compositions that are capable of inhibiting A ⁇ 40 and A ⁇ 42 in vivo activity to reduce the progression of AD.
  • compositions that are capable of inhibiting A ⁇ 40 and/or A ⁇ 42 in vivo cytotoxicity to reduce the progression of AD.
  • compositions that inhibit the formation of, or promote the degradation of, A ⁇ multimers including but not limited to A ⁇ forms of at least 40 kD. Administration of such compositions in vivo would provide the benefit of improved cognitive function for AD patients.
  • the disclosure provides beta amyloid (A ⁇ ) amount-reducing and/or A ⁇ anti- aggregation compounds and their use in pharmaceutical compositions.
  • the disclosure further includes methods of formulating pharmaceutical compositions and to methods of administering the compositions for treatment of disorders/diseases such as AD.
  • the disclosure provides a compound for the prevention, treatment, or amelioration of a symptom of Alzheimer's disease wherein the compound is unrelated to any known compound useful in treating Alzheimer's disease and, typically, unrelated to any known compound useful in treating AD or any related disease or disorder, such as neurological diseases (e.g., Parkinson's disease, Tourette's Syndrome, Transmissible Spongiform Encephalopathies such as familial or sporadic Creutzfeldt- Jakob disease, prion- related diseases, and the like).
  • neurological diseases e.g., Parkinson's disease, Tourette's Syndrome, Transmissible Spongiform Encephalopathies such as familial or sporadic Creutzfeldt- Jakob disease, prion- related diseases, and the like.
  • the compound is selected from the group consisting of a hexahydrobenzothiopheno[2,3-d]pyrimidin-2- ylsulfanyl acetamide, a phenyl triazole thiol, a benzyloxy naphthalene, an indole, a triazole, a hexahydro benzothieno pyrimidine, a tetrahydro benzothiophene, a thioxo thiazolidinone and a hydrotris (3-(4-cumenyl)-5-methylpyrazol-l-yl) borate, a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable ester thereof, and a pharmaceutically acceptable amide thereof, and wherein the compound reduces beta amyloid amount, inhibits beta amyloid aggregation, or both.
  • Another aspect of the disclosure provides a compound for the prevention, treatment, or amelioration of a symptom of a disease or disorder related to Alzheimer's disease, such as Alzheimer's disease itself, wherein the compound is selected from the group consisting of a 3-[2-(4-oxo-5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-3-yl)ethyl]- 5,6,7,8-tetrahydro benzothiopheno[2,3-d]pyrimidin-4-one, N-hexyl-5,6,7,8- tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-amine, N-[(2-benzyloxy- 1 - naphthyl)methyleneamino]-2-(2,4-dichlorophenoxy) acetamide, 2-hydroxy-N-( 1 - naphthylmethyleneamino) acetamide, (5Z)-5-[(3,4-[(3,
  • the compound reduces beta amyloid amount by at least 5% compared to a control. In other embodiments, the compound reduces beta amyloid aggregation by at least 1% compared to a control. Other embodiments comprise a compound wherein beta amyloid amount, beta amyloid aggregation, or both are reduced by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 90%, 95%, or 99%.
  • Another aspect of the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound described herein for treating a disease or disorder related to Alzheimer's disease, such as Alzheimer's disease itself, wherein the compound reduces beta amyloid amount compared to a control.
  • An embodiment of this aspect of the disclosure is a pharmaceutical composition wherein the compound reduces beta amyloid amount by at least about 5% compared to a control.
  • a related aspect of the disclosure provides a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a compound described herein that reduces beta amyloid aggregation compared to a control.
  • An embodiment of this aspect of the disclosure provides a pharmaceutical composition wherein the beta amyloid aggregation is reduced by at least about 1% compared to a control.
  • Other embodiments comprise a pharmaceutical composition wherein the compound inhibits beta amyloid amount, beta amyloid aggregation, or both are reduced by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 90%, 95%, or 99%.
  • kits for treating a disease or disorder related to Alzheimer's disease comprising a pharmaceutical composition described herein.
  • kits include an instruction for appropriate use of the composition, and optionally, the composition is provided in unit dosage form.
  • Another aspect of the disclosure is a method of treating a disease or disorder related to Alzheimer's disease, such as Alzheimer's disease itself, comprising administering to a subject a therapeutically effective amount of a pharmaceutical composition described herein.
  • the compound reduces beta amyloid amount by at least about 5% compared to a control, for example, the compound reduces beta amyloid aggregation by at least about 5% compared to a control.
  • the composition is effective to reduce beta amyloid level and aggregation, each by at least about 1% relative to a control.
  • inventions of the method comprise a pharmaceutical composition wherein the measure of Alzheimer's disease (e.g., inhibition of beta amyloid amount, inhibition of beta amyloid aggregation, inhibition of both beta amyloid amount and aggregation) is reduced by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 90%, 95%, or 99%.
  • the measure of Alzheimer's disease e.g., inhibition of beta amyloid amount, inhibition of beta amyloid aggregation, inhibition of both beta amyloid amount and aggregation
  • Yet another aspect of the disclosure is a method of ameliorating a symptom associated with a disease or disorder related to Alzheimer's disease, such as Alzheimer's disease itself, comprising administering to a subject an amount of a pharmaceutical composition described herein that is effective to ameliorate a symptom of Alzheimer's disease.
  • the composition inhibits beta amyloid amount by at least about 1%.
  • the composition inhibits beta amyloid aggregation by at least about 5%.
  • the composition inhibits both beta amyloid amount and beta amyloid aggregation, each by at least about 5%.
  • inventions of the method comprise a pharmaceutical composition wherein the measure of amelioration of Alzheimer's disease (e.g., inhibition of beta amyloid amount, inhibition of beta amyloid aggregation, inhibition of both beta amyloid amount and aggregation) is reduced by at least 1%, 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 90%, 95%, or 99%.
  • the measure of amelioration of Alzheimer's disease e.g., inhibition of beta amyloid amount, inhibition of beta amyloid aggregation, inhibition of both beta amyloid amount and aggregation
  • a method of inhibiting or preventing the onset of a disease or disorder related to Alzheimer's disease, such as Alzheimer's disease itself comprising administering to a subject a prophylactically effective amount of a pharmaceutical composition as described herein.
  • the composition inhibits beta amyloid amount by at least about 1%.
  • the composition inhibits beta amyloid aggregation by at least about 1 %.
  • inventions of the method comprise a pharmaceutical composition wherein the measure of prevention of Alzheimer's disease (e.g., inhibition of beta amyloid amount, inhibition of beta amyloid aggregation, inhibition of both beta amyloid amount and aggregation) is reduced by at least 5%, 10%, 15%, 20%, 25%, 30%, 40%, 50%, 75%, 90%, 95%, or 99%.
  • the measure of prevention of Alzheimer's disease e.g., inhibition of beta amyloid amount, inhibition of beta amyloid aggregation, inhibition of both beta amyloid amount and aggregation
  • any known route of administration of the pharmaceutical composition is contemplated, for example by administering the composition orally.
  • Another aspect of the disclosure is a use of a pharmaceutical composition as described herein for preventing, treating, or ameliorating a symptom of a disease or disorder related to Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 2-[(4-oxo-5,6,7,8-tetrahydro-3H-benzothiopheno[2,3-d]pyrimidin-2-yl)sulfanyl]acetaldehyde having the formula:
  • Rl is a carboxyl group ( — C(O) — OH), a hydrogen ( — H — ), a trifluoromethyl group ( — C(F 3 )), a phenol group ( — Ph — OH), an — SO 3 group, or a hydroxyl ( — OH) group;
  • R2 is a trifluoromethyl phenyl group (-Ph-CF 3 ), a methylphenyl ( — Ph — CH 3 ), — Ph- CH 2 — OH, a phenol group (— Ph- OH), a furan or a thiophene;
  • R3 is a -NH2, a -N(CH3)2, a -NH-(C(CH3)2), a -NH-Ph-meta-CH3; and wherein the composition is effective to inhibit production of beta amyloid monomer or promote degradation of A ⁇ monomer amount by at least about 5%
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 2-[(4-oxo- 5,6,7,8-tetrahydro-3H-benzothiopheno[2,3-d]pyrimidin-2-yl)sulfanyl]acetaldehyde having the formula:
  • Rl is a carboxyl group ( — C(O) — OH), a hydrogen ( — H — ), a trifluoromethyl group ( — C(F 3 )), a phenol group ( — PIi — OH), an — SO 3 group, or a hydroxyl ( — OH) group;
  • R2 is a trifluoromethyl phenyl group ( — Ph — CF 3 ), a methylphenyl ( — PIi — CH 3 ), — PIi — CH 2 — OH, a phenol group (— Ph-OH), a furan or a thiophene;
  • R3 is a-NH2, a -N(CH3)2, a -NH-(C(CH3)2), a -NH-Ph-meta-CH3; and wherein the composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 120 kD forms to 60 kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • Another aspect of the disclosure is drawn to a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 4-phenyl-5-[(4-phenyl-5-sulfanyl-l,2,4-triazol-3-yl)methyl]-l,2,4-triazole-3-thiol having the formula:
  • Rl is — CH2 — Ph — CH3, — CH2— Ph-OH, — CH2— Ph- COOH, — CH2— C(O) — Ph- NH2, — CH2— C(O)- Ph- NH- C(O) - CH3, or— CH2— C(O) - N(Ph)(C(CH3)2; wherein R2 is — OH, — C(CH3)3, — CH2-C(O)-OH, — F or — CF3; and wherein the composition is effective to inhibit production of beta amyloid monomer or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control.
  • Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) amount or promoting the degradation of existing A ⁇ (e.g., monomer) amount.
  • a ⁇ e.g., monomer
  • Another aspect of the disclosure is a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 4-phenyl-5- [(4-phenyl-5-sulfanyl-l,2,4-triazol-3-yl)methyl]-l,2,4-triazole-3-thiol having the formula:
  • Rl is — CH2 — Ph — CH3, — CH2— Ph-OH, — CH2— Ph- COOH, — CH2— C(O) — Ph- NH2, — CH2— C(O)- Ph- NH- C(O) - CH3, or— CH2— C(O) - N(Ph)(C(CH3)2; wherein R2 is — OH, — C(CH3)3, — CH2-C(O)-OH, — F or — CF3; and wherein the composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 120 kD forms to 60 kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an N-(benzylideneamino)-2-[(4,5-diphenyl- 1 ,2,4-triazol-3-yl)sulfanyl]acetamide having the formula:
  • Rl is — CH(CH3)2, — CF3, — O — Ph,
  • composition is effective to inhibit production of beta amyloid monomer amount or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control.
  • Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of
  • a ⁇ e.g., monomer
  • promoting the degradation of existing A ⁇ e.g., monomer
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an N- (benzylideneamino)-2-[(4,5-diphenyl-l ,2,4-triazol-3-yl)sulfanyl]acetamide having the formula:
  • Rl is — CH(CH3)2, — CF3, — O — Ph,
  • composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an N-[(2-benzyloxy-l -naphthyl)methyleneamino]-2-(2,4-dichlorophenoxy)acetamide having the formula:
  • Rl is — CH((CH3)2)
  • composition is effective to inhibit production of beta amyloid monomer or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control.
  • Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or promoting the degradation of existing A ⁇
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an N-[(2- benzyloxy- 1 -naphthyl)methyleneamino]-2-(2,4-dichlorophenoxy)acetamide having the formula:
  • Rl is — CH((CH3)2)
  • composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 120 kD forms to 60 kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 4-hydroxy-l-[2-(lH-indol-3-yl)ethyl]-2H-pyrrol-5-one having the formula:
  • Rl is — C(O) — C(CH3)3,
  • composition is effective to inhibit production of beta amyloid monomer amount or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control.
  • Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or promoting the degradation of existing A ⁇ (e.g., monomer).
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 4-hydroxy-l- [2-(lH-indol-3-yl)ethyl]-2H-pyrrol-5-one having the formula:
  • Rl is — C(O) — C(CH3)3,
  • composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 5-(4-quinolyl)-4H-l,2,4-triazole-3-thiol having the formula:
  • Rl is a phenyl ( — Ph),
  • Another aspect of the disclosure is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 5-(4- quinolyl)-4H-l,2,4-triazole-3-thiol having the formula:
  • Rl is a phenyl ( — Ph), — CH2— C(O)-OH, —Cm— para— Ph-C(O) — OH, para— Ph-Cl or para— Ph-C(O) —OH; wherein R2 is a para— Ph- OH, para— Ph- O— CH3, — CH2— para— Ph- NH2, CH2— p ⁇ r ⁇ — Ph- NH-C(O) — CH3 or -Ph; wherein R3 is apara— Ph-OH, para— Ph- NH2— CH3, — C(CH3)3, — CH2— para— Ph- CH((CH3)2), or para — Ph — CH3; and wherein the composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 120 kD forms to 60 kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • compositions comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 3-[2-(4-oxo-5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-3-yl)ethyl]-5,6,7,8- tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-one having the formula:
  • Rl is a. para — Ph — O — CH3, a CH2- para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, or a hydrogen (-H); wherein R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H); wherein R3 is — CH3, — C((CH3)3), -C(O) — O— CH2— CH3, or a hydrogen (-H); and wherein the composition is effective to inhibit production of beta amyloid monomer amount or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control. Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or promoting the degradation of existing A ⁇ (e.g., monomer).
  • Another aspect of the disclosure is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 3-[2-(4-oxo- 5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-3-yl)ethyl]-5,6,7,8- tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-one having the formula:
  • Rl is a para — Ph — O — CH3, a CH2- para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, or a hydrogen (-H);
  • R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H);
  • R3 is — CH3, — C((CH3)3), -C(O) — O— CH2— CH3, or a hydrogen (-H); and wherein the composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 12O kD forms to 6O kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an N-hexyl-5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-amine having the formula:
  • Rl is a para — Ph — O — CH3, a CH2- para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, or a hydrogen (-H); wherein R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H); wherein R3 is — CH3, — C((CH3)3), -C(O) — O— CH2— CH3, or a hydrogen (-H); and wherein the composition is effective to inhibit production of beta amyloid monomer or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control. Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or promoting the degradation of existing A ⁇ (e.g., monomer).
  • a ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of an N-hexyl- 5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-amine having the formula:
  • Rl is a para — Ph — O — CH3, a CH2- para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, or a hydrogen (-H);
  • R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H);
  • R3 is — CH3, — C((CH3)3), -C(O) — O— CH2— CH3, or a hydrogen (-H); and wherein the composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 12O kD forms to 6O kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 2-hydroxy-N-(l-naphthylmethyleneamino)acetamide having the formula:
  • R2 is an isopropyl, a benzyl, a parachlorobenzyl, or an ethyl; wherein R3 is
  • composition is effective to inhibit production of beta amyloid monomer or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control.
  • Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or promoting the degradation of existing A ⁇ (e.g., monomer).
  • Another aspect of the disclosure is a pharmaceutical composition
  • a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 2-hydroxy-N- (l-naphthylmethyleneamino)acetamide having the formula:
  • R2 is a isopropyl, benzyl, parachlorobenzyl, or ethyl; wherein R3 is
  • composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 IcD (e.g., degrading 120 kD forms to 60 kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 3-(p-tolyl)-5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-one having the formula:
  • Rl is a. para — Ph — O — CH3, a CH2 — para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, — S— CH2— C(O) — N— Ph- meta— CH3, or a hydrogen (-H); wherein R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H); wherein R3 is — CH3, — C((CH3)3), -C(O) — O — CH2 — CH3, or a hydrogen ( — H); and wherein the composition is effective to inhibit production of beta amyloid monomer or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control. Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or promoting the degradation of existing A ⁇
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a 3-(p-tolyl)- 5,6,7,8-tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-one having the formula:
  • Rl is a para — Ph — O — CH3, a CH2 — para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, — S— CH2— C(O) — N— Ph- meta— CH3, or a hydrogen (-H); wherein R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H); wherein R3 is — CH3, — C((CH3)3), -C(O) — O — CH2 — CH3, or a hydrogen ( — H); and wherein the composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 120 kD forms to 60 kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a (5Z)-5-[(3,4-diethoxyphenyl)methylene]-3-methyl-2-thioxo-thiazolidin-4-one having the formula:
  • Rl is — Ph, — CH2 — (C(C1)3); wherein R2 is CH2— Ph, — C— ((CH3)3), — C(O)- NH2, -C(O)-OH, — CH2— OH; and wherein the composition is effective to inhibit production of beta amyloid monomer or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control.
  • Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or promoting the degradation of existing A ⁇ (e.g., monomer).
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a (5Z)-5-[(3,4- diethoxyphenyl)methylene]-3-methyl-2-thioxo-thiazolidin-4-one having the formula:
  • composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 120 kD forms to 60 kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a hydrotris (3-(4-cumenyl)-5-methylpyrazol-l-yl) borate having the formula:
  • composition is effective to inhibit production of beta amyloid monomer or promote degradation of A ⁇ monomer amount by at least about 5% when compared to a control.
  • Inhibiting A ⁇ amount is achieved by any combination of inhibiting the production of A ⁇ (e.g., monomer) or promoting the degradation of existing A ⁇ (e.g., monomer).
  • composition comprising a pharmaceutically acceptable carrier and a therapeutically effective amount of a hydrotris (3- (4-cumenyl)-5-methylpyrazol-l-yl) borate having the formula:
  • composition is effective to inhibit beta amyloid aggregation into A ⁇ multimers or to promote the degradation of A ⁇ multimers by at least about 5% when compared to a control.
  • the composition is effective to inhibit beta amyloid aggregation in A ⁇ forms of at least 40 kD or to promote the degradation of A ⁇ forms of at least 40 kD (e.g., degrading 120 kD forms to 60 kD).
  • kits comprising the composition described in the preceding two paragraphs, any of the methods of treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any of the methods of ameliorating a symptom of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, any method of inhibiting or preventing the onset of a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, described herein wherein the pharmaceutical composition of the preceding two paragraphs is administered, a use of the composition of the preceding two paragraphs for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself, and a use of the composition of the preceding two paragraphs in the preparation of a medicament for treating a disease or disorder associated with Alzheimer's disease, such as Alzheimer's disease itself.
  • Embodiments of the various aspects of the disclosure drawn to compositions useful to inhibit A ⁇ aggregation and to methods of preventing, treating or ameliorating a symptom of a disease associated with Alzheimer's disease, such as Alzheimer's disease itself, comprise the inhibition of the formation, and/or the promotion of degradation, of A ⁇ multimers, including but not limited to A ⁇ multimers of at least 40 kilodaltons.
  • the composition inhibits the formation of, or promotes the degradation of, an A ⁇ aggregate that is a A ⁇ multimer, including but not limited to A ⁇ multimers that have a molecular weight of at least 40 kilodaltons.
  • the method inhibits the formation of, or promotes the degradation of, an A ⁇ aggregate that is a A ⁇ multimer, including but not limited to A ⁇ multimers that have a molecular weight of at least 40 kilodaltons.
  • Figure 1 illustrates a schematic of a process that is used to identify potent compounds that lower in vivo beta amyloid amounts.
  • Figure 2 illustrates an alternate embodiment of a process that is used to identify potent compounds that lower in vivo beta amyloid amount and/or A ⁇ anti-aggregation activity.
  • Figure 3 shows chemical compounds (i.e., compound no. 1, A2641934 (Formula 5); compound no. 3, A2739476 (Formula 1); and compound no. 6, A3414817 (Formula 1 1)) exhibiting anti-oligomerization activity by in vitro aggregation assay.
  • A Western blot analysis of HMW A ⁇ 42 oligomers in the presence of novel compounds.
  • B Quantification of HMW A ⁇ 42 oligomers.
  • Figure 4 shows identification of chemical compounds exhibiting anti- oligomerization activity by in vitro aggregation assay.
  • Four compounds (L 176117, A3932292 (Formula 6)); (7216540379, A4971549 (Formula 8)); (863536, A6239807 (Formula 9)); and (19-2800, A 1862443 (Formula 12)) were subjected to in vitro A ⁇ aggregation assay and found to have anti-A ⁇ aggregation activity.
  • the lower panel discloses the results of photo-induced cross-linking of unmodified proteins (PICUP) assays confirming the anti-oligomeric A ⁇ activity of compounds identified using in vitro anti-aggregation assays.
  • PICUP photo-induced cross-linking of unmodified proteins
  • Figure 5 provides the results of a short-term in vivo feasibility study in the TgCRND ⁇ mouse model of AD.
  • Compound 1 (A2641934, Formula 5) and Compound 3 (A2739476, Formula 1) were chosen for the short-term feasibility study.
  • A Total brain A ⁇ 42 and A ⁇ 40 in TgCRND8 mice treated with either Compound 1 (A2641934, Formula 5) or Compound 3 (A2739476, Formula 1).
  • B High molecular weight (HMW) soluble oligomeric content in the brain by Western blot analysis.
  • Figure 6 shows the results of an assay of anti-oligomerization activity by in vitro aggregation assay.
  • Compound 1 (A2641934, Formula 5), Compound 3 (A2739476, Formula 1), and Compound No. 6, A3414817 (Formula 11) were subjected to the assay.
  • A Western blot analysis of HMW A ⁇ 42 oligomers in the presence of the compounds.
  • B Quantification of HMW A ⁇ 42 oligomers.
  • Figure 7 reveals the results of in vitro anti-aggregation assays of compounds L176117 (i.e., A3932292); 7216540379 (i.e., A4971549); 863538 (i.e., A6239807); and 19- 2800 (i.e., Al 862443).
  • the data confirms that each of the four compounds identified as probables for anti-aggregation activity using MODEL 1 v 5 did exhibit A ⁇ anti-aggregation (anti-oligomerization) activity.
  • the technology disclosed herein uses Forward EngineeringTM, which is based on molecular topology (MT), to identify and/or design novel compounds in chemical classes unrelated to current anti-AD agents. These compounds exhibit dual anti-amyloid/anti- aggregation activity to enable (1) prevention and/or reduction of A ⁇ peptides, (2) halting A ⁇ deposition and/or (3) reduction of soluble A ⁇ 42.
  • MT molecular topology
  • treatment is defined to include preventing, lowering, stopping, or reversing the progression or severity of a condition or symptom being treated.
  • the present invention includes both medical therapeutic and/or prophylactic administration, as appropriate.
  • an effective amount is an amount of a pharmaceutical or nutraceutical composition that is effective in treating the target condition or symptom.
  • An effective of amount of any of the compounds disclosed in Tables 1 to 3 used to treat AD is an amount sufficient to reduce A ⁇ 40, A ⁇ 42, HMW soluble A ⁇ 40 fragments, HMW A ⁇ 42 fragments, or any combination of these.
  • the terms “A ⁇ 40” or “Abeta40” or “A ⁇ 40” each refer to the 40 amino acid peptide or protein fragment that is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function primarily in the endoplasmic reticulum.
  • APP amyloid precursor protein
  • a ⁇ 40 or “Abeta40” or “A ⁇ 40” each are meant to refer to the peptides of 40 amino acids that appear in the amyloid plaques in the brains of Alzheimer's disease patients.
  • the terms “A ⁇ 40” or “Abeta40” or “A ⁇ 4 o” are also used interchangeably throughout the specification.
  • amyloid precursor protein or "APP” refers to a transmembrane glycoprotein of undetermined function that can be cleaved or processed by ⁇ - , ⁇ - and ⁇ -secretases to generate A ⁇ protein of 39 to 43 amino acids in length.
  • a ⁇ protein refers to the C-terminal end of a beta amyloid peptide generated by cleaving within the transmembrane region of APP and generating any number of isoforms of 39-43 amino acid residues in length.
  • Ab protein as used herein, is meant to encompass the two most common isoforms, A ⁇ 40 and A ⁇ 42.
  • a ⁇ protein is meant to encompass peptides of 39-43 amino acids that appear to be the main constituent of amyloid plaques in the brains of Alzheimer's disease patients.
  • the terms “A ⁇ 42” or “Abeta42” or A ⁇ 42 " each refer to the 42 amino acid peptide or protein fragment that is formed after sequential cleavage of the amyloid precursor protein (APP), a transmembrane glycoprotein of undetermined function primarily in the trans-Golgi network.
  • APP amyloid precursor protein
  • a ⁇ 42 or “Abeta42” or A ⁇ 42 " are each meant to refer to the peptides of 42 amino acids that appear in the amyloid plaques in the brains of Alzheimer's disease patients.
  • the terms “A ⁇ 42” or “Abeta42” or “A ⁇ 42 " are also used interchangeably throughout the specification.
  • HMW soluble A ⁇ 40 species or “HMW soluble A ⁇ 40 fragments” refer to the extracellular soluble high-molecular-weight A ⁇ 40 peptides or fragments that are formed upon oligomerization and/or aggregation of A ⁇ 40 peptides and have been implicated in the etiology of spatial memory reference deficits during progression of AD.
  • high molecular weight is meant A ⁇ 40 protein, A ⁇ 40 peptide, A ⁇ 40 oligomers, A ⁇ 40 peptide fractions and/or A ⁇ 40protein fractions that have a molecular weight of more than about 40 kilodaltons.
  • HMW soluble A ⁇ 42 species or “HMW soluble A ⁇ 42 fragments” refer to the extracellular soluble high-molecular-weight A ⁇ 42 peptides or fragments that are formed upon oligomerization and/or aggregation of A ⁇ 42 peptides and have been implicated in the etiology of spatial memory reference deficits during progression of AD.
  • high molecular weight is meant A ⁇ 42 protein, A ⁇ 42 peptide, A ⁇ 42 oligomers, A ⁇ 42 peptide fractions and/or A ⁇ 42protein fractions that have a molecular weight of more than about 40 kilodaltons.
  • AD Alzheimer's disease
  • Major pathological features of AD include deposition and accumulation of Abeta amyloid protein (also known as senile or neuritic plaque); the aggregation of highly phosphorylated tau proteins in neurons known as neurofibrillary tangles; and the loss of neurons.
  • anti-aggregation refers to the ability of a compound to inhibit aggregation into A ⁇ multimers or to inhibit aggregation into higher molecular weight species of more than about 40 kilodaltons, or to promote the degradation of A ⁇ multimers or the degradation of HMW species of A ⁇ of greater than about 40 kD.
  • An example of promoting degradation is an increase in conversion of, e.g., a 120 kD form of A ⁇ multimer into an 80 kD form of A ⁇ multimer, relative to a control.
  • anti-oligomerization refers to the ability of a compound to inhibit oligomerization into A ⁇ multimers or to inhibit oligomerization into higher molecular weight species of more than about 40 kilodaltons, or to promote degradation of A ⁇ multimers or HMW species of A ⁇ of greater than about 40 kD. For example, promoting the degradation of an A ⁇ multimer of 90 kD into an A ⁇ multimer of 50 kD demonstrates an anti- oligomerization activity.
  • free drug refers to solid particles consisting essentially of the compounds disclosed in Tables 1-3 and to chemically synthesized copies of any of the compounds disclosed in Tables 1-3.
  • sustained compound refers to a compound or composition that prevents or retards the settling of solid particles of any of the compounds disclosed in Tables 1 to 3 from a liquid suspension of the particles.
  • solution refers to solid particles of any of the compounds disclosed in Tables 1-3 dispersed in a liquid carrier.
  • the term “suspension” also refers to a liquid composition containing free drug particles of any of the compounds disclosed in Tables 1-3.
  • solution refers to a liquid composition having any of the compounds disclosed in Tables 1-3 dissolved therein.
  • solvate refers one or more molecules of a solute associated with a molecule of a compound, such as the compounds disclosed in Tables 1-3 associated with a molecule of water or acetic acid.
  • solid oral dosage form as used herein is used in a general sense to refer to pharmaceutical compositions administered orally.
  • General oral dosage forms are recognized by those skilled in the art to include such forms as tablets and capsules, for example.
  • d90 The nomenclature describing the particle size is commonly referred to herein as the "d90."
  • a d90 of 40 means that at least 90% of the particles have a particle size less than 40 microns.
  • oral dosage form as used herein is used in a general sense to refer to pharmaceutical compositions administered via the mouth.
  • Oral dosage forms are recognized by those skilled in the art to include such forms as liquid formulations, tablets, capsules, and gelcaps.
  • Solid oral dosage forms are recognized by those skilled in the art to include such forms as tablets, capsules, gelcaps and aerosols.
  • compositions are pharmaceutically acceptable.
  • pharmaceutically acceptable means carriers, excipients, diluents, salt forms of any of the compounds disclosed in Tables 1-3 or any chemically synthesized copy of any of the compounds disclosed in Tables 1-3 and other formulation ingredients that are compatible with all other ingredients of a composition, and are not deleterious to an individual treated with the composition.
  • IC 50 as used herein is the measure of potency of a compound to inhibit beta amyloid amount and/or A ⁇ anti-aggregation activity.
  • the IC 50 is the concentration of a compound that results in 50% beta amyloid production in a single dose-response experiment. Determining the IC 5O value for a compound is readily carried out by known in vitro methodology generally described in Y. Cheng et al., Biochem. Pharmacol., 22, pp. 3099-3108 (1973).
  • the term "activity profile” as used herein refers to capable of modulating a specific molecular target to result in a therapeutic effect. Furthermore, the term “activity profile”, as used herein refers to exertion of biological efficacy or activity against one or more molecular targets in vitro or in vivo. [0092] As used herein, the term “therapeutically effective amount” refers to an amount of the biologically active extracts which is sufficient to alleviate, ameliorate, prevent, and/or clear the symptoms and/or the pathology of a condition or disease contemplated to be treatable by monomelic and oligomeric beta amyloid inhibitors.
  • indices or “topological indices” or “TIs” or “topological descriptors” each refer to the algorithms that are used mathematically convert a topological signature of a compound into a single characteristic number.
  • indices or “topological indices” or “TIs” or “topological descriptors” are used interchangeably throughout the specification.
  • drugability refers to the feasibility of a target to be effectively modulated by a small molecule ligand that has appropriate (a) potency, (b) selectivity, (c) specificity, (d) defined mechanism of action (MOA), (e) ADME-Tox properties, (f) relatively easy synthesis route, and (g) patentability to be developed into a drug candidate with appropriate properties for the desired therapeutic use.
  • drugs given by other routes usually have an absolute bioavailability of less than one (F ⁇ 1).
  • Oral bioavailability predictions are expressed in percentage (%) of orally administered drug that reaches systemic circulation. In general, values between 0 and 100% are acceptable for therapeutic agents. Higher values are desired for orally administered drugs.
  • Urine excretion refers to the amount of a drug that is eventually excreted unchanged in the urine. Urine excretion is expressed as a percentage of the administered dose. In general, values between 0 and 100% are acceptable for therapeutic agents.
  • bound in plasma refers to the degree a drug is bound to the proteins within blood plasma. The less bound a drug is, the more efficiently it can traverse cell membranes or diffuse. Values between 0 and 100% are acceptable. Lower values are generally desired for therapeutic agents.
  • the term "clearance” refers to a measurement of the renal excretion ability or the inverse of the time constant that describes a removal rate of a substance from the body divided by its volume of distribution (or total body water).
  • the clearance of a drug generally varies as a function of body size, therefore acceptable values for therapeutic agents have a wide range.
  • the clearance of a drug should generally show an intermediate value (not too high and not too low). If the clearance is high (above 200) then there may be low plasmatic concentration. If clearance is low (below 10) there may be higher toxicity.
  • volume of distribution refers to the volume into which the amount of a drug would need to be uniformly distributed in order to produce the observed blood concentration. Volume of distribution generally varies as a function of body size, therefore acceptable values for therapeutic agents have a wide range.
  • the term “elimination half-life- ⁇ ” refers to the time necessary to reduce the drug concentration up to 50% of initial concentration.
  • the term “beta” is used since it is calculated only for bicompartmental drugs which have two simultaneous rates of elimination because the elimination process is biexponential. In general, values between 0 and 48 hours are generally acceptable for therapeutic agents. Ideally the period should be 24 hours. Too few hours imply inefficacy and too many hours imply toxicity.
  • peak life refers to the time required to achieve a maximal concentration. The peak time occurs when the rate of absorption equals the rate of elimination from the reference compartment. The peak life depends on the rate of drug absorption into blood from the site of administration and the rate of elimination. Lower values are generally desired for therapeutic agents.
  • peak concentration (C m3x ) refers to the highest concentration of drug in plasma that would be encountered in a given dose interval. Lower values are generally desired for therapeutic agents.
  • logP refers to a measure of the lipophilic character of the compound (the larger the logP the more lipophilic).
  • P is a ratio of octanol to water partition.
  • Optimal values for therapeutic agents are between about 3 and about 7.
  • water solubility index (WSI) refers to the solubility of a substance in water. In general, the larger value, the better water solubility index. Furthermore, WSI >1 implies solubility > 10 g/L. Variable, larger values are generally desired for therapeutic agents.
  • LD50 oral rat (mg/Kg)
  • LD50 oral rat (mg/Kg)
  • LD50, oral rat is a measure of acute toxicity. In general, higher values are generally desired for therapeutic agents.
  • LD50IV rat (mg/Kg)
  • rat (mg/Kg) refers to the median lethal dose in rats using intravenous administration at one time, hi general, higher values are always desired for therapeutic agents.
  • NOEL oral, rat refers to the non-observed effect level (NOEL) or the highest concentration of a compound where no detectable biological effect (of any sort) is observed.
  • the term "carcinogenicity” refers to the potential for a chemical agent to cause cancer. A determination of Yes, Probable or Possible indicates that, while the potential is low, chronic exposure needs further evaluation to make a full determination of toxicity. Potency values greater than zero (> 0) may indicate a compound as being carcinogenic as compared to Aflatoxin B 1.
  • mutagenicity refers to the potential for a chemical agent to cause a change in genetic material and cause mutations above the natural background level. A determination of Yes, Probable or Possible indicates that, while the potential is low, chronic exposure needs further evaluation to make a full determination of toxicity. Potency values > 0 may indicate a compound as being mutagenic as compared to aminoanthracene.
  • the term “teratogenicity” refers to the ability to cause defects in a developing fetus. This is distinct from mutagenicity, which causes genetic mutations in sperms, eggs or other cells. A determination of Yes, Probable or Possible indicates that, while the potential is low, chronic exposure needs further evaluation to make a full determination of toxicity. An activity reference is not included for this property.
  • neurotoxicity refers to the potential for a chemical agent to affect and/or cause damage to the nervous system. A determination of Yes, Probable or Possible indicates that, while the potential is low, chronic exposure needs further evaluation to make a full determination of toxicity. An activity reference is not included for this property.
  • hematoxicity refers to the potential for a chemical agent to damage red blood cells, disrupt blood clotting, cause organ degeneration or general tissue damage. An activity reference is not included for this property.
  • cytotoxicity refers to the potential for a chemical agent to cause damage to cells. In general, variable, larger values are desired for therapeutic agents.
  • the term "therapeutic index” refers to the therapeutic index (also known as therapeutic ratio), or a comparison of the amount of a therapeutic agent that causes the therapeutic effect to the amount that causes toxic effects. Quantitatively, it is the ratio given by the dose required to produce the toxic effect divided by the therapeutic dose. Variable, larger values generally above 10 are desired for therapeutic agents.
  • blood-brain-barrier refers to the dense layer of endothelial cells that create a barrier between the blood and brain parenchyma. Data in the form of log (brain/blood) values for commercially successful marketed drugs was used to create the BBB filter.
  • percent (%) success rate refers to the number of compounds determined to have positive experimental activity when compared to the total number of compounds tested for each model.
  • the disclosure provides compounds in chemical classes unrelated to current AD compounds that have the activity profile of inhibiting beta amyloid production, deposition, and/or formation of extracellular high-molecular- weight (HMW) oligomeric A ⁇ 40 and/or A ⁇ 42 species and are useful for treating AD.
  • the present invention further includes methods of administering the pharmaceutical compositions to inhibit beta amyloid production, deposition and/or formation of extracellular HMW beta amyloid species.
  • HMW high-molecular- weight
  • MT allows for the inclusion of multiple bioactive properties. Hence, identification of multi-functional single-agent compounds is possible.
  • the Forward EngineeringTM platform uses and expands upon the principles governing molecular connectivity theory of numerically characterizing molecular structure, or in the present case, active anti-AD drugs/agents using topological descriptors to build each model. Topological characterization has been shown to embody sufficient molecular information to provide strong correlation to therapeutic efficacy. This characterization method is necessary because molecular topology (MT) is founded on the assumption that (1) molecular formulas can be mathematically characterized and (2) mathematically determined parameters of molecules can be correlated with the molecules' experimentally measured properties (e.g., IC 50 values).
  • TIs topological indices
  • Algorithms procedures for converting the topological structures of a molecule into a single characteristic number.
  • TIs topological indices
  • Algorithms procedures for converting the topological structures of a molecule into a single characteristic number.
  • the core features of Forward EngineeringTM are speed, low cost, risk mitigation Absorption, Distribution, Metabolism, Excretion & Toxicity (ADME/Tox) evaluation, and novel compound discovery.
  • FIG. 1 A schematic of the process that is used to identify potent compounds with (1) in vitro or in vivo A ⁇ lowering and/or (2) A ⁇ anti-aggregation activity is illustrated in Figure 1.
  • at least one predictive in silico model 20 based on MT is built.
  • Model 20 is based on data from in vitro assay systems used to evaluate beta amyloid amount- lowering activity.
  • model 20 includes the molecular topological digital fingerprint for in vitro beta amyloid amount-lowering activity.
  • model 20 is used to screen or analyze at least one chemical compound database 30 to identify a plurality of compounds having the molecular topological digital fingerprint contained in model 20.
  • compounds are evaluated in standard in vitro and/or in vivo evaluation systems 40 to confirm beta amyloid amount-lowering activity.
  • two compounds 50 and a positive control, losartan are disclosed in Table 1 below.
  • positive control is meant any agent already known to have anti-AD activity, such as beta amyloid amount-lowering activity, anti-aggregation activity or any other experimental or current agent used in the treatment of AD.
  • Column 1 of Table 1 discloses an assigned identification (ID) number while column 2 includes the molecule number.
  • Column 3 of Table 1 contains the chemical class while column 4 includes the chemical 2-D structure.
  • Column 5 of Table 1 contains the molecular weight while column 6 contains one example of a preferred vendor.
  • Column 7 of Table 1 contains the catalog ID number for the preferred vendor of column 6 while column 8 includes the predicted amount- lowering activity for beta amyloid (% Ctrl Abetal) at the lOO ⁇ M as a % of the control (% control is 100%). % Ctrl Abetal is a composite measure of A ⁇ 40 and A ⁇ 42 amount-lowering activity. Table 1 further includes the positive control losartan that was identified as being active by model 20 which demonstrates that model 20 is good. Compounds assigned ID Nos. 1 and 7 (A2960599 and A1876199, respectively) are predicted to be 9.6 and 12.2, respectively versus 26 for losartan at 100 ⁇ M.
  • each compound is associated with a biological property, i.e., %A ⁇ -lowering or oligomeric A ⁇ anti-aggregation activity (when compared to a control); is associated with the corresponding 2-D formula (which was used as input data for topological characterization).
  • Good representative set of agents includes a very heterogeneous group of structurally diverse (1) A ⁇ lowering compounds and/or (2) A ⁇ anti-aggregation compounds and a group of inactive compounds that are structurally similar to (1) and (2) compounds above with respect to atoms, heteroatoms, bonds and cycles.
  • training set of compounds is generally provided in the form of a mol.file of the 2-D structure or molecular formula of experimental/current agents, it is to be understood that the training set can be provided in any general format, such as in an excel spreadsheet, powerpoint slide or the like.
  • Model building using the Forward EngineeringTM platform generally includes the steps of (1) selecting relevant topological descriptors for the training set of compounds, (2) characterizing the compounds with the topological descriptors, (3) mapping the topological descriptors to activity (or active and inactive compounds) and (4) cross-validating the model after the training set of compounds have been programmed into Forward EngineeringTM.
  • the Forward EngineeringTM platform typically includes one or more indices (Topological Indices or TIs) that are used to identify the molecular signature of a compound.
  • TIs are derived from procedures (algorithms) for converting the topological structures of a molecule into a single characteristic number. In general, there are over 400 published TIs that can be used for MT. In one example, four main types of topological indices that are correlated with therapeutic activity are used to analyze the training set of compounds.
  • the TIs include (a) connectivity indices that take into account the weight of the bond and use the diagonal of the matrix; (b) topological charge indices that evaluate the charge transfer between pairs of atoms and therefore the global charge transfers in the molecule using the distance matrix; (c) geometrical indices where information regarding vertices, bonds, path walks, path lengths, accessibility, volume, Weiner and several sub-graphs are used; and (d) electrotopological or atomic indices in which the atomic weights are used.
  • the TIs that are appropriate for characterizing the training set of A ⁇ -lowering or A ⁇ anti-aggregation agents are selected using an algorithm built into Forward EngineeringTM. Additional information can be found in Galvez et al, J. Chem. Inf.
  • each compound is mathematically characterized by the selected TIs using equations reported in Galvez et al which also describe rigorous validation of the use of TIs in the process of drug discovery. These equations are not included here due to space considerations.
  • the end result is the conversion of the inputted 2-D mol. files into well-defined topological sets of numerical values.
  • the next step is to create a discriminant function (DF) between these numerical values and the analyzed A ⁇ lowering or anti-aggregation activity as reported in IC50s, ED50s, and the like, using Forward EngineeringTM.
  • the discriminant functions are obtained by applying the "linear discriminant analysis" (LDA) or other statistical method as needed to all the different groups of compounds.
  • LDA linear discriminant analysis
  • the model is tested to make sure that the DF (model) works.
  • the test is performed by analyzing a group of known active (positive control) and inactive (negative control) A ⁇ amount-lowering compounds to see if the model is able to discern activity. Should the model be capable of discerning activity, the model is deemed good and capable of identifying compounds in other chemical classes with the same topological signature.
  • the test is performed by screening a chemical compound database and seeing if the compounds selected represent known active compounds. Should the model be capable of selecting known active compounds, the model is deemed good and capable of identifying compounds in other chemical classes with the same topological signature.
  • Suitable examples of databases that can be analyzed to confirm the predictive capability of a model, select and/or identify potent compounds include Repurposing Databases that contain (1) past and current commercial drugs, (2) successful Phase II candidates, (3) candidates in Phase III currently in the development pipeline as these are already validated for safety in humans and/or (4) Phase HI candidate failures that did not meet the primary efficacy endpoints, but are otherwise safe, Existing Chemical Databases, such as Available Chemical Database (ACD) and Screening Chemical Database (SCD); Natural Bioactives database, such as Dictionary of Natural Products (DNP), or Isolates of Natural Products (INP).
  • ADME/Tox filters that are also included as part of Forward EngineeringTM. Pre-qualification is accomplished by application of ADME/Tox filters to compound selections.
  • the ADME/Tox filters simulate the evaluation of potent hits using diverse in vitro and in vivo ADME/Tox assays during conventional drug discovery.
  • the ADME/Tox filters applied to compounds according to the disclosure are (1) based on successfully marketed and rigorously tested commercial drugs and/or (2) in vivo human clinical data.
  • the ADME/Tox filters applied to compounds according to the disclosure are a component of Forward EngineeringTM.
  • ADME/Tox filters that are included as part of Forward Engineering include, but are not limited to, oral Availability (%), half-life- ⁇ (hours), urinary excretion (%), peak time (hours), bound in plasma (%), Cmax (mg/L), clearance (L/h), LogP, volume of distribution (L), water solubility, LD 50 oral (rat (mg/Kg)), teratogenicity, LD 5 o IV (rat (mg/Kg)), neurotoxicity, NOEL Oral (rat (mg/Kg/day)), hematoxicity, carcinogenicity, cytotoxicity MNTC ( ⁇ M), mutagenicity, therapeutic index, and/or the blood-brain-barrier (BBB).
  • an output set of compounds is generated.
  • the output set includes known active and inactive compounds/agents
  • the output set of compounds generally includes 80 to 100 compounds.
  • the solvent-only sample control e.g., dimethyl sulfoxide (DMSO)
  • each compound is associated with a predictive efficacy value in units of % Ctrl Abetal at a concentration of lOO ⁇ M.
  • Percent Ctrl Abetal is a composite value for A ⁇ 40- and A ⁇ 42 amount-lowering activity as a percent of control (solvent), hi another example, the solvent- only control is DMSO and the predicted efficacy for DMSO is 100%. This means that the solvent-only sample does not lower beta amyloid amount in vitro or allows 100% of beta amyloid amount-lowering activity to occur.
  • the positive control compound/agent generally comprises from about 5% to about 100% activity, based on the activity of a solvent-only control, hi one embodiment, the positive control comprises about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 13%, about 12%, about 10%, about 9%, about 5% or about 2% activity of the (solvent) control, hi another embodiment, the positive control is losartan and the predictive value comprises about 26% of the solvent-only control.
  • the positive control comprises about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 13%, about 12%, about 10%, about 9%, about 5%, about 2%, about 1% or less than about 1% activity of the DMSO solvent-only sample.
  • Test compound concentrations comprise about l ⁇ M, about lO ⁇ M, about 50 ⁇ M or about lOO ⁇ M during evaluation.
  • Compounds can comprise from about 0.1 % to about 200%, from about 0.5% to about 150%, from about 1% to about 100%, from about 5% to about 95%, or from about 10% to about 90% of the activity of the positive control.
  • compounds comprise about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5% or about 2% of activity with respect to the solvent-only control activity of about 100%.
  • compounds lower or reduce beta amyloid levels and/or activity when compared to the original beta amyloid levels and/or activity present in untreated samples or patients.
  • compounds lower or reduce beta amyloid levels and/or activity to less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to, or treated with, the compound.
  • compounds lower or reduce or inhibit aggregation of monomelic and/or dimeric beta amyloid peptides.
  • compounds lower or reduce or inhibit monomelic and/or dimeric beta amyloid peptide aggregation to by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% activity with respect to the solvent-only control activity demonstrating about 100% activity.
  • compounds comprise more than about 100%, about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 13%, about 12%, about 10%, about 9%, about 5%, about 2%, less than about 2%, less than about 1 % predicted or experimental activity when compared to the predicted or experimental activity of a solvent-only control sample, such as DMSO, and/or known active compounds and/or agents, such as abienol, arthonionic acid, candesartan, diazoxide, erfocalciferol, euphol, furosemide, losartan, nitrendipine, pristimerol diacetate, psoromic acid, or valsartan.
  • a solvent-only control sample such as
  • the percent (%) success rate of each model can range up to about 85%.
  • the % success rate comprises from about 1% to about 85%, from about 2% to about 85%, from about 1% to about 80%, from about 1% to about 75%, from about 2% to about 75%, from about 5% to about 75%, or from about 5% to about 75%.
  • the % success rate is about 14%, about 26%, about 37%, about 40%, about 47%, about 53%, about 59% or about 73%.
  • pre-qualified compounds with in vivo beta amyloid amount-lowering activity in chemical classes unrelated to current beta amyloid-lowering agents and/or AD medicines were obtained according to the process 100 illustrated in Figure 2.
  • MODEL IA 101 was built using a training set that comprises 156 cardiovascular drugs associated with in vitro A ⁇ amount-lowering activity.
  • the training set comprising 156 cardiovascular drugs was uploaded into Forward EngineeringTM prior to building MODEL IA 101.
  • MODEL IA 101 was effective in predicting compounds able to lower beta amyloid levels in vitro.
  • MODEL IA lOl was used to analyze chemical compound databases and to identify compounds in new chemical classes that have A ⁇ 40 - and/or A ⁇ 42 amount-lowering activity (see Examples). Thereafter, the compounds are assayed for activity.
  • MODEL IB 102 is also built using a training set that comprises 54 antihypertensive drugs associated with in vitro A ⁇ amount-lowering activity (see Examples). The training set comprising 54 antihypertensive drug was uploaded into Forward EngineeringTM prior to building MODEL IB 102. MODEL IB 102 is able to predict compounds in new chemical classes able to lower beta amyloid levels in vitro (see Examples). After confirming that MODEL IB 102 is good, compound databases were screened by MODEL IB 102 and also used to identify compounds with A ⁇ 40- and/or A ⁇ 42 amount-lowering activity.
  • MODEL Iv4 105 is effective in identifying compounds with in vitro and in vivo efficacy. After confirming that MODEL 1 V4 105 was good, compound databases were screened by MODEL Iv4 105 and used to identify compounds that were submitted for evaluation of beta amyloid amount-lowering activity. Prior to testing, the compounds were screened with ADME/Tox filters 106 that include, but are not limited to, BBB and LDH filters.
  • MODEL Iy 5 108 data from compounds from MODEL Iv 4 were combined with in vivo A ⁇ anti-aggregation data to form MODEL Iy 5 108, which is effective in predicting compounds with in vitro and in vivo activity.
  • MODEL Iv 5 was used to screen compound databases and to identify compounds that demonstrated in vitro and in vivo activity. Thereafter, compounds were submitted for in vitro and in vivo evaluation.
  • the 1 st 6 compounds of Table 3 are the internal controls known to have in vivo anti-aggregation activity.
  • the latter 7 compounds of Table 3 are novel compounds in new chemical classes identified as having anti-aggregation activity by MODEL lvs-
  • the final column of Table 3 contains experimental in vitro anti-aggregation data obtained for the 7 novel compounds expressed as a percent of solvent-only control (DMSO is the vehicle with 100% activity).
  • Figures 1 and 2 include models based on data from compounds evaluated using both in vitro and in vivo assays, it is to be understood that models based solely on data from compounds evaluated using in vivo assays also can be used to identify compounds with in vivo efficacy.
  • tetrahydrobenzothiophene was unexpectedly selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • novel compounds having the Formula 1 were identified as being able to inhibit beta amyloid production and/or aggregation.
  • the tetrahydrobenzothiophene comprises 2-[(4-oxo-5,6,7,8-tetrahydro-3H- benzothiopheno[2,3-d]pyrimidin-2-yl)sulfanyl]acetaldehyde compound family (Formula 1).
  • N-(2-methylphenyl)-2- ⁇ [3-(4-methylphenyl)-4-oxo-3,4,5,6,7,8- hexahydro[l]benzothieno[2,3-d]pyrimidin-2-yl]sulfanyl ⁇ acetamide was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to, or treated with, the compound of Formula 1.
  • compounds that include the following R-groups (Formula IA), as part of Formula 1 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • Rl is a carboxyl group ( — C(O) — OH), a hydrogen ( — H — ), a trifluoromethyl group (-C(F 3 )), a phenol group ( — Ph- -OH), a — SO3, or a hydroxyl ( — OH) group;
  • R2 is a trifluoromethyl phenyl group ( — Ph — CF 3 ), a methylphenyl ( — Ph — CH 3 ), — Ph- CH 2 — OH, a phenol group ( — Ph- OH), a furan or a thiophene;
  • R3 is a NH2, a — N(CH3)2, a — NH(C(CH3)2), a — NH- Ph- meta— CH3 of Formula 1 and the expected ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation was generally less than about 100%, about 99%, about 98%, about 9
  • the compounds comprising Formula 1 in combination with any of the R groups disclosed in Formula IA were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1% when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • the compounds comprising Formula 1 in combination with any of the R groups disclosed in Formula IA were predicted to have a % ctl Abetal of about 12.81% to about 54.15% ; a % ctl Abeta40-l of about 30.04% to about 87.04%; a % ctl Abeta42-1 of about 24.81% to about 78.61%; a % ctl LDH of about 78.02% to about 170.52%; and a % ctl MTT of about 90.06% to about 104.71%, as disclosed in Table 29.
  • the compounds comprising Formula 1 in combination with any of the R groups disclosed in Formula IA were predicted to have EC50 values of about -39.51 ⁇ M to about 136.75 ⁇ M.
  • the compounds comprising Formula 1 in combination with any of the R groups of Formula IA were predicted to have a bioavailabilty of about 43.09 to about 100; intestinal absorption of about 9.78 to about 100; log (blood/brain) passage of about -2.06 to about 0.32; bound in plasma (%) of about 9.17 to about 100%; and metabolites (%hep, elim) of about 0 to about 0.69 (Table 29).
  • a second tetrahydrobenzothiophene was also selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation, and this selection could not be predicted from known Alzheimer's therapeutics.
  • the tetrahydrobenzothiophene comprises 3-(p-tolyl)-5,6,7,8- tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-one compound family ( Figure 4A).
  • N-(2-methylphenyl)-2- ⁇ [3-(4-methylphenyl)-4-oxo-3 ,4,5,6,7,8- hexahydro[l]benzothieno[2,3-d]pyrimidin-2-yl]sulfanyl ⁇ acetamide was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to or treated with the compound of Formula 2.
  • compounds that include the following R-groups (Formula 2A), as part of Formula 2 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • Formula 2A R-groups
  • Rl is apara— Ph- O— CH3, a CH2— para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, a — S— CH2— C(O) — N— Ph- meta— CH3, or a hydrogen (-H);
  • R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H);
  • R3 is — CH3, — C((CH3)3), -C(O) — O— CH2— CH3, or a hydrogen (-H) of Formula 2 and the expected ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%,
  • the compounds comprising Formula 2 in combination with any of the R groups disclosed in Formula 2 A were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1 % when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • the novel compounds comprising Formula 2 in combination with any of the R groups disclosed in Formula 2 A were predicted to have a % ctl Abetal of about 1 1.45% to about 39.72% ; a % ctl Abeta40-l of about 30.56% to about 71.97%; a % ctl Abeta42-1 of about 30.68% to about 100.04%; a % ctl LDH of about 100.55% to about 170.21%; and a % ctl MTT of about 79.01% to about 104.71% (Table 30).
  • the novel compounds comprising Formula 2 in combination with any of the R groups disclosed in Formula 2 A were predicted to have EC50 values of about 79.24 ⁇ M to about 136.75 ⁇ M.
  • the novel compounds comprising Formula 2 in combination with any of the R groups of Formula 2 A were predicted to have a bioavailabilty of about 42.61 to about 100; intestinal absorption of about 23.09 to about 100; log (blood/brain) passage of about -1.83to about -0.30; bound in plasma (%) of about 60.78 to about 100%; and metabolites (%hep, elim) of about 0 to about 0.69 (Table 30).
  • a third hexahydrobenzothienopyrimidine was surprisingly selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • the hexahydrobenzothienopyrimidine comprises 3-[2-(4-oxo-5,6,7,8- tetrahydrobenzothiopheno[2,3-d]pyrimidin-3-yl)ethyl]-5,6,7,8- tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-one compound family (Formula 3).
  • 3-[2-(4-oxo-5,6,7,8-tetrahydro-[l]benzothiolo[2,3-d]pyrimidin-3-yl)ethyl]- 5,6,7,8-tetrahydro-[l]benzothiolo[2,3-d]pyrimidin-4-one was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to or treated with the compound of Formula 3.
  • compounds that include the following R- groups were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • Formula 3A R- groups
  • Rl is a para— Ph- O— CH3, a CH2— para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, or a hydrogen (-H);
  • R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H);
  • R3 is — CH3, — C((CH3)3), -C(O) — O— CH2— CH3, or a hydrogen ( — H) of Formula 3 and the predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%
  • the compounds comprising Formula 3 in combination with any of the R groups disclosed in Formula 3 A were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1 % when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • a positive active compound such as
  • the compounds comprising Formula 3 in combination with any of the R groups disclosed in Formula 3 A were predicted to have a % ctl Abetal of about 8.10% to about 16.37% ; a % ctl Abeta40-l of about 27.72% to about 54.63%; a % ctl Abeta42-1 of about 26.21% to about 67.98%; a % ctl LDH of about 152.66% to about 286.83%; and a % ctl MTT of about 78.80% to about 104.71%.
  • the compounds comprising Formula 3 in combination with any of the R groups disclosed in Formula 3 A were predicted to have EC50 values of about 124.86 ⁇ M to about 185.60 ⁇ M.
  • the novel compounds comprising Formula 3 in combination with any of the R groups of Formula 3 A were predicted to have a bioavailabilty of about 40.49 to about 100; intestinal absorption of about 13.47 to about 100; log (blood/brain) passage of about -2.0 Ho about -0.04; bound in plasma (%) of about 47.44 to about 100%; and metabolites (%hep, elim) of about 0 to about 0.96 (Table 31).
  • a fourth hexahydrobenzothienopyrimidine was selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation. Relative to known Alzheimer's therapeutics, the selection was surprising and unexpected. In general, novel compounds having the Formula 4:
  • the hexahydrobenzothienopyrimidine comprises N-hexyl-5,6,7,8- tetrahydrobenzothiopheno[2,3-d]pyrimidin-4-amine compound family (Formula 3).
  • N-hexyl-5,6,7,8-tetrahydro-[ 1 ]benzothiolo[2,3-d]pyrimidin-4-amine was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to, or treated with, the novel compound of Formula 4.
  • compounds that include the following R-groups (Formula 4A), as part of Formula 4 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • Rl is a para — Ph — O — CH3, a CH2 — para — Ph- CH3, C(O) — O— CH3, C(O) — NH2, or a hydrogen (-H);
  • R2 is a — CH2— Ph, -Ph, —OH, — CH2— C(O) — NH2, or a hydrogen (-H);
  • R3 is — CH3, — C((CH3)3), -C(O) — O— CH2— CH3, or a hydrogen (-H) of Formula 3 and the predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%
  • the compounds comprising Formula 4 in combination with any of the R groups disclosed in Formula 4A were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1% when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • the compounds comprising Formula 4 in combination with any of the R groups disclosed in Formula 4A were predicted to have a % ctl Abetal of about 7.80 to about 20.45% ; a % ctl Abeta40-l of about 47.91% to about 121.69%; a % ctl Abeta42-1 of about 32.59% to about 111.36%; a % ctl LDH of about 78.96% to about 161.17%; and a % ctl MTT of about 79.18% to about 104.71% (Table 32).
  • the compounds comprising Formula 4 in combination with any of the R groups disclosed in Formula 4A were predicted to have EC50 values of about 73.40 ⁇ M to about 135.78 ⁇ M.
  • the compounds comprising Formula 4 in combination with any of the R groups of Formula 4A were predicted to have a bioavailabilty of about 42.28 to about 100; intestinal absorption of about 20.84 to about 100; log (blood/brain) passage of about -1.89to about 0.07; bound in plasma (%) of about 78.68 to about 100%; and metabolites (%hep, elim) of about 0.00 to about 12.31 (Table 32).
  • a phenyl triazole thiol was also surprisingly selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • the phenyltriazolethiol comprises N-(benzylideneamino)-2-[(4,5-diphenyl-l,2,4-triazol-3-yl)sulfanyl]acetamide compound family (Formula 5).
  • 2-[2-[(E)-[[2-[[5-(4-tert- butylphenyl)-4-phenyl-l,2,4-triazol-3-yl]sulfanyl]acetyl] hydrazinylidene]methyl]phenoxy]acetic acid was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to or treated with the compound of Formula 5.
  • compounds that include the following R-groups (Formula 5A), as part of Formula 5 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • Formula 5A R-groups
  • Rl is — CH(CH3)2, — CF3, — O— Ph, — CH2— Ph, or — C(CH3)3;
  • R2 is — O— CH3, — O— CH2— CH3, — O— CH2— C(O)- NH2, — NH- CH2— C(O)-OH, HN- €H2— C(O>— NH2, O— CH2— Ph, O—CH2— Ph-OH, O—CH2— Ph-C(O)-OH, O — CH2 — C(O) — OH of Formula 5 and the predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about
  • the compounds comprising Formula 5 in combination with any of the R groups disclosed in Formula 5 A were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1 % when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • a positive active compound such as
  • the compounds comprising Formula 5 in combination with any of the R groups disclosed in Formula 5A were predicted to have a % ctl Abetal of about 15.88 to about 36.51% ; a % ctl Abeta40-l of about 33.15% to about 55.72%; a % ctl Abeta42-1 of about 48.37% to about 94.04%; a % ctl LDH of about 218.03% to about 367.58%; and a % ctl MTT of about 76.59% to about 104.71% (Table 33).
  • the compounds comprising Formula 5 in combination with any of the R groups disclosed in Formula 5 A were predicted to have EC50 values of about -29.52 ⁇ M to about 55.32 ⁇ M.
  • the compounds comprising Formula 5 in combination with any of the R groups of Formula 5 A were predicted to have a bioavailabilty of about 41.17 to about 100; intestinal absorption of about 20.96 to about 100; log (blood/brain) passage of about - 1.55to about 0.12; bound in plasma (%) of about 18.28 to about 100%; and metabolites (%hep, elim) of about 0.05 to about 63.79 (Table 33).
  • a sixth novel benzyloxy naphthalene was selected on the basis of having similar molecular topological characteristics as active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • the benzyloxynaphthalene comprises N-[(2-benzyloxy-l -naphthyl)methyleneamino]-2-(2,4- dichlorophenoxy)acetamide compound family (Formula 6).
  • 2-(2,4- dichlorophenoxy)-N-[[2-[(4-fluorophenyl)methoxy]naphthalen-l-yl] methylideneamino] butanamide was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to or treated with the compound of Formula 6.
  • compounds that include the following R-groups (Formula 6A), as part of Formula 6 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • Formula 6A R-groups
  • Rl is — CH((CH3)2), — CH2— O— Ph, — CH2— Ph, or CH2— CH3;
  • R2 is — CF3, —OH, —CH2— C(O)-OH or — F of Formula 6 and the predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, or about 1% when compared to DMSO at 100% activity.
  • the compounds comprising Formula 6 in combination with any of the R groups disclosed in Formula 6 A were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1 % when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • a positive active compound such as
  • the compounds comprising Formula 6 in combination with any of the R groups disclosed in Formula 6A were predicted to have a % ctl Abetal of about 18.15 to about 34.79% ; a % ctl Abeta40-l of about 3.63% to about 6.31%; a % ctl Abeta42-1 of about 7.51% to about 12.03%; a % ctl LDH of about 140.55% to about 202.42%; and a % ctl MTT of about 8.52% to about 10.40 (Table 9).
  • the compounds comprising Formula 6 in combination with any of the R groups disclosed in Formula 6A were predicted to have EC50 values of about -6.29 ⁇ M to about 78.35 ⁇ M.
  • the compounds comprising Formula 6 in combination with any of the R groups of Formula 6A were predicted to have a bioavailabilty of about 41.38 to about 98.97; intestinal absorption of about 22.84 to about 51.53; log (blood/brain) passage of about -1.17to about 0.51; bound in plasma (%) of about 52.53 to about 100%; and metabolites (%hep, elim) of about 0.07 to about 37.12 (Table 34).
  • a benzyloxy naphthalene was selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • the benzyloxynaphthalene comprises a 2-hydroxy-N-(l-naphthylmethyleneamino)acetamide compound family (Formula 7).
  • 2-(2,4-dichlorophenoxy)-N-[[2-[(4- fluorophenyl) methoxy]naphthalen-l-yl] methylideneaminojbutanamide was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to, or treated with, the compound of Formula 7.
  • compounds that include the following R- groups as part of Formula 7 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • Formula 7A R- groups
  • the R groups disclosed in Formula 7A have a predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation that is generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, or about 1% when compared to DMSO at 100% activity.
  • the compounds comprising Formula 7 in combination with any of the R groups disclosed in Formula 7 A were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1% when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • the compounds comprising Formula 7 in combination with any of the R groups disclosed in Formula 7 A were predicted to have a % ctl Abetal of about 18.19 to about 39.91% ; a % ctl Abeta40-l of about 0.70 to about 57.83%; a % ctl Abeta42-1 of about 2.23 to about 71.72%; a % ctl LDH of about 127.91% to about 209.13%%; and a % ctl MTT of about 2.61% to about 65.18% (Table 10).
  • the compounds comprising Formula 7 in combination with any of the R groups disclosed in Formula 7A were predicted to have EC50 values of about -21.16 ⁇ M to about 87.89 ⁇ M.
  • the compounds comprising Formula 7 in combination with any of the R groups of Formula 7A were predicted to have a bioavailabilty of about 41.26 to about 97.59; intestinal absorption of about 20.20 to about 78.32; log (blood/brain) passage of about -1.25to about 0.60; bound in plasma (%) of about 36.04 to about 100%; and metabolites (%hep, elim) of about 0.03 to about 42.85 (Table 35).
  • a thioxothiazolidinone was also selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • the thioxothiazolidinone comprises the (5Z)-5-[(3,4-diethoxyphenyl)methylene]-3-methyl-2- thioxo-thiazolidin-4-one compound family (Formula 8).
  • 2-[(5Z)-5- [(3 ,4-diethoxyphenyl)methylidene] -4-oxo-2-sulfanylidene- 1 ,3 -thiazolidin-3-yl] -2- phenylacetic acid was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to, or treated with, a compound of Formula 8.
  • compounds that include the following R-groups (Formula 8A), as part of Formula 8 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • the R groups disclosed in Formula 8 A have a predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation that was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, or about 1% when compared to DMSO at 100% activity.
  • the compounds comprising Formula 8 in combination with any of the R groups disclosed in Formula 8 A were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1 % when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • a positive active compound such as
  • the compounds comprising Formula 8 in combination with any of the R groups disclosed in Formula 8A were predicted to have a % ctl Abetal of about 14.51 to about 25.56% ; a % ctl Abeta40-l of about 1 to about 61.58%; a % ctl Abeta42-1 of about 1.67 to about 72.04%; a % ctl LDH of about 113.5% to about 155.93%; and a % ctl MTT of about 2.13% to about 78.98% (Table 11).
  • the compounds comprising Formula 8 in combination with any of the R groups disclosed in Formula 8A were predicted to have EC50 values of about 39.60 microM to about 108.27 microM.
  • the compounds comprising Formula 8 in combination with any of the R groups of Formula 8 A were predicted to have a bioavailabilty of about 43.91 to about 100; intestinal absorption of about 45.37 to about 100%; log (blood/brain) passage of about -1.10 to about -0.27; bound in plasma (%) of about 100%; and metabolites (%hep, elim) of about 0.0 to about 2.93 (Table 36).
  • Another unexpected compound, an indole was selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • the indole comprises the 4-hydroxy-l-[2-(lH-indol-3-yl)ethyl]-2H-pyrrol-5-one compound family (Formula 9A).
  • methyl 4-[3-(4-chlorobenzoyl)-4-hydroxy-l-[2-(lH- indol-3-yl)ethyl]-5-oxo-2H-pyrrol-2-yl]benzoate was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to or treated with the compound of Formula 9.
  • compounds that include the following R-groups (Formula 9A), as part of Formula 9 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • Formula 9A R-groups
  • the R groups disclosed in Formula 9A have a predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation that was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, or about 1% when compared to DMSO at 100% activity.
  • the compounds comprising Formula 9 in combination with any of the R groups disclosed in Formula 9 A were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1 % when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • a positive active compound such as
  • the compounds comprising Formula 9 in combination with any of the R groups disclosed in Formula 9A were predicted to have a % ctl Abetal of about 23.57 to about 36.13% ; a % ctl Abeta40-l of about 9.19 to about 51.09%; a % ctl Abeta42-1 of about 16.62 to about 58.05%; a % ctl LDH of about 108.22% to about 176.36%; and a % ctl MTT of about 30.33% to about 104.17% (Table 12).
  • the compounds comprising Formula 9 in combination with any of the R groups disclosed in Formula 9A were predicted to have EC50 values of about 25.78 ⁇ M to about 51.40 ⁇ M.
  • the compounds comprising Formula 9 in combination with any of the R groups of Formula 9 A were predicted to have a bioavailabilty of about 42.84 to about 100; intestinal absorption of about 29,73 to about 76; log (blood/brain) passage of about -0.74 to about 0.25; bound in plasma (%) of about 62.58% to about 98.97%: and metabolites (%hep, elim) of about 0.0 to about 2.34 (Table 37).
  • a tenth compound, a triazole was yet another unexpected compound family selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • the triazole comprises 5-(4-quinolyl)-4H-l,2,4-triazole-3 -thiol compound family (Formula 10).
  • 2-[[5-[2-(4-methylphenyl)quinolin-4-yl]-4-phenyl-l ,2,4-triazol-3- yl]sulfanyl] acetic acid was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to or treated with the novel compound of Formula 10.
  • compounds that include the following R-groups were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • the R groups disclosed in Formula 1OA have a predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation that was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, or about 1% when compared to DMSO at 100% activity.
  • the compounds comprising Formula 10 in combination with any of the R groups disclosed in Formula 1OA were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1% when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • the compounds comprising Formula 10 in combination with any of the R groups disclosed in Formula 1OA were predicted to have a % ctl Abetal of about 14.98 to about 48.09% ; a % ctl Abeta40-l of about 5.75 to about 56.65%; a % ctl Abeta42-1 of about 12.83 to about 96.97%; a % ctl LDH of about 115.15% to about 209.45%; and a % ctl MTT of about 25.07% to about 104.17% (Table 13).
  • the compounds comprising Formula 10 in combination with any of the R groups disclosed in Formula 1OA were predicted to have EC50 values of about 3.68 ⁇ M to about 74.17 ⁇ M.
  • the compounds comprising Formula 10 in combination with any of the R groups of Formula 1OA were predicted to have a bioavailabilty of about 42.06 to about 100; intestinal absorption of about 29.51 to about 100; log (blood/brain) passage of about -1.64 to about 0.28; bound in plasma (%) of about 62.97% to about 100%: and metabolites (%hep, elim) of about 0.0 to about 8.59 (Table 38).
  • Compound Family #11 - A341817 4-phenyl-5-[(4-phenyl-5-sulfanyl-l,2,4-triazol-3- y ⁇ )methy ⁇
  • a phenyl triazolethiol was also unexpectedly selected on the basis of having similar molecular topological characteristics to active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • the phenyltriazolethiol comprises the 4-phenyl-5-[(4-phenyl-5-sulfanyl-l,2,4-triazol-3- yl)methyl]-l,2,4-triazole-3 -thiol compound family (Formula 1 IA).
  • 2-[[5-[[5-[2-oxo-2-(N-propan-2-ylanilino)ethyl]sulfanyl-4-phenyl-l,2,4-triazol-3-yl] methyl]- 4-phenyl-l,2,4-triazol-3-yl]sulfanyl]-N-phenyl-N-propan-2-ylacetamide was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to,
  • compounds that include the following R- groups (Formula 1 IA), as part of Formula 11 were selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present.
  • the R groups disclosed in Formula 1 IA have a predicted ability to inhibit or reduce beta amyloid level, activity, production and/or aggregation that was generally less than about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, or about 1% when compared to DMSO at 100% activity.
  • the compounds comprising Formula 11 in combination with any of the R groups disclosed in Formula 1 IA were predicted to inhibit or reduce beta amyloid level, activity, production and/or aggregation by more than about 100%, more than about 200%, less than about 100%, less than about 99%, less than about 98%, less than about 97%, less than about 96%, less than about 95%, less than about 90%, less than about 85%, less than about 80%, less than about 75%, less than about 70%, less than about 65%, less than about 60%, less than about 55%, less than about 50%, less than about 45%, less than about 40%, less than about 35%, less than about 30%, less than about 26%, less than about 25%, less than about 20%, less than about 15%, less than about 10%, less than about 5%, less than about 2%, or less than about 1% when compared to the predicted activity of a positive active compound, such as abienol, arthonionic acid, candesartan, diazoxide,
  • a positive active compound such as
  • the compounds comprising Formula 11 in combination with any of the R groups disclosed in Formula 1 IA were predicted to have a % ctl Abetal of about 8.84 to about 40.58% ; a % ctl Abeta40-l of about 28.94 to about 72.71%; a % ctl Abeta42-1 of about 30.21 to about 93.88%; a % ctl LDH of about 171.13% to about 490.76%; and a % ctl MTT of about 104.71 (Table 14).
  • the novel compounds comprising Formula 11 in combination with any of the R groups disclosed in Formula 1 IA were predicted to have EC50 values of about -125.84 ⁇ M to about 68.95 ⁇ M.
  • the compounds comprising Formula 11 in combination with any of the R groups of Formula 1 IA were predicted to have a bioavailabilty of about 31.50 to about 96.59; intestinal absorption of about 4.01 to about 100; log (blood/brain) passage of about -3.40 to about 0.53; bound in plasma (%) of about 17.77% to about 100%: and metabolites (%hep, elim) of about 0.0 to about 10.92 (Table 39). ⁇
  • Another unexpected compound family characterized by organometallic (boron), was selected on the basis of having similar molecular topological characteristics as active positive compounds that lower or reduce the beta amyloid level, activity, production and/or aggregation.
  • novel compounds having the Formula 12 were identified as being able to inhibit beta amyloid production and/or aggregation.
  • organometallic (boron) hydrotris (3-(4-cumenyl)-5-methylpyrazol-l-yl)borate compound family (Formula 14A).
  • hydrotris (3-(4-cumenyl)-5-methylpyrazol-l-yl) borate was selected as being able to inhibit or reduce beta amyloid level, activity, production and/or aggregation by about 100%, about 99%, about 98%, about 97%, about 96%, about 95%, about 90%, about 85%, about 80%, about 75%, about 70%, about 65%, about 60%, about 55%, about 50%, about 45%, about 40%, about 35%, about 30%, about 26%, about 25%, about 20%, about 15%, about 10%, about 5%, about 2%, about 1% or less than about 1% of the original beta amyloid levels and/or activity present in samples not exposed to or treated with the novel compound of Formula 12.
  • the compounds comprising Formula 12 were predicted to have activities disclosed in Table 40.
  • a method of treating AD in a human or nonhuman animal body includes administering a therapeutically effective amount of any of the compounds in Tables 1-3, or any combination thereof, to the body.
  • the compounds of the present invention can be administered by any suitable route, for example by oral, buccal, inhalation, sublingual, rectal, vaginal, transurethral, nasal, topical, percutaneous, i.e., transdermal, or parenteral (including intravenous, intramuscular, subcutaneous, and intracoronary) administration.
  • Parenteral administration can be accomplished using a needle and syringe, or using a high pressure technique, like POWDERJECTTM.
  • Oral administration of any of the compounds listed in Tables 1-3 is the preferred route as oral administration is one of the most convenient and avoids the disadvantages associated with other routes of administration.
  • the compound can be administered parenterally, e.g., sublingually or buccally.
  • the compounds according to the disclosure are expected to be effective in lowering A ⁇ 40 and A ⁇ 42 activity levels both in vitro and in vivo.
  • the compounds disclosed herein generally have desirable characteristics, e.g., as outlined in Tables 1-3 as shown by computer modeling and comparisons, and may be used to treat patients to mitigate the symptoms of AD.
  • Cells in vitro and in vivo may be exposed to any of the compounds listed in Tables 1-3 for this purpose, for example.
  • Anti-amyloid and anti-aggregation agents are important commercial products that are used in many ways; similarly, any of the compounds disclosed in Tables 1 -3 may also be used for such purposes. Accordingly, potential uses would include use for diagnostics, cell testing, and as chemical therapeutics for commercial sale.
  • any combination of any of these compounds listed in Tables 1-3 may be used in vitro or in vivo to inhibit A ⁇ 40 and A ⁇ 42 levels and/or minimize extracellular HMW beta amyloid species and are valuable research tools for in vitro and in vivo treatment of cells.
  • Administration of Compositions may be used in vitro or in vivo to inhibit A ⁇ 40 and A ⁇ 42 levels and/or minimize extracellular HMW beta amyloid species and are valuable research tools for in vitro and in vivo treatment of cells.
  • salts of the compounds described herein may be synthesized according to methods known to those skilled in this art, see, for example Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor) June 2002.
  • such salts are prepared by reacting the free-base forms of these compounds with a stoichiometric amount of the appropriate acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of some appropriate salts are found, for example, in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985.
  • the compounds described herein are used in combination with one or more current and/or experimental AD agents for mitigation of the symptoms specific for AD.
  • the compounds described herein may be administered as a single active drug or mixtures thereof.
  • the compounds may be administered in oral dosage forms that include tablets, capsules, pills, powders, granules, elixirs, tinctures, suspensions, syrups, and emulsions. Further, the compounds may be administered in intravenous (bolus or infusion), intraperitoneal, subcutaneous, or intramuscular form.
  • the compounds described herein are typically to be administered in admixture with suitable pharmaceutical diluents, excipients, extenders, or carriers (termed herein as a pharmaceutically acceptable carrier, or a carrier) suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • suitable pharmaceutical diluents, excipients, extenders, or carriers suitably selected with respect to the intended form of administration and as consistent with conventional pharmaceutical practices.
  • the deliverable compound will be in a form suitable for oral, rectal, topical, intravenous injection or parenteral administration.
  • Carriers include solids or liquids, and the type of carrier is chosen based on the type of administration being used.
  • the compounds may be administered as a dosage that has a known quantity of the compound.
  • Suitable binders, lubricants, disintegrating compounds, coloring compounds, flavoring compounds, flow-inducing compounds, and melting compounds may be included as carriers, e.g., for pills.
  • an active drug component can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, gelatin, agar, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • Suitable binders include, for example, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, for example, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the compounds may also be used with liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine, or phosphatidylcholines.
  • the compounds may also be coupled to polymers as targetable drug carriers or as a prodrug.
  • Suitable biodegradable polymers useful in achieving controlled release of a drug include, for example, polylactic acid, polyglycolic acid, copolymers of polylactic and polyglycolic acid, caprolactones, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, and hydrogels, preferably covalently crosslinked hydrogels.
  • the active compounds can be administered orally in solid dosage forms, such as capsules, tablets, and powders, or in liquid dosage forms, such as elixirs, syrups, and suspensions.
  • the active compounds can also be administered parenterally, in sterile liquid dosage forms.
  • Capsules may contain the active compound and powdered carriers, such as lactose, starch, cellulose derivatives, magnesium stearate, stearic acid, and the like. Similarly, such diluents can be used to make compressed tablets. Both tablets and capsules can be manufactured as immediate release products or as sustained release products to provide for continuous or long-term release of the active compounds.
  • the deliverable form of the compounds can be sugar coated or film coated to mask any unpleasant taste and protect the tablet from the atmosphere, or enteric coated for selective disintegration in the gastrointestinal tract.
  • the drug components may be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like.
  • liquid forms include solutions or suspensions in water, pharmaceutically acceptable fats and oils, alcohols or other organic solvents, including esters, emulsions, syrups or elixirs, suspensions, solutions and/or suspensions reconstituted from non- effervescent granules and effervescent preparations reconstituted from effervescent granules.
  • Liquid dosage forms may contain, for example, suitable solvents, preservatives, emulsifying compounds, suspending compounds, diluents, sweeteners, thickeners, and melting compounds.
  • Liquid dosage forms for oral administration can contain coloring and flavoring, as needed.
  • water, a suitable oil, saline, aqueous dextrose (glucose), and related sugar solutions and glycols such as propylene glycol or polyethylene glycols are suitable carriers for parenteral solutions.
  • Solutions for parenteral administration preferably contain a water soluble salt of the active ingredient, suitable stabilizing compounds, and if necessary, buffer substances.
  • Antioxidizing compounds such as sodium bisulfite, sodium sulfite, or ascorbic acid, either alone or combined, are suitable stabilizing compounds.
  • citric acid and its salts and sodium EDTA are also used.
  • parenteral solutions can contain preservatives, such as benzalkonium chloride, methyl- or propyl-paraben, and chlorobutanol.
  • Suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences, Mack Publishing Company, a standard reference text in this field.
  • the compounds described herein may also be administered in intranasal form via use of suitable intranasal vehicles, or via transdermal routes, using those forms of transdermal skin patches known to those skilled in these arts. To be administered in the form of a transdermal delivery system, the dosage administration will generally be continuous rather than intermittent throughout the dosage regimen. Parenteral and intravenous forms may also include minerals and other materials to make them compatible with the type of injection or delivery system chosen.
  • kits for the treatment of AD may also be used in pharmaceutical kits for the treatment of AD, or other purposes, which comprise one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of any of the compounds disclosed in Tables 1-3.
  • kits may further include, if desired, one or more of various components, such as, for example, containers with the compound, containers with one or more pharmaceutically acceptable carriers, additional containers, and instructions.
  • the instructions may be in printed or provided in electronic form, for example, as inserts or labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components.
  • Dosage levels include from about 0.01 mg to about 2000 mg of active compound per kilogram of body weight per day as preferable dosages. Persons of ordinary skill in these arts will recognize that all doses and ranges between these explicit values are contemplated, e.g., 0.01 to 100, and 0.1 to 50 mg/kg per day.
  • the amount of active compound that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 0.01 mg to about 10,000 mg of an active compound; persons of ordinary skill in these arts will recognize that all doses and ranges between these explicit values are contemplated.
  • a suitable dosage adopted for oral or intravenous administration of any of the compounds disclosed herein may range from about 0.01 to about 1000 mg per dose, from once per week to 5 times daily and may be easily calculated from IC 5 o values.
  • MODEL 1 - comprising in vitro AB 40 and AB 42 lowering activity data.
  • MODEL 2 - comprising literature-based in vivo AB 40 and AB 42 lowering activity (rats) data.
  • MODEL 3 - comprising MSSM-based in vivo AB 40 and AB 42 lowering activity data.
  • MODEL 4 comprising in vivo beta amyloid lowering activity based on human clinical studies data.
  • MODEL 5 comprising MSSM-based in vivo oligomeric AB lowering activity data.
  • MODEL 1 was built first, followed by MODELs 2-4.
  • MODEL 5 was built last. Initially, training sets comprising data for MODEL specified above were assembled. Each training set included current/experimental agents with in vitro (MODEL 1 ), literature-based in vivo (MODEL 2), experimental in vivo (MODEL 3), human clinical in vivo (MODEL 4), and experimental in vivo beta amyloid anti-aggregation activity (MODEL 5). Each training set included a very heterogeneous group of structurally diverse active agents and a group of inactive compounds that are structurally similar to the active agents with respect to atoms, heteroatoms, bonds and cycles were uploaded into Forward EngineeringTM.
  • MODEL 1 In vitro A ⁇ 40 and A ⁇ 42 lowering activity -
  • MODEL IA was based on a training set that included 156 cardiovascular drugs with in vitro A ⁇ -lowering activity while MODEL IB was based on 54 anti-hypertensive drugs with in vitro A ⁇ -lowering activity.
  • Exemplary chemical members of each training set are provided in Tables 4 and 5 below.
  • column 1 discloses the drug name while column 2 contains the 2-D structure.
  • Column 3 contains the beta amyloid (A ⁇ 40 or A ⁇ 42) lowering activity expressed as a percent (%) of control.
  • the last column contains the release of the cytosolic lactase dehydrogenase (LDH) expressed as a percent (%) of control.
  • LDH cytosolic lactase dehydrogenase
  • MODEL 2 literature-based in vivo A ⁇ lowering activity - A ⁇ -lowering compounds that have been tested in vivo were obtained from both PubMed and Integrity. The data describing % lowering for A ⁇ 4 o and A ⁇ 42 were based on varying methods, animals, and controls as described in the literature. Rather than generally categorizing compounds in terms of active/inactive, they were categorized as having high (>50%), medium (21-49%) and low ( ⁇ 20%) activity.
  • a suitable example of a MODEL 2 training set is provided below:
  • MODEL 3 - in vivo AB lowering activity Twenty compounds were used to form the training set for MODEL 3. Data showing relative levels of A ⁇ activity in vivo were used to form the training set for MODEL 3. Examples of the data used to form the training set for MODEL 3 are provided in Table 7 below.
  • MODEL 4 In vivo AB lowering activity based on human clinical data - A ⁇ - lowering compounds that have been tested in human clinical trials were obtained from both PubMed and Integrity. An example is provided in Table 8.
  • column 1 discloses the drug name while column 2 contains the 2-D structure.
  • Column 3 discloses the clinical phase of each drug while column 4 contains the prescribed dosage for efficacy.
  • the last column contains the mechanisms of action (MOAs).
  • Column 1 of Table 9 contains the drug name while column 2 discloses the 2-D structure.
  • Column 3 discloses the measured in vivo beta amyloid lowering activity as a % of control while columns 4 and 5 disclose cytosolic release of LDH and release of MTT as measures of liver toxicity.
  • the last column of Table 9 contains the measured EC50 in microM for beta amyloid anti-aggregation activity.
  • the training sets were uploaded into the Forward EngineeringTM platform, that is available from Medisyn Technologies, Inc,. Minnetonka, MN.
  • relevant TIs were selected by the Forward EngineeringTM software program in order to analyze the compounds in the training set.
  • the TIs that were appropriate for characterizing the training set of beta amyloid reducing agents were selected using a proprietary algorithm built into Forward EngineeringTM.
  • each compound was mathematically characterized by the selected TI's using equations disclosed in the publications cited above, which also describe the rigorous validation of the use of TIs in the process of drug discovery.
  • the end result is the conversion of the 2-D structures into well-defined sets of numerical values.
  • each predictive model was tested to make sure that MODELs 1-5 were good.
  • each MODEL was used to screen ACD and SCD databases and a first output of approximately 100 compounds was generated.
  • Each output set included the predictive efficacies for each compound as a % of control.
  • the first output of compounds was reviewed to make sure that both known active compounds/agents ( ⁇ 75% beta amyloid lowering activity, % Ctrl Abetal) and inactive compounds/agents (>75% beta amyloid lowering activity, % Ctrl Abetal) at lOO ⁇ M concentration were present. Since the output of compounds included both known active and known inactive compounds, each MODEL was deemed good.
  • a second test was used to determine if each MODEL was able to predict efficacy of known active compounds/agents.
  • the positive control for A ⁇ -lowering activity was losartan, as disclosed in Table 10.
  • the predictive values for beta amyloid-lowering activity is a composite of A ⁇ 40- and A ⁇ 42-lowering activities, a true comparison between predicted and experimental values for beta amyloid-lowering activity cannot be made.
  • Several positive controls for MODELs 2-5 are listed in the Table 11 with activity reported in term of % anti- oligomeric (e.g., anti-aggregation) activity.
  • Column 1 of Table 10 contains the chemical class, while column 2 discloses the molecule name.
  • Columns 3 and 4 contain predicted and experimental anti-oligomeric activity in terms of EC50 since the predictive models are in vivo predictive models.
  • anti- oligomeric is meant the degree to which a compound prevents aggregation of beta amyloid (A ⁇ 40 and A ⁇ 42) in vivo.
  • Prequalif ⁇ cation of compounds -Compounds were prequalified for drug-like effectiveness and by screening with ADME/Tox filters as part of the Forward EngineeringTM platform.
  • columns 1 and 2 contain the molecule ID no. or name and chemical class while the latter columns contain the diverse ADME/Tox filters used for screening.
  • the ADME/Tox predictions predicted ranges for each ADME/Tox parameter became known. In general, each tested compound came within the acceptable ranges for each parameter and/or within the ranges (or value) of the internal controls provided.
  • Test compounds were A2960599, Al 876199 and Losartan as the positive control.
  • Test compounds were A2960599, A 1876199 and Losartan as the positive control.
  • Test compounds were A2960599, A 1876199 and Losartan as the positive control.
  • Positive controls in Table 14 include ergosterol, benzoic acid phenyl ester, steroid, benzoimidazole, dihydropiridine diester, and aminobutryic acid.
  • ADME/Tox properties included Log P, Oral Availability, Intestinal absorption, Blood Brain Barrier (BBB), Urinary Excretion, Nonrenal elimination, Metabolites (%hep.elim), Bound in plasma (%), and clearance (L/hr).
  • Positive controls listed in Table 15 include ergosterol, benzoic acid phenyl ester, steroid, benzoimidazole, dihydropiridine diester, and aminobutryic acid.
  • ADME/Tox properties included Dilution volume (Vd(L)), Half-life (beta), hours, peak time (hr), Peak concentration (mg/L), probability toxicity, high toxicity probability, LD50 rat oral (mg/Kg), LD50 rat IV (Mg/Kg), Oral NOEL Rat subchronic, and Oral NOEL rat chronic.
  • Positive controls listed in Table 16 include ergosterol, benzoic acid phenyl ester, steroid, benzoimidazole, dihydropindine diester, and aminobutryic acid.
  • ADME/Tox properties included probable carcinogenicity, carcinogenicity (potency), probable mutagenicity, probable neurotoxicity, probable hematoxicity, cytotoxicity (microM), and probable teratogenicity.
  • ADME/Tox properties listed in Table 17 included Log P, Oral Availability, Intestinal absorption, Blood Brain Barrier (BBB), Urinary Excretion, Nonrenal elimination, Metabolites (%hep.elim), Bound in plasma (%), and clearance (L/hr). TABLE 18 - ADME/TOX PREDICTIONS FOR KEY SELECTIONS WITH A ⁇
  • ADME/Tox properties included Dilution volume (Vd(L)), Half- life (beta), hours, peak time (hr), Peak concentration (mg/L), probability toxicity, high toxicity probability, LD50 rat oral (mg/Kg), LD50 rat IV (Mg/Kg), Oral NOEL Rat subchronic, and Oral NOEL rat chronic.
  • Vd(L) Dilution volume
  • Beta Half- life
  • hours peak time
  • Peak concentration mg/L
  • probability toxicity high toxicity probability
  • LD50 rat oral mg/Kg
  • LD50 rat IV Mg/Kg
  • Oral NOEL Rat subchronic Oral NOEL Rat subchronic
  • Oral NOEL rat chronic TABLE 19 - ADME/TOX PREDICTIONS FOR KEY SELECTIONS WITH A ⁇
  • Selections include A3932292, A4971549, A6239807, A1862443, and A5261232 from ACD.
  • ADME/Tox properties of the listed compounds included probable carcinogenicity, carcinogenicity (potency), probable mutagenicity, probable neurotoxicity, probable hematoxicity, cytotoxicity (microM), and probable teratogenicity.
  • ADME/Tox properties included Log P, Oral Availability, Intestinal absorption, Blood Brain Barrier (BBB), Urinary Excretion, Nonrenal elimination, Metabolites (%hep.elim), Bound in plasma (%), and clearance (L/hr).
  • ADME/Tox properties included Dilution volume (Vd(L)), Half-life (beta), hours, peak time (hr), Peak concentration (mg/L), probability toxicity, high toxicity probability, LD5O rat oral (mg/Kg), LD50 rat IV (Mg/Kg), Oral NOEL Rat subchronic, and Oral NOEL rat chronic.
  • ADME/Tox properties included probable carcinogenicity, carcinogenicity (potency), probable mutagenicity, probable neurotoxicity, probable hematoxicity, cytotoxicity (microM), and probable teratogenicity.
  • Embryonic day 16 cortico-hippocampal neuronal cultures were prepared from heterozygous Tg2576 transgenic mice (Tg2576 neurons) according to the method of Wang et al, 2007. Embryonic brain tissues were mechanically triturated and centrifuged. Neurons were seeded onto poly-d-lysine-coated 96-well plates at 1.0 ⁇ 10 5 cells per well and cultured in the serum-free chemically defined Neurobasal medium, supplemented with 2% B27, 0.5mM 1-glutamine, and 1% penicillin-streptomycin (Gibco-BRL; Invitrogen).
  • astrocytes ⁇ 2% were confirmed by the virtual absence of glialfibrillary acidic (GFAP) protein immunostaining. Plates were treated with 0.1 ⁇ M, l ⁇ M, lO ⁇ M, 50 ⁇ M, and lOO ⁇ M of each compound in duplicate for approximately 16 hours. Thereafter, conditioned medium was collected for A ⁇ detection using commercially available ELISA kits (BioSource).
  • GFAP glialfibrillary acidic
  • MODEL IA was used to predict that 24 compounds would have beta amyloid lowering activity. Of the 24 compounds, 21 compounds from MODEL lwere found to be active for A ⁇ 40 lowering activity while 16 were active for A ⁇ 42 lowering activity. This represents 88% and 67% success rates, respectively. Three compounds demonstrated activity at the lOO ⁇ M concentration, 3 at a concentration of 50 ⁇ M, 2 at a concentration of lO ⁇ M and 2 compounds were active at a concentration of l ⁇ M. The two compounds demonstrating activity at a concentration of l ⁇ M were A2960599 and Al 876199. These two compounds were predicted to have activities of 9.6 and 12.2, respectively, versus 26 for losartin, all tested at lOO ⁇ M. Results are shown in Table 23, with losartan as the positive control.
  • MODEL 1 B was used to identify 23 compounds with beta amyloid lowering activity. Of the 23 compounds (not shown), 26% success rate or 6 compounds lowered A ⁇ 42 levels in vitro and 26% success rate or 6 different compounds lowered A ⁇ 40 levels in vitro. After combining MODEL IA and IB, the MODEL was used to identify 22 compounds in 11 new chemical classes unrelated to classes containing known beta amyloid lowering activity. Of the 22 compounds, 13 compounds (59% success rate) were effective in lowering in vitro A ⁇ 42 levels at the lOO ⁇ M concentrations while 5 compounds were effective at the 50 ⁇ M concentration. Similarly, 16 compounds (73% success rate) were effective in lowering in vitro A ⁇ 40 levels at the lOO ⁇ M concentrations, 6 were effective at the 50 ⁇ M and 2 exerted activity at lO ⁇ M.
  • MODEL 4 was used to identify 37 compounds. Of the 37 compounds from MODEL 4, 5 compounds demonstrated in vitro A ⁇ lowering activity (a 14% success rate), as presented b the examples disclosed in Table 24. Concentrations tested were 1 ⁇ M, 1 O ⁇ M, 50 ⁇ M and 100 ⁇ M.
  • Column 1 of Table 24 contains the MSSM ID No. while column 2 contains the chemical class.
  • Column 3 includes the molecule ID No from ACD while column 4, contains the 2-D structure.
  • Column 5 contains the chemical name, if known, while column 6 contains the predicted beta amyloid lowering activity as a percent of control.
  • Columns 7-14 contain the experimental data for beta amyloid lowering activity (A ⁇ 40 and A ⁇ 42, respectively) tested at concentration of l ⁇ M, lO ⁇ M, 50 ⁇ M, and lOO ⁇ M.
  • F-12K medium ATCC, Manassas, VA
  • F-12K medium containing 15% (v/v) horse serum, 2.5% (v/v) fetal bovine serum, 100 units/ml penicillin, 0.1 mg/ml of streptomycin, and 25 ⁇ g/ml amphotericin B at 37°C in an atmosphere of 5% (v/v) CO 2 in air.
  • F-12K medium containing 0.5% (v/v) fetal bovine serum, 100 units/ml penicillin, 0.1 mg/ml streptomycin, and 25 ⁇ g /ml amphotericin B.
  • a cell suspension then was prepared by addition of this latter medium, but containing 100 ⁇ g/ml of nerve growth factor (Invitrogen), followed by agitation of the flask.
  • Cell concentration was determined using trypan blue staining, after which cells were plated at a density of 30,000 cells/well (90 ⁇ l total volume/well) in 96-well assay plates (Costar #3610, Corning Inc., Corning, NY). The nerve growth factor-induced differentiation of the cells was allowed to proceed for 48 hours, at which point toxicity assays were done.
  • MTT in vitro assays -Peptides were pre-incubated either with 0 or 25 ⁇ M compound in 1OmM sodium phosphate, pH 7.4, at 37°C for 0, 2, 3, or 7 days prior to addition of a 10 ⁇ l aliquot of the peptide: compound mixture to the differentiated PC 12 cells.
  • a ⁇ were incubated as described above, but in the absence of compound.
  • the peptide solutions were mixed with 0 or 25 ⁇ M compound immediately before addition to cells.
  • Cells were treated for 24 hours with a final concentration of 0 or approximately 2 ⁇ M A ⁇ alone or with A ⁇ plus 2.5 ⁇ M compound.
  • MTT solution Promega, Madison, WI
  • 15 ⁇ l of MTT solution were added to each well of the microtiter plate and the plate were incubated in the CO 2 incubator for an additional 3.5 hours.
  • the cells were lysed by the addition of 100 ⁇ l of solubilization solution (Promega, Madison, WI) followed by overnight incubation.
  • MTT reductions were assessed by measuring absorption at 570nm (corrected for background absorbance at 630nm) using a BioTek Synergy HT microplate reader (Bio-Tek Instruments, Winooski, Vermont). Controls included media with sodium phosphate ("negative”), peptides or fibrils ("positive”), and 1 ⁇ M staurosporine ("maximal positive").
  • LDH in vitro assays CytoTox-ONE Homogeneous Membrane Integrity assay was used to measure LDH.
  • Peptide and peptide:compound solutions prepared as described above for MTT in vitro assays were incubated with the cells for 48 hr. 100 ⁇ l of LDH reagent were added to each well. The plates incubated in the dark for 10 min, after which 50 ⁇ l of stop solution was added and the fluorescence measured using the BioTek Synergy HT microplate reader with excitation wavelength of 560 nm and emission wavelength of 590 nm. Controls included media with sodium phosphate ("negative”), peptide or fibrils ("positive”), and lysis solution (“maximal positive").
  • Monomelic or fibrillar A ⁇ 40 and A ⁇ 42 were added to cells at final concentrations of lO ⁇ M and 5 ⁇ M, respectively. Six replicates were performed for each treatment group and the data from 4 independent experiments were combined. Results were reported as mean ⁇ S. E. Percent toxicity was calculated according to the formula above, except the term Astaurospo ⁇ ne was replaced with Alysis. Ten (10) compounds from MODEL IA met all parameters for efficacy and favorable toxicology, including A2960599 and A2750186.
  • a ⁇ l-42 peptide was dissolved in l,l,l,3,3,3,-hexafluoro-2-propanol (HFIP; Sigma- Aldrich), incubated at room temperature for 60 minutes, aliquoted, vacuum dried, and stored at -80°C.
  • a ⁇ peptide was dissolved in DMSO and diluted into ddH2O to a final concentration of 100 ⁇ g/ml.
  • the peptide was mixed with an equal volume of compound (1 :1 ratio) and incubated at 37°C for 1 day. Following incubation, samples were centrifuged at 14,000 g for 10 minutes at 4°C.
  • the mixture was irradiated for Is and quenched immediately with lO ⁇ L of Tricine sample buffer (Invitrogen) containing 5% b- mercaptoethanol (Bitan et al., 2001).
  • the reaction was subjected to SDS-PAGE and visualized by silver staining (SilverXpress; Invitrogen).
  • MODEL Iy 4 Five compounds from MODEL Iy 4 (MODEL 4; Table 3) demonstrating A ⁇ -lowering activity were screened by MODEL Iv 5 (MODEL 5) to determine if any of the compounds had anti-aggregation activity. After rating the five compounds as "probable,” four of these compounds (L1761 17 or A3932292; 7216540379 or A4971549; 863538 or A6239807; and 19-2800 or A1862443) were also screened ( Figure 7). In addition, photo- induced cross-linking of unmodified proteins (PICUP) analysis was used to confirm the anti- oligomeric A ⁇ activity of A2641934, A2739476, and A3414817.
  • PICUP photo- induced cross-linking of unmodified proteins
  • Compounds 1 and 3 were subsequently subjected to short-term in vivo efficacy testing (Figure 5).
  • Figure 5 As Compounds 1 and 3 were highly insoluble, i.p administration was required. Specifically, two-month-old TgCRND 8 mice were treated with 2 mg/kg/day via i.p. injection. The treatment continued for two weeks. At ten weeks of age, animals were decapitated and brains were removed for neuropathology analysis. The 2 mg/kg/day treatment was well-tolerated as reflected by their normal body weight and food consumption. Total brain A ⁇ 42 was significantly reduced in both Compound 1 and Compound 3 treatment ( Figure 5a).
  • Column 1 of Table 25 contains the chemical class while column 2 contains the molecule identifier number or name.
  • Column 3 of Table 25 contains the predicted anti- aggregation activity of beta amyloid while the experimental results based on evaluation of anti-aggregation activity are disclosed in column 4.
  • Column 5 contains the experimental results from in vitro anti-aggregation testing.
  • Column 6 contains the test compound to peptide ratio that is required to inhibit aggregation by 50%. The smaller the ratio, the more potent the test compound.
  • Double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PSl-dE9) both directed to CNS neurons will be used. Both mutations are associated with early-onset Alzheimer's disease.
  • the "humanized" Mo/HuAPP695swe transgene allows the mice to secrete a human A-beta peptide. Both the transgenic peptide and holoprotein can be detected by antibodies specific for human sequence within this region (Signet Laboratories' monoclonal 6E10 antibody).
  • the included Swedish mutations (K595N/M596L) elevate the amount of A ⁇ produced from the transgene by favoring processing through the beta-secretase pathway.
  • Transgenic mice develop beta-amyloid deposits in brain as early as four months of age. These animals also display a slight alteration in their tail phenotype that is believed to be due to the mixed genetic background of the strain and is not related to transgene expression.
  • the Mo/HuAPP695swe transgene expresses a "humanized" mouse amyloid beta (A4) precursor protein gene modified at three amino acids to reflect the human residues and further modified to contain the K595N/M596L Swedish mutations linked to familial Alzheimer's.
  • A4 mouse amyloid beta
  • mice Male B6C3-Tg mice (Jax Laboratories) will be randomly assigned to the following compound treatment groups. Animals are treated at approximately 5 months of age with a starting dose of 5 mg/kg/day and increased 2-fold every 7-8 days until reaching a dose of 160 mg/kg/day according to the method of Wang et al (2006). In parallel control studies, age-, strain-, and gender-matched wild-type (WT) mice are subjected to the same treatment. Liquid consumption, food intake, and animal body weight are monitored weekly throughout the study.
  • mice are anesthetized with the general inhalation anesthetic l-chloro-2,2,2- trifluoroethyl difluoromethyl ether (Baxter Healthcare) and sacrificed by decapitation. Brains are harvested and hemi-dissected. One hemisphere is fixed in 4% paraformaldehyde for 24 hours for histological studies. Hippocampus and cortex are dissected from the opposite hemisphere, rapidly frozen, pulverized in liquid nitrogen, and stored at -80°C for biochemical studies.
  • Tg2576 mice and GSPE treatment - Tg2576 AD transgenic mice (catalog #001349; Taconic) are used.
  • a ⁇ peptide content in the brain accumulates exponentially between 7 and 15 months of age (Hsiao et al., 1996; Kawarabayashi et al., 2001). Therefore, animals are treated for 5 months, starting at 6 (for behavioral testing) and 10 (for neuropathology and mechanistic study) months of age.
  • mice which have a more robust plaque neuropathology (Callahan et al., 2001) and low mortality rate compared with the male Tg2576 mice, will be assigned to two different groups: the compound treatment group and the water control group. Animals are treated at approximately 5 months of age with a starting dose of 5 mg/kg/day and increased 2 fold every 7-8 days until reaching a dose of 160 mg/kg/day according to the method of Wang et al (2006). Animals have ad libitum access to the liquid and standard chow. After 5 months of treatment, mice are anesthetized with the general anesthetic ketamine HCl and xylazine (Fort Dodge Animal Health) and killed by decapitation. Brains are harvested as described previously (Wang et al., 2005).
  • mice are given a single dose of glucose postprandially (i.p. 2 g/kg body weight). Blood is collected from the tail vein periodically over a 2-hour period. Blood glycemic content is assessed using the OneTouch LifeScan System (LifeScan), following the manufacturer's instructions.
  • LifeScan OneTouch LifeScan System
  • frozen pulverized tissue is homogenized in 5.0 M guanidine buffer, diluted (1 : 10) in PBS containing 0.05% (vol/vol) Tween-20 and 1 mM Pefabloc protease inhibitors (Roche Biochemicals) and centrifuged for 20 minutes at 4°C.
  • Total A ⁇ 40 or A ⁇ 42 is quantified by sandwich ELISA (BioSource).
  • Serum A ⁇ content is analyzed using ELISA.
  • 4% paraformaldehyde-fixed brain is sectioned, and every 15th section is selected from a random start position and processed for thioflavin-S staining.
  • the amyloid burden is estimated using the Cavalieri principle with a small-size grid (50x50m) for point counting. Estimates of plaque volume will be obtained using a systematic random sampling procedure at 4Ox magnification.
  • Serum A ⁇ content is analyzed using the same ELISA kit, following manufacturer's instructions.
  • For stereological assessment of AD-type amyloid burden freshly harvested mouse brain hemispheres are immersed and fixed overnight in 4% paraformaldehyde. They are then sectioned in the coronal plane on a Vibratome at a nominal thickness of 50 ⁇ m. Every 12th section is selected from a random start position and processed for thioflavin-S staining. All stereologic analyses are performed using a Zeiss Axiophoto photomicroscope equipped with a Zeiss motorized stage and MSP65 stage controller, a high-resolution MicroFire digital camera, and a Dell computer running the custom-designed software Stereo Investigate (MBF Bioscience). The amyloid burden will be estimated using the Cavalieri principle with a small-size grid (25 * 25 ⁇ m) for point counting.
  • TgCRND8 Mouse Model The in vivo assessment of compound effects on A ⁇ activity levels were assessed. Short-term in vivo studies of compounds in the TGCRND8 mouse model of AD were conducted. Compounds 1 (A2641934) and 3 (A2739476) were chosen for the short-term feasibility study. Shown in Figure 5(A) is total brain A ⁇ 42 and A ⁇ 40 in TgCRND ⁇ mice treated with Compound 1 or compound 3. Fig. 5(B) shows the level of high molecular weight (HMW) soluble oligomeric content in the brain by Western blot analysis. Compounds 1 and 3 (A2641934 and A2739476), shown to have anti-aggregation activity by PICUP assay, were subsequently subjected to short-term in vivo efficacy testing (Fig. 5).
  • HMW high molecular weight
  • test compounds resulted in the use of i.p. injection for administration of test compounds. Nevertheless, i.p. injection created extreme discomfort for the animals, which required halting the study at the end of two weeks rather than the normal four weeks.
  • oral administration via solid food will be attempted in a four-week study to enable accurate selection of the most potent compound for continued drug development. Therefore, all eight compounds will be tested in vivo using two-month-old TgCRND ⁇ mice. Brain amyloid content, HMW oligomer levels and determination of bioavailability will also be performed.
  • Example 7 Evaluation of in vivo A ⁇ anti-aggregation or aggregation-lowering activity.
  • the level of soluble A ⁇ oligomers are measured both by dot blot assay and Western blot analysis and quantified by ELISA. Briefly, soluble amyloid peptide is extracted in PBS supplemented with protease inhibitor mixture stock (25x aqueous solution; Roche Applied Science). After centrifugation at 78,50Og for 1 hour at 4°C, the supernatant is analyzed. Five micrograms of total protein are spotted on nitrocellulose membrane and probed with 6E10 antibody (1 :1,000; Signet) specific for oligomeric forms of A ⁇ .
  • the immunoreactive signals are visualized using enhanced chemiluminescence detection (Pierce) and quantified densitometrically (Quantity One; Bio-Rad).
  • the same sample is also used for Western analysis. Seventy- five micrograms of total protein are separated by 10-20% Tris-Tricine gel, transferred to a
  • Results are confirmed using a dot blot immunoassay with an antibody (Al l) that selectively detects HMW A ⁇ species with molecular masses greater than 40 kDa.
  • Example 6 in vivo A ⁇ - lowering activity
  • Example 7 in vivo A ⁇ anti-aggregation activity
  • Example 8 Behavioral assessment of cognitive function by the Morris Water Maze (MWM) test - the MWM test is used to evaluate working and reference memory function in response to treatment with compounds in B6C3-Tg or Tg2576 mice.
  • Mice are tested in a 1.25m circular pool filled with water mixed with nontoxic white paint. Mice are trained to mount a hidden/submerged (1.5 cm below water surface) escape platform (14x14 cm) in a restricted region of the pool. Spatial memory is assessed by recording the latency time for the animal to escape from the water onto a submerged escape platform as a function of the number of learning trials during the learning phase. Twenty- four hours after the learning phase, mice are subjected to a 45-second probe trial wherein the escape platform is removed. The water maze activity is monitored with the San Diego Instrument Poly-Track video tracking system. The behavior analysis is consistently conducted during the last 4 hours of the day portion of the light cycle in an environment with minimal stimuli (e.g., noise, movement, or changes in light or temperature).
  • minimal stimuli
  • holoamyloid precursor protein is examined by Western blot analysis with the C8 antibody (raised against aa 676-695 of the human APP cytoplasmic domain). Immunoprecipitation is performed for detection of soluble APP (sAPP)- ⁇ or sAPP- ⁇ as described previously (Wang et al., 2005). The ⁇ -, ⁇ -, and ⁇ -secretase activities are assessed using commercially available kits (R&D Systems) (Ho et al., 2004; Wang et al., 2006). The ⁇ -, ⁇ -, and ⁇ - carboxy terminal fragments (CTFs) are assessed by Western blot analysis using conventional techniques.
  • CTFs carboxy terminal fragments
  • Frozen pulverized brain samples are homogenized in 9 volumes (w/v) of buffer (50 mM Tris, pH 7.4, 150 mM NaCl, 1% SDS, 5 mM EDTA, 2 mM 1 , 10-phenanthroline, and Sigma protease inhibitor mixture), boiled, sonicated, boiled again, and centrifuged at 16,000 g. Supernatant is diluted 10-fold with 50 mM Tris-HCl, and CTF fragments are immunoprecipitated with antibody (Ab) C8 (raised against aa 676-695 of the human APP cytoplasmic domain) bound to protein A Sepharose beads (Roche Biochemicals, Indianapolis, IN, USA).
  • buffer 50 mM Tris, pH 7.4, 150 mM NaCl, 1% SDS, 5 mM EDTA, 2 mM 1 , 10-phenanthroline, and Sigma protease inhibitor mixture
  • homogenate is added to secretase-specific APP peptide conjugated to the reporter molecules EDANS and DABCYL.
  • fluorescent emissions from EDANS are quenched by the physical proximity of the DABCYL moiety, which exhibits maximal absorption at the same wavelength (495 nm) as EDANS emission.
  • Cleavage of APP peptide by secretase physically separates the EDANS and DABCYL reporter molecules, allowing for the release of a fluorescent signal.
  • the level of secretase enzymatic activity is proportional to the fluorometric reaction in the homogenate (R&D Systems).
  • Table 27 provides active chemical compound names, the core chemical structure, or scaffold, of active compounds, as well as the structures of R groups that can be attached to the cores or scaffolds. It is expressly contemplated that an active compound will have any combination of R groups described for a given scaffold, as disclosed herein and in Table 27. Although an effort was made to provide as much information in Table 27 as possible, description provided in the application is not negated by its absence from Table 27 and the disclosure should be viewed in its entirety. DS AND R GROUPS

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Hospice & Palliative Care (AREA)
  • Psychiatry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention comprend des composés réduisant Aβ et/ou anti-agrégation de Aβ et leurs utilisations dans des compositions pharmaceutiques. La présente invention comprend en outre des procédés de formulations de compositions pharmaceutiques et des procédés d'administration des compositions pour le traitement de la maladie d'Alzheimer.
PCT/US2010/001041 2009-04-03 2010-04-05 Compositions pour le traitement de la maladie d'alzheimer WO2010114636A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
EP10759174A EP2413696A4 (fr) 2009-04-03 2010-04-05 Compositions pour le traitement de la maladie d'alzheimer
AU2010232923A AU2010232923A1 (en) 2009-04-03 2010-04-05 Compositions for treatment of Alzheimer's disease
CA2759187A CA2759187A1 (fr) 2009-04-03 2010-04-05 Compositions pour le traitement de la maladie d'alzheimer

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US21182109P 2009-04-03 2009-04-03
US61/211,821 2009-04-03

Publications (1)

Publication Number Publication Date
WO2010114636A1 true WO2010114636A1 (fr) 2010-10-07

Family

ID=42828621

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2010/001041 WO2010114636A1 (fr) 2009-04-03 2010-04-05 Compositions pour le traitement de la maladie d'alzheimer

Country Status (4)

Country Link
EP (1) EP2413696A4 (fr)
AU (1) AU2010232923A1 (fr)
CA (1) CA2759187A1 (fr)
WO (1) WO2010114636A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102391262A (zh) * 2011-07-20 2012-03-28 延边大学 含3-羧烷基罗丹宁衍生物的抗菌化合物
US20140142134A1 (en) * 2011-07-13 2014-05-22 Microbiotix, Inc. Inhibitors of bacterial type iii secretion system
WO2014186450A2 (fr) * 2013-05-14 2014-11-20 The Board Of Regents Of The University Of Texas System Inhibiteurs très puissants de porc-épic
WO2022120150A1 (fr) * 2020-12-03 2022-06-09 Duke University Dérivés d'amiloride et procédés d'utilisation de ceux-ci pour le traitement d'infections virales

Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4898867A (en) * 1987-09-16 1990-02-06 Taiho Pharmaceutical Company, Limited Thienopyrimidine derivaties as aldose-reductase inhibitors
US5019574A (en) * 1988-09-30 1991-05-28 Chugai Seiyaku Kabushiki Kaisha 3,4-diaminoquinoline and 3,4-diamino-5,6,7,8-tetrahydroquinoline compounds useful for improving psychoneural function
US5523314A (en) * 1992-09-10 1996-06-04 Eli Lilly And Company Compounds useful as hypoglycemic agents and for treating Alzheimer's disease
US5948819A (en) * 1994-04-06 1999-09-07 Shionogi & Co., Ltd α-substituted phenylacetic acid derivative, its production and agricultural fungicide containing it
US6069110A (en) * 1995-12-21 2000-05-30 Basf Aktiengesellschaft Bis- and tris(pyrazolyl)borate metal complex catalysts
US20020120139A1 (en) * 1997-11-06 2002-08-29 Deirdre Mary Bernadette Hickey Pyrimidinone compounds and pharmaceutical compositions containing them
US6559155B1 (en) * 1998-08-21 2003-05-06 Smithkline Beecham P.L.C. Pyrimidinone derivatives for the treatment of atherosclerosis
WO2005012286A1 (fr) * 2003-07-25 2005-02-10 Amgen Inc. Pyridones et pyrimidinones substituees a proprietes anti-inflammatoires
US20050153980A1 (en) * 2002-04-16 2005-07-14 Oliver Schadt Substituted indoles
US20050272789A1 (en) * 2001-04-27 2005-12-08 Hale Michael R Triazole-derived kinase inhibitors and uses thereof
US20070135502A1 (en) * 2001-11-21 2007-06-14 Bach Andrew T Heterocyclic compounds and methods of use
US20070225333A1 (en) * 2004-04-28 2007-09-27 Bryans Justin S 3-Heterocyclyl-4-Phenyl-Triazole Derivatives as Inhibitors of the Vasopressin Via Receptor
US20080039465A1 (en) * 2006-07-14 2008-02-14 Charvat Trevor T Triazolyl phenyl benzenesulfonamides
US20080044356A1 (en) * 2004-10-22 2008-02-21 Regents Of The University Of Minnesota Assemblies of Oligomeric Amyloid Beta Protein and Uses Thereof
US20080267911A1 (en) * 2007-04-18 2008-10-30 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
US20090023801A1 (en) * 2007-07-16 2009-01-22 Wyeth Inhibitors of beta amyloid production

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992001455A1 (fr) * 1990-07-25 1992-02-06 Luedke Hans Werner Medicament contre les maladies degeneratives des fonctions cerebrales du type de la maladie d'alzheimer et troubles du systeme cholinergique
ITMI20020347A1 (it) * 2002-02-21 2003-08-21 Polimeri Europa Srl Complessi tris-pirazolil borati di nichel e loro impiego nella omoco e ter-polimeririzzazione di alfa-olefine

Patent Citations (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4898867A (en) * 1987-09-16 1990-02-06 Taiho Pharmaceutical Company, Limited Thienopyrimidine derivaties as aldose-reductase inhibitors
US5019574A (en) * 1988-09-30 1991-05-28 Chugai Seiyaku Kabushiki Kaisha 3,4-diaminoquinoline and 3,4-diamino-5,6,7,8-tetrahydroquinoline compounds useful for improving psychoneural function
US5523314A (en) * 1992-09-10 1996-06-04 Eli Lilly And Company Compounds useful as hypoglycemic agents and for treating Alzheimer's disease
US5948819A (en) * 1994-04-06 1999-09-07 Shionogi & Co., Ltd α-substituted phenylacetic acid derivative, its production and agricultural fungicide containing it
US6069110A (en) * 1995-12-21 2000-05-30 Basf Aktiengesellschaft Bis- and tris(pyrazolyl)borate metal complex catalysts
US20020120139A1 (en) * 1997-11-06 2002-08-29 Deirdre Mary Bernadette Hickey Pyrimidinone compounds and pharmaceutical compositions containing them
US6559155B1 (en) * 1998-08-21 2003-05-06 Smithkline Beecham P.L.C. Pyrimidinone derivatives for the treatment of atherosclerosis
US20050272789A1 (en) * 2001-04-27 2005-12-08 Hale Michael R Triazole-derived kinase inhibitors and uses thereof
US20070135502A1 (en) * 2001-11-21 2007-06-14 Bach Andrew T Heterocyclic compounds and methods of use
US20050153980A1 (en) * 2002-04-16 2005-07-14 Oliver Schadt Substituted indoles
WO2005012286A1 (fr) * 2003-07-25 2005-02-10 Amgen Inc. Pyridones et pyrimidinones substituees a proprietes anti-inflammatoires
US20070225333A1 (en) * 2004-04-28 2007-09-27 Bryans Justin S 3-Heterocyclyl-4-Phenyl-Triazole Derivatives as Inhibitors of the Vasopressin Via Receptor
US20080044356A1 (en) * 2004-10-22 2008-02-21 Regents Of The University Of Minnesota Assemblies of Oligomeric Amyloid Beta Protein and Uses Thereof
US20080039465A1 (en) * 2006-07-14 2008-02-14 Charvat Trevor T Triazolyl phenyl benzenesulfonamides
US20080267911A1 (en) * 2007-04-18 2008-10-30 Probiodrug Ag Novel inhibitors of glutaminyl cyclase
US20090023801A1 (en) * 2007-07-16 2009-01-22 Wyeth Inhibitors of beta amyloid production

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2413696A4 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20140142134A1 (en) * 2011-07-13 2014-05-22 Microbiotix, Inc. Inhibitors of bacterial type iii secretion system
US9340551B2 (en) * 2011-07-13 2016-05-17 Microbiotix, Inc. Inhibitors of bacterial type III secretion system
CN102391262A (zh) * 2011-07-20 2012-03-28 延边大学 含3-羧烷基罗丹宁衍生物的抗菌化合物
WO2014186450A2 (fr) * 2013-05-14 2014-11-20 The Board Of Regents Of The University Of Texas System Inhibiteurs très puissants de porc-épic
WO2014186450A3 (fr) * 2013-05-14 2015-01-29 The Board Of Regents Of The University Of Texas System Inhibiteurs très puissants de porc-épic
US9783550B2 (en) 2013-05-14 2017-10-10 The Board Of Regents Of The University Of Texas System Highly potent inhibitors of porcupine
WO2022120150A1 (fr) * 2020-12-03 2022-06-09 Duke University Dérivés d'amiloride et procédés d'utilisation de ceux-ci pour le traitement d'infections virales

Also Published As

Publication number Publication date
EP2413696A4 (fr) 2012-10-24
AU2010232923A1 (en) 2011-11-03
EP2413696A1 (fr) 2012-02-08
CA2759187A1 (fr) 2010-10-07

Similar Documents

Publication Publication Date Title
Wang et al. Small molecule therapeutics for tauopathy in Alzheimer’s disease: walking on the path of most resistance
Zhang et al. Impairment of the autophagy–lysosomal pathway in Alzheimer's diseases: pathogenic mechanisms and therapeutic potential
EP2285366B1 (fr) Molecules inhibant une voie metabolique impliquant la proteine tyrosine kinase syk et procede d'identification de ces molecules
Skerratt Recent progress in the discovery and development of TRPA1 modulators
Tang et al. A novel drug candidate for Alzheimer's disease treatment: gx-50 derived from Zanthoxylum bungeanum
US20110027251A1 (en) Novel uses for 4-phenylbutyrate (4pba) and its pharmaceutically acceptable salts
Parry et al. Functional amyloid signaling via the inflammasome, necrosome, and signalosome: new therapeutic targets in heart failure
Yang et al. Pioglitazone ameliorates Aβ42 deposition in rats with diet-induced insulin resistance associated with AKT/GSK3β activation
US20100120787A1 (en) Modification of amyloid-beta load in non-brain tissue
Xiao et al. Tetrahydrocurcumin ameliorates Alzheimer's pathological phenotypes by inhibition of microglial cell cycle arrest and apoptosis via Ras/ERK signaling
WO2019205748A1 (fr) APPLICATION D'UN COMPOSÉ DANS L'INHIBITION DE L'ACCUMULATION D'Aβ ET LE TRAITEMENT DE LA MALADIE D'ALZHEIMER
WO2010114636A1 (fr) Compositions pour le traitement de la maladie d'alzheimer
JP2021001188A (ja) Ａｐｐ選択的ｂａｃｅ阻害のための組成物およびそのための使用
WO2011050095A2 (fr) Prévention et traitement des dysfonctions cognitives postopératoires (pocd)
Xi et al. Advances and perspectives of proteolysis targeting chimeras (PROTACs) in drug discovery
Zhang et al. TLR4-IN-C34 inhibits lipopolysaccharide-stimulated inflammatory responses via downregulating TLR4/MyD88/NF-κB/NLRP3 signaling pathway and reducing ROS generation in BV2 cells
Gitto et al. Discovery of neuroprotective agents based on a 5-(4-Pyridinyl)-1, 2, 4-triazole scaffold
Craft et al. Aminopyridazines attenuate hippocampus-dependent behavioral deficits induced by human β-amyloid in a murine model of neuroinflammation
Li et al. Ginsenoside Rg1 alleviates learning and memory impairments and Aβ disposition through inhibiting NLRP1 inflammasome and autophagy dysfunction in APP/PS1 mice
Wang et al. The therapeutic potential of berberine chloride against SARM1‐dependent axon degeneration in acrylamide‐induced neuropathy
Wei et al. An inhibitor of Grp94 inhibits OxLDL-induced autophagy and apoptosis in VECs and stabilized atherosclerotic plaques
Malik et al. Synthesis, characterization, in-silico, and pharmacological evaluation of new 2-amino-6‑trifluoromethoxy benzothiazole derivatives
Zhang et al. Design, synthesis and biological evaluation of novel osthole-based derivatives as potential neuroprotective agents
Abad et al. Effects of MDMA on neuroplasticity, amyloid burden and phospho-tau expression in APPswe/PS1dE9 mice
US11364211B2 (en) Methods for selecting phosphatase selective and non-selective phosphatase inhibitors

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 10759174

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2759187

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: 2010759174

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2010232923

Country of ref document: AU

Date of ref document: 20100405

Kind code of ref document: A