WO1998027972A2 - Anti-amyloidogenic agents - Google Patents
Anti-amyloidogenic agents Download PDFInfo
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- WO1998027972A2 WO1998027972A2 PCT/US1997/024181 US9724181W WO9827972A2 WO 1998027972 A2 WO1998027972 A2 WO 1998027972A2 US 9724181 W US9724181 W US 9724181W WO 9827972 A2 WO9827972 A2 WO 9827972A2
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- WIPO (PCT)
- Prior art keywords
- compound
- alkyl
- protein
- amyloidogenic protein
- acid
- Prior art date
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- 0 *(C1C=CC=CC1)c1ccccc1 Chemical compound *(C1C=CC=CC1)c1ccccc1 0.000 description 3
- QHXTYOSFGTWRJY-UHFFFAOYSA-N CC(C(O)=C)c1cc(C2=[IH]=NC=C2)ccc1 Chemical compound CC(C(O)=C)c1cc(C2=[IH]=NC=C2)ccc1 QHXTYOSFGTWRJY-UHFFFAOYSA-N 0.000 description 1
- NAPDPGHAUPOITB-UHFFFAOYSA-N CC(C(O)=O)c1cc(-c(cc2)ccc2C(C(F)(F)F)=O)ccc1 Chemical compound CC(C(O)=O)c1cc(-c(cc2)ccc2C(C(F)(F)F)=O)ccc1 NAPDPGHAUPOITB-UHFFFAOYSA-N 0.000 description 1
- DCJCSFSLTOPXKC-UHFFFAOYSA-N CC(C(O)=O)c1cc(-c2ccc(C=O)cc2)ccc1 Chemical compound CC(C(O)=O)c1cc(-c2ccc(C=O)cc2)ccc1 DCJCSFSLTOPXKC-UHFFFAOYSA-N 0.000 description 1
- PKIJCKJIXMXUCB-UHFFFAOYSA-N C[IH]1=CC(Cl)=CC=C1 Chemical compound C[IH]1=CC(Cl)=CC=C1 PKIJCKJIXMXUCB-UHFFFAOYSA-N 0.000 description 1
- VJXBYCZCWPIBRJ-UHFFFAOYSA-N OCc(cc1I)cc(I)c1O Chemical compound OCc(cc1I)cc(I)c1O VJXBYCZCWPIBRJ-UHFFFAOYSA-N 0.000 description 1
Classifications
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- 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
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/603—Salicylic acid; Derivatives thereof having further aromatic rings, e.g. diflunisal
-
- 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
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
- A61K31/055—Phenols the aromatic ring being substituted by halogen
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- 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
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- 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
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
Definitions
- Alzheimer's disease includes acetylcholinesterase inhibitors which are intended to inhibit the degradation of acetylcholine .
- the disease is senile systemic amyloidosis or familial amyloid polyneuropathy I; or Alzheimer's disease; or spongiform encephalopathy.
- the amyloidogenic protein is transthyretin or a variant thereof.
- the compound has the formula (la), (la'), (lb), (lc) , (Id), or is selected from the individually disclosed compounds.
- the compound is fenoprofen or flufenamic acid.
- the invention also features those disclosed compounds which have novel structures.
- Fig. 1 is a ball-and-stick model of the flufenamic binding site of TTR. Only residues that line the binding cavity are displayed. Flufenamic acid is shown in one of the two binding modes. Because of the two-fold symmetry along the binding channel two molecules fit the final 2 ] F 0
- the CF 3 substituent occupies the innermost T4 hologen binding pocket, interacting with Ser-117, Thr- 119, Leu-110 and Ala-108 providing hydrophilic and hydrophobic fluorine contacts.
- the aromatic rings interact with the hydrophobic patch between the residues Leu-17 and Ala-108. Finally the carboxylate group on the outer phenyl ring is placed at the entrance of hte funnel-shaped binding pocket forming electrostatic interactions with two Lys-15 residues. The image has been generated using the program 0 (18) .
- Figure 2 shows that upon binding of flufenamic acid, the side chans of Ser-117, Thr-119, and Lys-15 undergo conformational changes as indicated.
- the Ser-117 residues particiate in intersubunit hydrogen bonding while the Thr-119 side rotates to form a hydrogen bond to an ordered water molecule which is hydrogen bonded to carbonyl oxygen of Asp-18' on an adjacent subunit.
- amyloidogenic precursor proteins are, respectively: ⁇ protein ( ⁇ protein 1-40, 1-41, 1-42, and 1-43), immunoglobin light chain (intact light chain or fragments thereof) (several single site variants) , serum amyloid A (amyloid A
- transthyretin transthyretin or fragments thereof
- transthyretin over 45 transthyretin variants
- cystatin C cystatin C minus 10 residues
- ⁇ _- microglobulin same
- apolipoprotein A-l fragments thereof
- gelsolin 71 amino acid fragment thereof
- Islet amyloid polypeptide or IAPP fragment of IAPP
- calcitonin fragmentments thereof
- prion prion or fragments thereof
- atrial natriuretic factor or ANF atrial natriuretic factor or ANF
- lysozyme lysozyme or fragments thereof
- insulin sine
- fibrinogen fragments thereof
- the amyloidogenic protein is selected from any of the above, excluding lysozyme, insulin, or both.
- An amyloidogenic protein is a precursor protein, or fragment thereof, which can be converted into an insoluble amyloid fibril in vivo .
- Amyloidogenic proteins include a non-fibril conformation, the normally-folded amyloid protein, or a tertiary or quaternary structure that precedes the amyloid such as an oligomer or partially folded protein in the case of a proteolytic fragment of an amyloidogenic protein.
- Amyloidogenic proteins are generally soluble and include nonnative quaternary structures that precede amyloid fibril assembly, such as a 16-mer, a 44-mer, or a 64-mer.
- Amyloidogenic proteins also include fibril components (as listed in parentheses above) .
- An amyloidogenic protein-stabilizing compound can act by binding reversibly, and preferably selectively, to one or more amyloidogenic proteins. Binding to a protein can stabilize an existing protein conformation, or render the protein resistant to the abnormal degradation or partial denaturation which results in amyloid formation or deposition. The binding of the amyloid stabilizing compound to any of the above reduces, in part or whole, the overall formation of amyloid. Examples of amyloid stabilizing compounds are formulae (la) , (lb) , (lc) , and (Id) . An amyloidogenic protein-stabilizing compound can also act by irreversible binding (covalent linkage) to the amyloidogenic protein.
- An amyloidogenic protein-stabilizing compound preferably binds to an amyloidogenic protein, e.g., transthyretin, with a higher affinity that it binds to a non-amyloidogenic protein.
- a non- amyloidogenic protein is a protein or receptor, such as a hormone receptor, a human serum binding protein, or an amyloid fibril.
- a higher affinity refers to a K a relative to amyloidogenic protein at least 5 times lower (e.g., about one or more magnitudes lower) than the ⁇ L_ of the non-amyloidogenic protein.
- TTR liver transplant studies have indicated that TTR amyloid can be cleared in vivo .
- the combination of the rate of clearance of amyloidogenic proteins e.g., the quaternary structures such as a 16-mer
- the rate of fibril formation are considered together.
- an amyloidogenic protein-drug conjugate includes a drug, e.g., an amyloidogenic protein-stabilizing compound reversibly bound to an amyloidogenic protein.
- the reversibly binding is with high affinity (low K_) , and with a low off-rate relative to on-rate so the drug occupies the amyloidogenic protein for an effective period of time.
- Transthyretin includes the wild type protein and any of the more than fifty variants having one or more mutations that are associated with the onset of either senile systemic amyloidosis or familial amyloid polyneuropathy, such as Val-30-Met mutation. Although most single site mutations do not significantly affect the tertiary or quaternary structure of tetrameric TTR, they may nevertheless destabilize the protein. A variant can be used in an in vi tro assay wherein a disclosed compound binds to TTR with a higher affinity than a serum protein.
- Human serum binding proteins include thyroxine binding globulin (TBG) , serum albumin, globulins, transferrin, ceruplasmin, glycoproteins, ⁇ -lipoproteins, and /3-lipoproteins.
- Thyroid hormone receptors generally regulate growth, development, and metabolic rates in different tissues including cardiovascular, skeletal, gastrointestinal, and neuromuscular systems.
- Thyroid metabolites of thyroxine such as T3 and agonists or antagonists thereof bind to thyroid hormone receptors. Excessive exposure to thyroid hormone agonists may result in, for example, bradycardia, menstrual abnormalities, weight gain, or anxiety.
- a amyloidogenic protein-stabilizing compound preferably has a relatively low affinity for a thyroid hormone receptors, e.g., binds with a K_ that is at least one order of magnitude, and preferably 1.5, 2, 2.5, or more orders of magnitude higher than the K ⁇ for thyroid metabolites such as T3.
- the compounds disclosed herein which inhibit intermolecular aggregation can be used as therapeutics for any disease or condition that is mediated by an amyloid protein which requires assembly, such as self- assembly of dimeric or oligomeric forms for activity (e.g., neurotoxicity or organ dysfunction).
- One aspect of the invention therefore features a method of inhibiting amyloid protein assembly, including exposing an aqueous solution of amyloid protein at physiological temperature and pH to an amyloidogenic protein- stabilizing compound.
- One embodiment further includes measuring the extent of amyloid protein assembly.
- a preferred compound inhibits TTR fibril formation (Example 7) .
- Sedimentation velocity experiments demonstrated that TTR undergoes conformational change-mediated dissociation to form a monomeric amyloidogenic intermediate which self-assembles into amyloid in the absence of the inhibitor compound (Example 6) , but not in its presence (binds to transthyretin, but does not bind in a pharmacologically significant (or adverse) way to thyroxine binding globulin (TBG) (Example 9) , a thyroid hormone receptor (i.e., is not a potent thyroxine agonist or antagonist) (Example 10), or other plasma proteins.
- TTR oligomeric protein transthyretin
- Another aspect of the invention is a method of imaging an amyloidogenic protein in vivo, including administering a detectable label (e.g., radiolabel or fluorescent label) linked to a disclosed compound, and detecting said label.
- a detectable label e.g., radiolabel or fluorescent label
- One embodiment of this method distinguishes between active (e.g., functional or pathological) conformations or assemblies and inactive or precursor conformations.
- the link can be a covalent bond or an antibody-antigen interaction.
- the invention also includes a method for treating a human light chain deposition disease, comprising administering a pharmaceutically effective amount of a composition including a deposition-inhibiting compound having a formula selected from the formulae (la), (la'), (lb) , (lc) , (Id) , and a non-steroidal anti-inflammatory drug.
- a composition including a deposition-inhibiting compound having a formula selected from the formulae (la), (la'), (lb) , (lc) , (Id) , and a non-steroidal anti-inflammatory drug.
- the invention also features methods of making medicaments for treating human amyloid diseases or conditions characterized, e.g, those by undesired amyloid protein assembly by formulating the designated compounds with a pharmacologically acceptable carrier.
- R a is H or C 1-6 alkyl; each of R b and R c is independently C 1-6 alkyl; provided that at least two of R x - R 17 are each independently selected from halo, C 0 _ 8 hydroxyalkyl , or - A-B, wherein A is branched or straight C 0 . 6 alkylene, C 1 _ 6 acyl , or Ci-g aminoalkylene;
- n and m are independently an integer between 0 and 2, inclusive (e.g., between 0 and 1) .
- a proximate pair of substituents such as R 2 and R 7 or R 6 and R 1X , can be taken together to form a covalent bond. Representative examples of formula (la) are shown in Scheme D.
- R 8 alkyl, -A-B where A is C 0 _ 3 alkylene, C ⁇ acyl , or C 1-4 aminoalkylene, and B is R a , - COOR a , or -0R a , R a being H, C 1-5 alkyl, C 2 _ 6 heterocyclic radical, or C 2 . 5 alkoxyalkyl .
- R 6 is H and each of R 3 , R 5 , and any remaining R ⁇ or R 4 is independently selected from H, I, Br, hydroxy, C 2 . 8 heterocyclic radical, and cyano.
Abstract
Description
Claims
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
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AU57277/98A AU5727798A (en) | 1996-12-23 | 1997-12-23 | Anti-amyloidogenic agents |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
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US77193896A | 1996-12-23 | 1996-12-23 | |
US08/771,938 | 1996-12-23 |
Publications (4)
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WO1998027972A2 true WO1998027972A2 (en) | 1998-07-02 |
WO1998027972A9 WO1998027972A9 (en) | 1998-11-05 |
WO1998027972A3 WO1998027972A3 (en) | 1999-02-18 |
WO1998027972A8 WO1998027972A8 (en) | 2001-05-31 |
Family
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Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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PCT/US1997/024181 WO1998027972A2 (en) | 1996-12-23 | 1997-12-23 | Anti-amyloidogenic agents |
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AU (1) | AU5727798A (en) |
WO (1) | WO1998027972A2 (en) |
Cited By (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2001078709A2 (en) * | 2000-04-12 | 2001-10-25 | Minerva Biotechnologies Corporation | Treatment of neurodegenerative disease |
EP1284729A1 (en) * | 2000-04-13 | 2003-02-26 | Mayo Foundation For Medical Education And Research | A(beta)42 lowering agents |
US6670399B2 (en) * | 1999-12-23 | 2003-12-30 | Neurochem (International) Limited | Compounds and methods for modulating cerebral amyloid angiopathy |
GB2421433A (en) * | 2004-12-08 | 2006-06-28 | Sytera Inc | Modulators of retinol binding protein and/or transthyretin for use in the treatment of retinol related diseases |
WO2006110477A2 (en) * | 2005-04-07 | 2006-10-19 | Astrum Therapeutics Pty. Ltd. | Compounds to treat amyloidosis and prevent death of beta-cells in type 2 diabetes mellitus |
US7214696B2 (en) | 2002-12-19 | 2007-05-08 | The Scripps Research Institute | Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding |
US7268164B2 (en) | 1997-03-12 | 2007-09-11 | Queens University At Kingston | Anti-epileptogenic agents |
US7321065B2 (en) | 2003-04-18 | 2008-01-22 | The Regents Of The University Of California | Thyronamine derivatives and analogs and methods of use thereof |
US7339079B2 (en) | 2003-04-18 | 2008-03-04 | The Regents Of The University Of California | Thyronamine derivatives and analogs and methods of use thereof |
EP2007385A2 (en) * | 2006-03-23 | 2008-12-31 | Mount Sinai School of Medicine | Cardiovascular composition and use the same for the treatment of alzheimers disease |
US7504437B2 (en) | 2001-01-26 | 2009-03-17 | Btg International Limited | Benzylamine analogues |
US7678823B2 (en) | 2004-10-04 | 2010-03-16 | Myriad Pharmaceticals, Inc. | Compounds for alzheimer's disease |
US7727511B2 (en) | 2003-05-07 | 2010-06-01 | General Electric Company | Agents for imaging soluble a-beta |
EP2266550A1 (en) * | 2009-06-15 | 2010-12-29 | Institut Curie | Antagonists of ß-catenin for preventing and/or treating neurodegenerative disorders |
US7868033B2 (en) | 2004-05-20 | 2011-01-11 | Foldrx Pharmaceuticals, Inc. | Compounds, compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding |
US8314152B2 (en) | 2004-06-23 | 2012-11-20 | Acucela, Inc. | Methods and compositions for treating ophthalmic conditions with retinyl derivatives |
US8524748B2 (en) | 2008-10-08 | 2013-09-03 | Panmira Pharmaceuticals, Llc | Heteroalkyl biphenyl antagonists of prostaglandin D2 receptors |
US9169214B2 (en) | 2012-12-21 | 2015-10-27 | The Board Of Trustees Of The Leland Stanford Junior University | Compounds and compositions that bind and stabilize transthyretin and their use for inhibiting transthyretin amyloidosis and protein-protein interactions |
US9249112B2 (en) | 2011-09-16 | 2016-02-02 | Pfizer Inc. | Solid forms of a transthyretin dissociation inhibitor |
US9610270B2 (en) | 2011-10-24 | 2017-04-04 | Som Innovation Biotech, S.L. | Therapy for transthyretin-associated amyloidosis |
US10172959B2 (en) | 2014-08-14 | 2019-01-08 | Mamoun M. Alhamadsheh | Systems for stabilizing and delivering active agents |
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1997
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- 1997-12-23 AU AU57277/98A patent/AU5727798A/en not_active Abandoned
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Cited By (49)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US7268164B2 (en) | 1997-03-12 | 2007-09-11 | Queens University At Kingston | Anti-epileptogenic agents |
US6670399B2 (en) * | 1999-12-23 | 2003-12-30 | Neurochem (International) Limited | Compounds and methods for modulating cerebral amyloid angiopathy |
WO2001078709A3 (en) * | 2000-04-12 | 2003-04-17 | Minerva Biotechnologies Corp | Treatment of neurodegenerative disease |
WO2001078709A2 (en) * | 2000-04-12 | 2001-10-25 | Minerva Biotechnologies Corporation | Treatment of neurodegenerative disease |
EP1284729A1 (en) * | 2000-04-13 | 2003-02-26 | Mayo Foundation For Medical Education And Research | A(beta)42 lowering agents |
EP1284729A4 (en) * | 2000-04-13 | 2007-12-19 | Mayo Foundation | A(beta)42 lowering agents |
US7504393B2 (en) | 2001-01-26 | 2009-03-17 | Btg International Limited | Benzylamine analogues |
US7514475B2 (en) | 2001-01-26 | 2009-04-07 | Btg International Limited | Benzylamine analogues |
US7504437B2 (en) | 2001-01-26 | 2009-03-17 | Btg International Limited | Benzylamine analogues |
US7214695B2 (en) | 2002-12-19 | 2007-05-08 | The Scripps Research Institute | Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding |
US7214696B2 (en) | 2002-12-19 | 2007-05-08 | The Scripps Research Institute | Compositions and methods for stabilizing transthyretin and inhibiting transthyretin misfolding |
US7560488B2 (en) | 2002-12-19 | 2009-07-14 | The Scripps Research Institute | Methods for treating transthyretin amyloid diseases |
US8168663B2 (en) | 2002-12-19 | 2012-05-01 | The Scripps Research Institute | Pharmaceutically acceptable salt of 6-carboxy-2-(3,5 dichlorophenyl)-benzoxazole, and a pharmaceutical composition comprising the salt thereof |
US8653119B2 (en) | 2002-12-19 | 2014-02-18 | The Scripps Research Institute | Methods for treating transthyretin amyloid diseases |
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AU5727798A (en) | 1998-07-17 |
WO1998027972A3 (en) | 1999-02-18 |
WO1998027972A8 (en) | 2001-05-31 |
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