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WO2022098847A1 - Analogues de tolcapone et procédés d'utilisation - Google Patents

Analogues de tolcapone et procédés d'utilisation Download PDF

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Publication number
WO2022098847A1
WO2022098847A1 PCT/US2021/058021 US2021058021W WO2022098847A1 WO 2022098847 A1 WO2022098847 A1 WO 2022098847A1 US 2021058021 W US2021058021 W US 2021058021W WO 2022098847 A1 WO2022098847 A1 WO 2022098847A1
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compound
formula
ttr
alkyl
tolcapone
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Michael Roberts
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Corino Therapeutics Inc
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Corino Therapeutics Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B59/00—Introduction of isotopes of elements into organic compounds ; Labelled organic compounds per se
    • C07B59/001—Acyclic or carbocyclic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C205/00—Compounds containing nitro groups bound to a carbon skeleton
    • C07C205/45—Compounds containing nitro groups bound to a carbon skeleton the carbon skeleton being further substituted by at least one doubly—bound oxygen atom, not being part of a —CHO group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic

Definitions

  • Transthyretin (ATTR) amyloidosis includes a group of amyloid diseases specifically associated with transthyretin (TTR) protein.
  • TTR is a 127 amino acid 55 KD homo-tetrameric produced primarily in the liver and secreted into the plasma. Dissociation of the TTR-tetramer at the T4-binding interface generates monomers that misfold and aggregate to form amyloid fibrils. These fibrils, together with unstable fibril precursors, produce cell death and tissue damage.
  • TTR dissociation can be the result of a genetic mutation (hereditary ATTR), aging (wt ATTR) or both.
  • genetic mutation herein.
  • wt ATTR aging
  • amyloidogenic mutations in TTR with diverse clinical manifestations, including hATTR-polyneuropathy (familial amyloid polyneuropathy (FAP)) and hATTR-cardiomyopathy (familial amyloid cardiomyopathy (FAC)).
  • FAP amyloid polyneuropathy
  • FAC hATTR-cardiomyopathy
  • hATTR hereditary ATTR results in a mix of progressive neurological and cardiological impairment. Life expectancy is generally between 5 and 15 years following diagnosis.
  • liver transplantation has been used to treat hATTR since the 1990’s, particularly hATTR- PN.
  • a liver transplantation must take place before significant organ damage has occurred and, in some cases, does not prevent the progression of amyloidosis.
  • transplantation is a major surgical procedure carrying its own risks.
  • TTR stabilizing agent Sant’ Anna R. et al. Nature Communications volume 7, Article number: 10787 (2016), as has AGIO (Penchalla SC et al., Proc Natl Acad Sci USA. 2013 Jun 11; 110(24): 9992-7).
  • Oligonucleotides have also been used to reduce translation of the mRNA encoding TTR protein, thus reducing further amyloid deposition throughout the body. Both RNA interference and antisense approaches have been reported. (Adams, D. et al, N. Engl. J. Med. 379, 11-21 (2016); Benson, M.D et al., N. Engl. J. Med. 379, 22-31 (2016).
  • modified forms of tolcapone, 3-OMT and 3-deoxytolcapone are provided wherein at least one hydrogen atom of the parent compound (i.e., tolcapone, 3-OMT or 3- deoxytolcapone) is replaced with an alkyl, alkenyl, alkynyl, acyl, polypeptide or deuterium (D).
  • compounds of Formula I are provided:
  • R 1 is selected from OH, OD, OR 1a , H, D, alkyl, alkenyl, alkynyl, and polypeptide;
  • R la is selected from alkyl, alkenyl, alkynyl, acyl and polypeptide; each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from alkyl, alkenyl, alkynyl, H and D; and the compound is not tolcapone, 3-OMT, or 3-deoxytolcapone.
  • R 1a is C 1 to C20 alkyl, for example (-(CY2) n -CY 3 ), wherein n
  • each Y is independently selected from H and D.
  • R la is a polypeptide, for example a polypeptide comprising 2 to 500 amino acid residues.
  • R la is selected from H, D, alkyl, alkenyl, alkynyl, acyl and polypeptide; and each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from alkyl, alkenyl, alkynyl, H and D; and the compound is not tolcapone.
  • R la is a polypeptide, for example a polypeptide comprising 2 to 500 amino acid residues.
  • R lb wherein each of R lb , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from alkyl, alkenyl, alkynyl, H and D; and the compound is not 3-OMT.
  • R lb is selected from alkyl, alkenyl and alkynyl.
  • R lc , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from alkyl, alkenyl, alkynyl, H and D; and the compound is not 3-deoxytolcapone.
  • R lc is selected from alkyl, alkenyl and alkynyl.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from H and D; and wherein “linker” is selected from alkyl, alkenyl, alkynyl, acyl and polypeptide.
  • compounds of Formula le are provided: wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from H and D; and wherein “linker” is selected from alkyl, alkenyl and alkynyl.
  • a compound of Formulas I, la, lb, Ic, Id or le comprises at least one D.
  • each R is selected from the group consisting of OH, OR’, H, alkyl, alkenyl, alkynyl, polypeptide, nitro, nitrile, C(O)OR”, iodine, chlorine, bromine, fluorine;
  • R’ is selected from alkyl, alkenyl, alkynyl, acyl and polypeptide;
  • R is selected from H or alkyl; and at least one R is iodine, bromine, chlorine, fluorine or C(O)OR’ ’ .
  • the halogen may be an isotope, for example 18 F, 36 C1, 76 Br, 123 I, 125 I or 131 I.
  • compositions comprising at least one compound described herein are provided.
  • the composition is a pharmaceutical composition that comprises at least one compound described herein and at least one pharmaceutical carrier or excipient.
  • the pharmaceutical composition may be a solid oral dosage form, a liquid oral dosage form or a semi-solid oral dosage form.
  • a compound described herein binds to transthyretin in the T4-binding interface.
  • a compound described herein stabilizes the transthyretin tetramer.
  • a compound described herein prevents the fibrillogenesis of transthyretin.
  • a method for treating an amyloid-associated disease or condition in a subject in need thereof comprising (i) administering to a subject in need thereof a therapeutically effective amount of at least one compound described herein or a pharmaceutical composition comprising the same.
  • the subject is asymptomatic. In another embodiment, the subject has been diagnosed with early-onset hATTR-polyneuropathy. In a further embodiment, the subject has been diagnosed with late-onset hATTR-polyneuropathy.
  • the subject has been diagnosed with hATTR-polyneuropathy (familial amyloid polyneuropathy (FAP)), hATTR-cardiomyopathy (familial amyloid cardiomyopathy (FAC)), hATTR-leptomeningeal, wtATTR-cardiomyopathy, or a combination thereof.
  • FAP familial amyloid polyneuropathy
  • FAC familial amyloid cardiomyopathy
  • hATTR-leptomeningeal wtATTR-cardiomyopathy, or a combination thereof.
  • the amyloid-associated disease or condition is ATTR caused by a genetic mutation (hATTR), aging (wtATTR) or a combination or both.
  • the amyloid-associated disease is hereditary ATTR.
  • the amyloid- associated disease or condition is hATTR-polyneuropathy (hATTR-PN).
  • the amyloid-associated disease or conditions is hATTR-cardiomyopathy (hATTR-CM).
  • the amyloid-associated disease or condition is caused primarily by wild-type (wt) transthyretin and is clinically manifest as ATTR-cardiomyopathy (ATTR-CM).
  • the amyloid-associated disease or condition is hATTR-Leptomeningeal (hATTR- Lepto).
  • the method of treatment results in an increase in TTR stabilization from baseline or compared to a reference subject treated with conventional tolcapone or other TTR stabilizers.
  • the method of treatment results in an increase in TTR concentration from baseline or compared to a reference subject treated with conventional tolcapone or other TTR stabilizers.
  • the method of treatment results in an improvement in the subject’s modified body mass index score (mBMI) from baseline or compared to a reference patient treated with conventional tolcapone or other TTR stabilizers.
  • mBMI modified body mass index score
  • the method of treatment results in an improvement in the subject’s Neuropathic Impairment Score (NIS) or modified Neuropathic Impairment Score (mNIS) from baseline or compared to a reference subject treated with conventional tolcapone or other TTR stabilizers.
  • NIS Neuropathic Impairment Score
  • mNIS modified Neuropathic Impairment Score
  • the method of treatment results in an improvement in the subject’s Norfolk QOL-DN score from baseline or compared to a reference subject treated with conventional tolcapone or other TTR stabilizers.
  • the method of treatment results in a delayed progression of disease from baseline or compared to a reference subject treated with conventional tolcapone or other TTR stabilizers.
  • the method of treatment results in reduced hospitalizations or mortality compared to untreated subjects or reference subjects treated with conventional tolcapone or other TTR stabilizers.
  • the method of treatment further comprises diagnosing the subject with ATTR prior to administering at least one tolcapone analog describe herein or pharmaceutical composition comprising the same. In a particular embodiment, the method further comprising administering one or more additional therapeutic agents to the subject.
  • the one or more additional therapeutic agents are selected from the group consisting of TTR stabilizing agents, TTR gene silencing agents, TTR amyloid fibril degrading/disruptor agents, agents used to treat neuropathy or symptoms of neuropathy, anticonvulsants, anti-depressants, pain relievers, anti-hypotensives or combinations thereof
  • a method for increasing the stabilization of TTR tetramers in vitro comprising providing at least one compound described herein to an in vitro assay, wherein the at least one compound described herein protects the TTR tetramers against urea-mediated dissociation.
  • a method for increasing the stabilization of TTR tetramers in vitro comprising providing at least one compound described herein to an in vitro assay, wherein the at least one compound described herein protects the TTR tetramers against acid-mediated denaturation.
  • a method for increasing the stabilization of TTR tetramers in vivo comprising providing at least one compound described herein to an animal model.
  • acyl refers to a carboxylic acid ester in which the non-carbonyl moiety of the ester group is selected from straight, branched, or cyclic alkyl, alkoxyalkyl including methoxymethyl, aralkyl including benzyl, aryloxyalkyl such as phenoxymethyl, aryl including phenyl optionally substituted with halogen, Cl to C4 alkyl or Cl to C4 alkoxy, sulfonate esters such as alkyl or aralkyl sulphonyl including methanesulfonyl, the mono, di or triphosphate ester, trityl or monomethoxy trityl, substituted benzyl, trialkylsilyl (e.g. dimethyl-t-butylsilyl) or diphenylmethylsilyl.
  • Aryl groups in the esters typically include a phenyl group.
  • the term “aggregate” refers to an assembly containing more than one monomer, i.e. dimers, trimers and higher order assemblies. In amyloidosis, the aggregation pathway typically proceeds through the formation of oligomers and protofibrils, which lead to the mature fibrils, Generally, while the compounds, compositions and methods are described in terms of “comprising” various components or steps, the compounds, compositions and methods can also “consist essentially of or “consist of the various components and steps.
  • alkyl as used herein, unless otherwise specified, includes a saturated straight, branched, primary, secondary, or tertiary hydrocarbon of Ci to Cs, Ci to Cis or Ci to C20. The term includes both substituted and unsubstituted alkyl groups.
  • Moieties with which the alkyl group can be substituted are selected from the group consisting of hydroxyl, halo (F, Cl, Br, I), amino, alkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, sulfate, phosphonic acid, phosphate, or phosphonate, either unprotected, or protected as necessary, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991, hereby incorporated by reference.
  • alkyl group is said to be substituted with an alkyl group, this is used interchangeably with "branched alkyl group”.
  • alkyls and/or substituted alkyls includes, but are not limited to, methyl, trifluoromethyl, ethyl, propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3 -methylpentyl, 2,2-dimethylbutyl, and 2,3 -dimethylbutyl.
  • the alkyl group may be deuterated, one or more hydrogen (H) atoms is replaced with a corresponding number of deuterium (D) atoms.
  • alkenyl includes a hydrocarbon radical straight, branched or cyclic of C2 to C6, C2 to C10 or C2 to C15, and at least one carbon to carbon double bond.
  • alkenyl groups include, but are not limited to, ethenyl, propenyl and butenyl.
  • the alkenyl group may be deuterated, one or more hydrogen (H) atoms is replaced with a corresponding number of deuterium (D) atoms.
  • alkynyl refers to a hydrocarbon radical straight or branched, of C2 to Ce, C2 to C10 or C2 to C15, and at least one carbon to carbon triple bond.
  • alkynyl groups include, but are not limited to, ethynyl, propynyl and butynyl.
  • the alkynyl group may be deuterated, one or more hydrogen (H) atoms is replaced with a corresponding number of deuterium (D) atoms.
  • amyloidosis refers to a condition in which abnormal protein deposits in various tissues, damaging the tissue and function of the involved organ.
  • amyloid-associated disorders includes diseases associated with the accumulation of amyloid. Such diseases include amyloid is restricted to one organ (“localized amyloidosis”) or present in several organs (“systemic amyloidosis”).
  • amyloid cardiomyopathy refers a myocardial disease caused by infiltration of amyloid into the cardiac tissue.
  • amyloid fibril refers to an insoluble peptide or protein aggregates that is fibrous, predominantly P-sheet, and highly ordered. Mature amyloid fibrils are long and straight, usually comprising four to six filaments. They specifically bind certain dyes such as Congo red and thioflavin T.
  • amyloid plaque refers to an extracellular deposit composed mainly of proteinaceous fibrils. Generally, the fibrils are composed of a dominant protein or peptide; however, the plaque may also include additional components that are peptide or nonpeptide molecules, as described herein.
  • amyloid proteins refers to a protein which is involved in the formation of fibrils, plaques and/or amyloid deposits, either by being part of the fibrils, plaques and/or deposits as such or by being part of the biosynthetic pathway leading to the formation of the fibrils, plaques and/or amyloid deposits.
  • amyloid typing refers to a method of identifying the particular amyloid protein forming an amyloid deposit.
  • baseline refers to a value measured before the deuterated or halogenated tolcapone compound or pharmaceutical composition thereof is administered to a subject.
  • the term “clearance” or “clearance rate” refers to the rate at which a compound is removed from the blood stream.
  • the term “deuterated” refers to a compound, e.g., tolcapone, in which one or more hydrogen atoms is replaced with a corresponding number of deuterium (D) atoms.
  • D deuterium
  • the effects of deuterium substitution on pharmacologic action and the rate of metabolism are known to be variable and unpredictable. Many drugs have multiple sites where metabolism is possible. The site(s) where deuterium substitution is required and the extent of deuteration necessary to see an effect on metabolism, if any, while maintaining pharmacologic action will be different for each drug.
  • the effects of deuterium modification on a compound’s metabolic properties are not predictable even when deuterium atoms are incorporated at known sites of metabolism.
  • the term “dosage” refers to the information of the amount of the therapeutic to be taken by the subject and the frequency of the number of times the therapeutic is to be taken by the subject.
  • dose refers to the amount or quantity of the therapeutic to be taken each time.
  • half-life As used herein, the terms “half-life” “in vivo half-life” and “elimination half-life” refer to the time by which half of the administered amount of a compound is removed from the blood stream.
  • halogenated refers to a compound, e.g., tolcapone, in which one or more substituent (e.g., hydroxyl group, nitro group or hydrogen) is replaced with a corresponding number of iodine (I), bromine (Br), chlorine (Cl) or fluorine (F) atoms.
  • substituent e.g., hydroxyl group, nitro group or hydrogen
  • the effects of halogen substitution on pharmacologic action and the rate of compound metabolism are known to be variable and unpredictable. Many drugs have multiple sites where metabolism is possible. The site(s) where halogen substitution is required and the extent of halogenation necessary to see an effect on metabolism, if any, while maintaining pharmacologic action will be different for each drug.
  • the effects of halogen modification on a compound’s metabolic properties are not predictable even when halogen atoms are incorporated at known sites of metabolism.
  • in vitro means preformed or carried out outside of a living organism.
  • in vitro systems include cell-based in vitro systems.
  • liver function refers to or more physiological functions performed by the liver. Liver function can be analyzed using conventional assays, such as alanine aminotransferase (ALT) analysis or aspartate transaminase (AST) analysis.
  • ALT alanine aminotransferase
  • AST aspartate transaminase
  • the term “metabolism” with reference to a compound such as tolcapone refers to the metabolic breakdown of drugs by living organisms, typically by specialized enzymes that are highly expressed in the liver and small intestine.
  • metabolic rate refers to the overall rate of metabolism of a compound, which determines the duration and intensity of a compound’s pharmacologic action.
  • metabolic stability refers to the susceptibility of compound to biotransformation. Metabolic stability results are typically reported as measures of intrinsic clearance.
  • pharmaceutically acceptable excipients and/or carriers refers to pharmaceutically acceptable materials, compositions or vehicles. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity or other problems or complications commensurate with a reasonable benefit/risk ratio.
  • composition refers to a formulation of a deuterated or halogenated tolcapone compound disclosed herein in a medium generally accepted in the art for the delivery of the biologically active compound to a mammal, e g., a human.
  • a medium includes all pharmaceutically acceptable carriers, diluents or excipients therefor.
  • the term "pharmaceutically acceptable salt” refers to salts prepared from pharmaceutically acceptable non-toxic bases.
  • the salt is an alkaline or alkaline earth metal salt.
  • the term "pharmacokinetic property” refers to a parameter that describes the disposition of an active agent in an organism or host and in particular, to describe the absorption, distribution, metabolism, and excretion of a compound.
  • polyneuropathy refers to a general degeneration of peripheral nerves that spreads toward the center of the body. Polyneuropathy can affect nerves responsible for feeling (sensory neuropathy), movement (motor neuropathy), or both (sensorimotor neuropathy). It may also affect the autonomic nerves.
  • polypeptide refers to a linear organic polymer consisting of at least 2 amino-acid residues bonded together (i.e., peptide bonds) to form a chain.
  • one suitable polypeptide is T7 (sequence: His-Ala-Ile-Tyr-Pro-Arg-His).
  • the polypeptide comprises about 2 to about 10, about 2 to about 20, about 2 to about 100, about 2 to about 250, or about 2 to about 500.
  • prophylactically effective amount refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Often, but not necessarily, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount is less than the therapeutically effective amount.
  • the terms "subject” or “patient” or “individual” or “animal” refers to humans, veterinary animals (e.g., cats, dogs, cows, horses, sheep, pigs, etc.) and experimental animal models of diseases (e.g., mice, rats).
  • substituted with deuterium refers to the replacement of one or more hydrogen atoms in a given compound (e g., tolcapone) with a corresponding number of deuterium atoms.
  • substituted with iodine refers to the replacement of one or more hydroxyl groups, nitro groups, or hydrogen atoms in a given compound (e.g., tolcapone) with a corresponding number of iodine atoms.
  • substituted with bromine refers to the replacement of one or more hydroxyl groups, nitro groups, or hydrogen atoms in a given compound (e g., tolcapone) with a corresponding number of bromine atoms.
  • substituted with chlorine refers to the replacement of one or more hydroxyl groups, nitro groups, or hydrogen atoms in a given compound (e g., tolcapone) with a corresponding number of chlorine atoms.
  • substituted with fluorine refers to the replacement of one or more hydroxyl groups, nitro groups, or hydrogen atoms in a given compound (e g., tolcapone) with a corresponding number of fluorine atoms.
  • compound e g., tolcapone
  • tolcapone a compound that is greater than the additive activity of the compounds if administered individually.
  • the term "therapeutically effective amount” refers to the amount of a compound that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disease which is addressed.
  • the particular dose of compound administered according to this invention will be determined by the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.
  • the term “therapeutic index” refers to the ratio between the toxic dose and the therapeutic dose of a drug, used as a measure of the relative safety of the drug for a particular treatment.
  • treatment refers to prophylaxis of the condition, ameliorating or stabilizing the specified condition, reducing or eliminating the symptoms of the condition, slowing or eliminating the progression of the condition, and preventing or delaying reoccurrence of the condition in a previously afflicted patient or subject.
  • treatment refers to ameliorating or stabilizing a specified condition, reducing or eliminating the symptoms of the condition, or slowing or eliminating the progression of the condition.
  • the term "therapeutic response" means an improvement in at least one measure of amyloid disease, including but not limited to a reduction in the size of existing amyloid deposits or plaques, a decrease in the rate of amyloid deposition, or improved organ function as measured by standard techniques.
  • transthyretin refers to the polypeptide gene product of a transthyretin gene/transcript, e g., a transthyretin protein, peptide, or polypeptide, such as those encoded by transthyretin Genbank Accession Nos. NP_000362.1 and NP_038725.1. TTR is also known as prealbumin, HsT2651, PALB, and TBPA.
  • TSR amyloidosis refers to any disease or disorder characterized by an accumulation of transthyretin (TTR) amyloid fibril deposits.
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of compounds of the present invention calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier or vehicle.
  • wild-type with reference to TTR amyloidosis refers to a form of TTR amyloidosis that does not result from genetic mutation and typically, although not exclusively involves deposition of amyloid in cardiac tissue.
  • wild-type with reference to TTR amyloidosis refers to a form of TTR amyloidosis that does not result from genetic mutation and typically, although not exclusively involves deposition of amyloid in cardiac tissue.
  • the present invention relates to analogs of tolcapone, 3-OMT and 3- deoxytolcapone.
  • R 1 is selected from OH, OD, OR la , H, D, alkyl, alkenyl, alkynyl, and polypeptide;
  • R la is selected from alkyl, alkenyl, alkynyl, acyl and polypeptide; each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from alkyl, alkenyl, alkynyl, H and D; and the compound is not tolcapone, 3-O-methyl tolcapone or 3-deoxytolcapone.
  • R la is Ci to C20 alkyl, which may be optionally substituted by one or more deuteriums.
  • R la is C2 to C20 alkenyl, which may be optionally substituted by one or more deuteriums. In another embodiment of Formula I, R la is C2 to C20 alkynyl, which may be optionally substituted by one or more deuteriums.
  • R la is Ci to C20 acyl, which may be optionally substituted by one or more deuteriums.
  • R la is a polypeptide, for example a polypeptide comprising 2 to 500 amino acid residues, or 2 to 20 amino acid residues.
  • R 1 is alkyl, OR 1 or polypeptide.
  • the compound of Formula I comprises at least one D.
  • R 1 is selected from OH, OD, OCH3, OCD3, , alkenyl, alkynyl, H and D; each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from H and D; and the compound contains at least one D.
  • a deuterated form of tolcapone wherein at least one hydrogen atom of tolcapone is replaced with a deuterium.
  • the deuterated compound may comprise one or more deuterium, such as, for example, two, three, four, five, six, seven, eight, nine or ten or more deuteriums.
  • R la is selected from H, D, alkyl, alkenyl, alkynyl, acyl and polypeptide; each of R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from alkyl, alkenyl, alkynyl, H and D; and the compound is not tolcapone.
  • R la is Ci to C20 alkyl, which may be optionally substituted by one or more deuteriums.
  • R la is Ci to C20 alkenyl, which may be optionally substituted by one or more deuteriums.
  • R la is Ci to C20 alkynyl, which may be optionally substituted by one or more deuteriums.
  • R la is Ci to C20 acyl, which may be optionally substituted by one or more deuteriums.
  • R la is a polypeptide, for example a polypeptide comprising 2 to 500 amino acid residues.
  • R la is alkyl or polypeptide.
  • the compound of Formula I comprises at least one D.
  • each of R la , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from H and D, and the compound contains at least one D.
  • R la and R 9 are each selected from alkyl, polypeptide, H and D, wherein at least one of R la and R 9 are D.
  • Exemplary compounds of Formula la 1 include the following: In another particular embodiment, compounds of Formula Ia2 are provided:
  • Formula la 2 wherein R la , R 9 and R 5 are each selected from alkyl, H and D, and the compound contains at least one D.
  • Exemplary compounds of Formula Ia2 include the following:
  • Exemplary compounds of Formula la 3 include the following:
  • R la , R 2 , R 8 and R 9 are independently selected from alkyl, H and D, and the compound contains at least one D.
  • Exemplary compounds of Formula Ia4 include the following:
  • Exemplary compounds of Formula las include the following:
  • analogs of 3-OMT are also provided herein.
  • the analog of 3- OMT is a compound based on 3-OMT wherein at least one hydrogen atom of 3-OMT is replaced with a deuterium.
  • the analog of 3-OMT can contain one or more deuterium, such as, for example, two, three, four, five, six, seven, eight, nine or ten or more.
  • the compound is a compound of Formula lb:
  • R lb wherein each of R lb , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from alkyl, alkenyl, alkynyl, H and D; and the compound is not 3-OMT.
  • R lb is Ci to C20 alkyl, which may be optionally substituted by one or more deuteriums.
  • R lb is Ci to C20 alkenyl, which may be optionally substituted by one or more deuteriums.
  • R lb is Ci to C20 alkynyl, which may be optionally substituted by one or more deuteriums.
  • the compound contains at least one D.
  • the compound is a compound of Formula Ibi:
  • R lb and R 9 are each selected from alkyl, H and D, wherein at least one of R lb and R 9 are D.
  • Exemplary compounds of Formula Ibi include the following:
  • compounds of Formula Ib2 are provided: Formula lb wherein each R lb , R 9 and R 5 are selected from alkyl, H and D, and the compound contains at least one D.
  • Exemplary compounds of Formula Ib2 include the following:
  • Exemplary compounds of Formula lb 3 include the following:
  • R lb , R 2 , R 8 and R 9 are independently selected from, alkyl, H and D, and the compound contains at least one D.
  • Exemplary compounds of Formula Ib4 include the following:
  • Exemplary compounds of Formula lbs include the following:
  • analogs of 3-deoxytolcapone are also provided herein.
  • the analog of 3-deoxytolcapone is a compound based on 3-deoxytolcapone wherein at least one hydrogen atom of 3-deoxytolcapone is replaced with a deuterium.
  • the analog of 3- deoxytolcapone can contain one or more deuterium, such as, for example, two, three, four, five, six, seven, eight, nine or ten or more.
  • R lc , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from alkyl, alkenyl, alkynyl, H and D; and the compound is not 3-deoxytolcapone
  • R lc is selected from alkyl, alkenyl and alkynyl.
  • the compound comprises at least one D.
  • the compound is of Formula Ici:
  • R lc and R 9 are each selected from alkyl, H and D, wherein at least one of R lc and R 9 are D.
  • the compound is of Formula IC2:
  • R lc , R 9 and R 5 are each selected from an alkyl, H and D, and the compound contains at least one D.
  • Exemplary compounds of Formula Ic2 include the following:
  • the compound is of Formula Ics:
  • Exemplary compounds of Formula Ic3 include the following:
  • the compound is of Formula Icr:
  • R lc , R 2 , R 8 and R 9 are independently selected from alkyl, H and D, and the compound contains at least one D.
  • Exemplary compounds of Formula Ic4 include the following:
  • the compound is of Formula lc 5 :
  • Exemplary compounds of Formula lc 5 include the following:
  • compounds of Formula Id are provided: wherein R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from H and D; and wherein “linker” is selected from alkyl, alkenyl, alkynyl, acyl and polypeptide.
  • R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently selected from H and D; and wherein “linker” is selected from alkyl, alkenyl and alkynyl.
  • a compound of any of the foregoing formulas comprises at least one D.
  • halogenated analogs of tolcapone have least one of the hydroxyl groups, nitro groups or hydrogen atoms of tolcapone replaced with iodine (I), bromine (Br), chlorine (Cl), or fluorine (F).
  • I iodine
  • Br bromine
  • Cl chlorine
  • F fluorine
  • each R is independently selected from the group consisting of OH, OR’, H, alkyl, alkenyl, alkynyl, polypeptide, nitro, nitrile, C(O)OR”, iodine, chlorine, bromine, and fluorine;
  • R’ is selected from alkyl, alkenyl, alkynyl, acyl and polypeptide
  • R is selected from H or alkyl; and at least one R is iodine, bromine, chlorine, fluorine or C(O)OR”.
  • the halogen may be an isotope, for example 18 F, 36 C1, 76 Br, 123 I, 125 I or 131 I.
  • at least one R is OR’, for example methoxy.
  • at least one R is alkyl, for example methyl.
  • at least one R is OR’ wherein R’ is acyl.
  • at least one R is a polypeptide.
  • R is C2 to C20 alkenyl.
  • R is C2 to C20 alkynyl.
  • R is a polypeptide, for example a polypeptide comprising 2 to 500 amino acid residues.
  • R is C2 to C20 alkenyl.
  • R’ is C2 to C20 alkynyl.
  • R’ is a polypeptide, for example a polypeptide comprising 2 to 500 amino acid residues.
  • the compound is a compound of Formula Ila:
  • R is selected from the group consisting of iodine, bromine, chlorine and fluorine.
  • halogenated tolcapone compounds of Formula Ila include the following:
  • the compound is a compound of Formula lib : wherein R 1 is selected from the group consisting of OH, OR’, H, alkyl, polypeptide iodine, bromine, chlorine and fluorine; wherein R’ is selected from alkyl and acyl;
  • R 2 is selected from the group consisting of iodine, bromine, chlorine, fluorine and nitro, C(O)OR”;
  • R’ is selected from H or alkyl; and wherein at least one of R 1 or R 2 is iodine, bromine, chlorine, fluorine or
  • Exemplary halogenated tolcapone compounds of Formula lib include the following:
  • the tolcapone compound is a compound of Formula lie:
  • R 1 is selected from the group consisting of OH, OR’, H, alkyl, polypeptide iodine, bromine, chlorine and fluorine;
  • R’ is selected from alkyl and acyl
  • R 3 , R 4 , R 6 and R 7 are each independently selected from the group consisting of iodine, bromine, chlorine, fluorine and hydrogen;
  • R 10 is selected from iodine, bromine, chlorine and nitro or C(O)OR”;
  • R is selected from H or alkyl; wherein at least one of R 1 , R 3 , R 4 , R 6 , R 7 or R 10 is iodine, bromine, chlorine, or fluorine.
  • halogenated tolcapone compounds of Formula lie include the following:
  • Pharmaceutically acceptable salts include, e.g., compounds disclosed herein containing one or more basic functional groups include in particular the acid addition salts thereof.
  • Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, adipate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulphate/sulphate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methyl sulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palm
  • the compounds disclosed herein have an improved therapeutic index compared to tolcapone.
  • the compounds disclosed herein have improved pharmacokinetic (PK), pharmacodynamic (PD) and/or toxicological properties compared to conventional tolcapone.
  • the one or more improved properties are selected from (i) a decreased rate of metabolism, (ii) an increased rate of stability, (iii) an increased half-life, (iv) an improved volume of distribution and (v) improved permeability through the blood-brain barrier or other tissues.
  • the pharmacokinetic property is improved by about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45% or about 50% or more compared to tolcapone.
  • the compounds described herein have an increased elimination halflife compared to tolcapone.
  • the elimination half-life of the compound described herein is greater than about 3.0, greater than about 3.2, greater than about 3.4, greater than about 3.6 greater than about 3.8, greater than about 4.0, greater than about 4.2, greater than about 4.4, greater than about 4.6, greater than about 4.8 or greater than about 5.0 hours.
  • the elimination half-life of the compound described herein is greater than about 5.0, greater than about 5.5, greater than about 6.0, greater than about 6.5, greater than about 7.0, greater than about 7.5, greater than about 8.0, greater than about 8.5, greater than about 9.0, greater than about 9.5, greater than about 10.0, greater than about 10.5, greater than about 11.0, greater than about 11.5 or greater than about 12.0 hours.
  • the elimination half-life of the compound described herein is between about 4 and about 12 hours, about 5 and about 11 hours, about 6 and about 10 hours or about 7 and about 9 hours.
  • the elimination half -life of the compound described herein is about 3.0, about 3.2, about 3.4, about 3 6, about 3.8, about 4.0, about 4.2, about 4.4, about 4.6, about 4.8, about 5.0, about 5.2, about 5.4, about 5.6, about 5.8, about 6.0, about 6.2, about 6.4, about 6.6, about 6.8, about 7.0, about 7.2, about 7.4, about 7.6, about 7.8, about 8.0, about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11 0, about 11.5 or about 12.0.
  • the elimination half-life of the compound described herein is greater than about 14 hours, greater than about 16 hours, greater than about 18 hours, greater than about 20 hours, greater than about 22 hours or greater than about 24 hours. In one embodiment, the elimination half -life of the compound described herein is between about 12 and about 24 hours, about 14 and about 22 hours, or about 16 and about 20 hours.
  • the elimination half -life of the compound described herein is about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, or about 24 or more hours.
  • the toxicity of the compound disclosed herein is reduced compared to tolcapone, as measured by a liver function test.
  • the toxicity of the compound described herein is about 10%, about 15%, about 20%, about 25%, about 30%, about 40%, about 45% or about 50% or less compared to tolcapone.
  • the liver function test is a liver enzyme test and more particularly, a serum glutamic-pyruvic transaminase (ALT), serum glutamic-oxaloacetic transaminase (AST).
  • ALT serum glutamic-pyruvic transaminase
  • AST serum glutamic-oxaloacetic transaminase
  • a composition comprises at least one compound described herein, e.g. at least two compounds, at least three compounds, or at least four compounds.
  • a pharmaceutical composition comprises at least one compound described herein and at least one pharmaceutical carrier or excipient.
  • the pharmaceutical composition is useful for the manufacture of a medicament.
  • compositions can be designed for administration to subjects or patients in need thereof via a number of different routes of administration including oral, intravenous, buccal, rectal, ocular, parenteral, intraperitoneal, intradermal, intrathecal, intramuscular, subcutaneous or nasal.
  • the pharmaceutical composition is designed for oral administration.
  • Oral administration is a part of enteral administration, which also includes buccal (dissolved inside the cheek), sublabial (dissolved under the lip) and sublingual administration (dissolved under the tongue).
  • the pharmaceutical composition may be a solid oral dosage form, a liquid oral dosage form or a semi-solid oral dosage form.
  • Solid oral dosage forms can include tablets, chewable tablets, gastro-resistant tablets, modified release tablets, extended release tablets, capsules, soft capsules, gastro-resistant capsules, modified release capsules, extended release capsules, caches, granules, gastro-resistant granules, modified release granules, powders and the like.
  • Liquid oral dosage forms include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, drops and elixirs.
  • the oral dosage form may contain one or more excipients selected from the group consisting of anti-adherents, anti-oxidants, binding agents, buffering agents, chelating agents, coating agents, coloring agents, disintegrants, emollients, emulsifying agents, fillers, flavoring agents, glidants, humectants, levigitating agents, lubricants, plasticizers, polishing agents, preservatives, solvents, sorbents, stabilizing agents, surface active agents, suspending agents, tonicity agents, viscosity-imparting agents and wetting agents.
  • excipients selected from the group consisting of anti-adherents, anti-oxidants, binding agents, buffering agents, chelating agents, coating agents, coloring agents, disintegrants, emollients, emulsifying agents, fillers, flavoring agents, glidants, humectants, levigitating agents, lubricants, plasticizers, polishing agents, preservative
  • the pharmaceutical formulation may be, for example, a tablet comprising a tablet comprising a core and a film coating.
  • the tablet core comprises lactose monohydrate, microcrystalline cellulose, dibasic calcium phosphate anhydrous, sodium starch glycolate, povidone, talc and magnesium stearate and the film coating comprises hydroxypropyl methylcellulose, titanium dioxide, talc, ethyl cellulose, triacetin, and sodium lauryl sulfate, with the following dye system: yellow iron oxide.
  • the pharmaceutical composition comprises between about 0.1 and about 10% of the at least one compound described herein by weight of the pharmaceutical compositions.
  • the pharmaceutical composition in the form of a unit dose comprising at least one compound described herein or a pharmaceutically acceptable salt thereof in an amount of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg or more.
  • the pharmaceutical composition may further comprise one or more additional therapeutic agents.
  • the one or more therapeutic agents may be a TTR stabilizer, a TTR gene silencer, a TTR degrading agent, or a complementary therapeutic agent.
  • the pharmaceutical composition may further comprise one or more therapeutic agents used to treat neurological disorders, cardiovascular disorders or both.
  • a method for treating an amyloid-associated disease or condition by administering at least one compound described herein, either alone or in the form of a pharmaceutical composition, to a subject in need thereof.
  • the disease pathology is systemic.
  • the disease pathology is central.
  • the disease pathology is both systemic and central.
  • amyloid-associated disease or condition may involve any amyloid protein, i.e., any protein within the amylome. Dozens of proteins and peptides have been shown to convert to an aggregated amyloid state, representing a diverse group of otherwise unrelated molecules.
  • Representative, non-limiting disease associated molecules include the P-amyloid peptide of Alzheimer’s disease, the a-synuclein protein of Parkinson’s disease, the islet amyloid polypeptide (IAPP, or amylin) of type 2 diabetes, and lysozyme of lysozyme amyloidosis (ALys).
  • the subject has previously been diagnosed with amyloid-associated disease by any suitable method, such as genetic testing, laboratory testing (e g , serum biomarkers), tissue biopsy (including immunohistochemistry or proteomic analysis), imaging, clinical presentation or combinations thereof.
  • a method is disclosed for (i) testing a subject to determine if they have or are susceptible to an amyloid-associated disease or disorder and (ii) administering to the subject at least one compound described herein or a pharmaceutical composition comprising the same.
  • the testing comprises detecting the presence of amyloid by means of a tissue biopsy, wherein the tissue biopsy is subjected to a Congo-red stain and exhibits birefringence.
  • the tissue is then subject to amyloid typing to confirm the particular protein involved in the amyloidosis.
  • the amyloid typing method comprises immunohistochemical staining of the tissue with appropriate antisera (e.g., anti-transthyretin).
  • the amyloid typing method comprises gene sequencing or mass spectrometry.
  • the amyloid-associated disease or condition is ATTR caused by a genetic mutation (hATTR), aging (wtATTR) or a combination or both.
  • the subject treated according to the methods disclosed herein may be at any stage of the disease, including asymptomatic, early-stage or late-stage.
  • the amyloid-associated disease is hereditary ATTR, i.e., ATTR primarily resulting from one or more pathogenic mutations in the TTR gene.
  • ATTR hereditary ATTR
  • hATTR impacts the nerves, heart, kidneys, eyes, and brain. The rate of cardiac versus neurological involvement depends on the underlying TTR mutation.
  • the one or more pathologic mutations in the TTR gene are selected from single nucleotide substitution, deletion or duplication.
  • the particular mutation may be homogenous or heterogenous.
  • the amyloid-associated disease or condition is ATTR caused by one or more pathogenic mutations.
  • the one or more pathogenic mutations impacts the C-D loop of the TTR protein.
  • the one or more pathogenic mutation is selected from the group consisting of mutations that already have been.
  • the one or more pathogenic mutation is selected from the group consisting of Gly6Ser, CyslOArg, Leul2Pro, Leul2Val, Metl3Ile, Aspl8Asn, Aspl8Gly, Aspl8Glu, Alal9Asp, Val20Ile, Arg21Gln, Ser23Asn, Pro24Ser, Ala25Ser, Ala25Thr, Val28Met, Val28Ser, VaBOLeu, VaBOMet, VaBOAla, VaBOGly, VaBOLeu, VaB2Ala, VaB2Gly, Phe33Ile, Phe33Leu, Phe33Val, Phe33Cys, Arg34Gly, Arg34Thr, Lys35Asn, Lys35Thr, Ala36Asp,
  • Glu51_Ser52dup Ser52Pro, Gly53Arg, Gly53Glu, Gly53Ala, Glu54Leu, Glu54Lys, Glu54Gly, Glu54Asp, Glu54Gln, Leu55Gln, Leu55Arg, Leu55Pro, His56Arg, Gly57Arg, Leu58Arg, Leu58His, Thr59Arg, Thr59Lys, Thr60Ala, Thr60Ile, Glu61Lys, Glu61Gly, Glu61Ala, Glu62Lys, Phe64Ile, Phe64Leu, Phe64Ser, Phe64Val, Gly67Arg, Gly67Glu, Ile68Leu, Tyr69His, Tyr69Ile, Lys70Asn, Val71Ala, Glu72Gly, Ile73Val, Asp74His, Ser77Phe, Ser77Tyr, Tyr78Phe, Ala81Thr, Ala81Val, G
  • the pathogenic mutation underlying the hereditary ATTR is VaBOMet (i.e., substitution of valine for methionine in position 30 of the transthyretin protein). Sousa A, et al. Am J Med Genet. 1995;60:512-521).
  • the subject treated according to the present invention has asymptomatic hATTR resulting from VaBOMet, early-onset hATTR resulting from VaBOMet or late-onset hATTR resulting from VaBOMet.
  • an amyloid-associated disease or condition is hATTR- polyneuropathy (hATTR-PN).
  • hATTR-PN is a generally caused by a genetic mutation (i.e., a point mutation) in the transthyretin gene, with V30M being the most common.
  • the age of onset of hATTR-PN can vary widely, from early-stage (> about 40 years old) to late-stage (> about 50 years old).
  • hATTR-PN is clinically heterogeneous, on the mutation and the subject’s geographic origin.
  • hATTR-PN usually presents as a length-dependent sensory polyneuropathy with autonomic disturbances.
  • Symptoms of peripheral neuropathy include, e.g., tingling, pins and needles in the feet and hands; weakness and pain in the arms and legs; loss of sensation (numbness); and loss of thermal sensibility in the feet.
  • Symptoms of automatic neuropathy include, e.g., postural hypotension; disturbed bowel function, nausea, vomiting; urinary retention; impotence; and reduced sweating. Average survival is about 10 years after symptoms present. As the patients age, central manifestations begin to develop.
  • the amyloid-associated disease or conditions is hATTR- cardiomyopathy (hATTR-CM).
  • hATTR-CM presents clinically as heart disease (restrictive cardiomyopathy) and sometimes carpal tunnel syndrome, with the latter often occurring years before the former.
  • the mutant TTR is V122I.
  • Symptoms of hATTR- CM include, e.g., chest pain (angina), shortness of breath; palpitations and abnormal heart rhythms; ankle swelling (edema) fatigue; nausea; weight loss; and dizziness.
  • amyloid-associated disease or condition is caused primarily by wild-type (wt) transthyretin and more particularly, is clinically manifest as ATTR- cardiomyopathy (ATTR-CM).
  • wt wild-type
  • ATTR-CM ATTR- cardiomyopathy
  • Symptoms include slowly progressive energy decline, exercise intolerance, weight loss and gastro-intestinal (GI) complaints, as well as left and right sided congestive heart failure (CHF), with normal systolic function and clear diastolic dysfunction, arrythmias.
  • an amyloid-associated disease or condition is hATTR- Leptomeningeal (hATTR-Lepto).
  • hATTR-Lepto is caused primarily by an ultra-rare genetic mutation in TTR that causes predominantly central pathology through accumulation of amyloid in the meninges of the brain.
  • the compounds disclosed herein can be administered to a patient suffering from any disease including a disorder, condition or symptom for which tolcapone, 3-OMT or 3- deoxytolcapone is known or hereafter discovered to be therapeutically effective.
  • Indications for which tolcapone, 3-OMT or 3-deoxytolcapone is also expected to be effective include ATTR, Parkinson’s Disease, schizophrenia, polycystic kidney disease and obsessive compulsive disorder.
  • Methods of treating a disease in a patient comprise administering to a patient in need of such treatment the compounds disclosed herein.
  • the compounds disclosed herein may provide therapeutic or prophylactic plasma and/or blood concentrations of tolcapone, 3-OMT or 3-deoxytolcapone following administration to a patient.
  • a method for treating Parkinson’s Disease in a patient comprises administering a compound disclosed herein to said patient.
  • Parkinson’s disease is a slowly progressive degenerative disorder of the nervous system characterized by tremor when muscles are at rest (resting tremor), slowness of voluntary movements, and increased muscle tone (rigidity).
  • Parkinson’s disease nerve cells in the basal ganglia, e.g., substantia nigra, degenerate, and thereby reduce the production of dopamine and the number of connections between nerve cells in the basal ganglia.
  • the basal ganglia are unable to smooth muscle movements and coordinate changes in posture as normal, leading to tremor, incoordination, and slowed, reduced movement (bradykinesia) (Blandini, et al., Mol. Neurobiol. 1996, 12, 73-94).
  • the efficacy of the compounds disclosed herein for treating Parkinson’s disease may be assessed using animal and human models of Parkinson’s disease and in clinical studies.
  • a method for treating obsessive compulsive disorder (OCD) in a patient comprises administering a compound disclosed herein to said patient.
  • OCD obsessive compulsive disorder
  • the primary symptom is recurrent obsessions (i.e., recurrent and intrusive thoughts, images or urges that cause marked anxiety) and/or compulsions (i.e., repetitive behaviors or mental acts that are performed to reduce the anxiety generated by one's obsessions) of sufficient severity to cause distress, be time consuming or to interfere significantly with a person's normal routine or lifestyle.
  • Anxiety is an associated feature of this disorder.
  • An affected person may, for example, show a phobic avoidance of situations that involve the cause of the obsession.
  • Typical obsessions concern contamination, doubting (including self-doubt) and disturbing sexual or religious thoughts.
  • Typical compulsions include washing, checking, ordering, and counting.
  • obsessive compulsive disorder can be characterized by at least 4, 5, 6, 7 or all 8 of these characteristics.
  • the present methods can result in a decrease in one or more behaviors associated with obsessive compulsive disorder.
  • the administration protocol of the disclosed method may vary.
  • at least one compound described herein or pharmaceutical composition comprising the same is administered to the subject in need thereof twice-daily or once-daily.
  • the dose of the at least one compound described herein compound may vary.
  • the dosage is less than the FDA-approved dosage for conventional tolcapone and in particular, about 10%, about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90% or about 100% less.
  • the dose of the at least one compound described herein is more than the FDA-approved dosage for conventional tolcapone and in particular, about 110%, about 120%, about 130%, about 140%, about 150%, about 160%, about 170%, about 180%, about 190% or about 200% more.
  • the dosage of the at least one compound described herein is less than about 600 mg, less than about 400 mg, less than about 300 mg, less than about 200 mg, less than about 150 mg, less than about 100 mg, or less than about 50 mg.
  • the administration comprises a daily dosage of less than about 600 mg, administered three times a day. In certain embodiments, the administration comprises a daily dosage of less than about 550 mg, less than about 500 mg, less than about 450 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg or less than about 100 mg- in each case, administered three times a day.
  • the administration comprising a daily dosage of less than about 600 mg, administered twice-daily.
  • the administration comprises a daily dosage of less than about 550 mg, less than about 500 mg, less than about 450 mg, less than about 400 mg, less than about 350 mg, less than about 300 mg, less than about 250 mg, less than about 200 mg, less than about 150 mg or less than about 100 mg- in each case, administered twice-daily.
  • the administration comprises a daily dosage of between about 100 mg and about 600 mg, about 150 mg and about 550 mg, about 200 mg and about 500 mg, about 250 mg and about 450 mg, about 300 mg and about 400 mg- in each case administered twice-daily.
  • the administration comprises a daily dosage of less than about 600 mg, administered once-daily.
  • the administration comprises a daily dosage of less than about 500 mg, less than about 400 mg, less than about 300 mg, less than about 200 mg or less than about 100 mg- in each case, administered once-daily.
  • the administration comprises a daily dosage ofbetween about 100 mg and about 600 mg, about 150 mg and about 550 mg, about 200 mg and about 500 mg, about 250 mg and about 450 mg, or about 300 mg and about 400 mg- in each case administered once- daily.
  • the form of administration may vary.
  • the form of administration is oral, ocular, intravenous, buccal, rectal, parenteral, intraperitoneal, intradermal, intrathecal, intramuscular, subcutaneous or nasal.
  • a method for treating amyloid-associated diseases or conditions (e.g., ATTR) by orally administering at least one compound described herein, either alone or in the form of a pharmaceutical composition, to a subject in need thereof.
  • the at least one compound described is formulated as a solid dosage form, e.g., a tablet or capsule, or other form, e.g., as a solution.
  • a method for treating amyloid-associated diseases or conditions (e.g., ATTR) by orally administering at least one compound described herein, either alone or in the form of a pharmaceutical composition, to a subject in need thereof, wherein the administration is twice-daily and the daily dosage is less than 600 mg, less than 500 mg, less than 400 mg, less than 300 mg, less than 200 mg, or less than 100 mg.
  • the at least one compound described is formulated as a solid dosage form, e.g., a tablet or capsule.
  • a method for treating amyloid-associated diseases or conditions (e.g., ATTR) by orally administering at least one compound described herein, either alone or in the form of a pharmaceutical composition, to a subject in need thereof, wherein the administration is twice-daily and the daily dosage is between about 100 mg and about 600 mg, more particularly, between about 200 mg and about 600 mg, even more particularly, or about 300 mg and about 600 mg.
  • ATTR amyloid-associated diseases or conditions
  • a method for treating amyloid-associated diseases or conditions by orally administering at least one compound described herein, either alone or in the form of a pharmaceutical composition, to a subject in need thereof, wherein the administration is once-daily and the total dose is less than 600 mg, less than 500 mg, less than 400 mg, less than 300 mg, less than 200 mg, or less than 100 mg.
  • a method for treating amyloid-associated diseases or conditions (e.g., ATTR) by orally administering at least one compound described herein, either alone or in the form of a pharmaceutical composition, to a subject in need thereof, wherein the administration is once-daily and the daily dosage is between about 100 mg and about 600 mg, more particularly, between about 200 mg and about 600 mg, even more particularly, or about 300 mg and about 600 mg.
  • ATTR amyloid-associated diseases or conditions
  • the methods disclosed herein provide an improved therapeutic index compared to conventional tolcapone.
  • the methods disclosed herein provide improved pharmacokinetics compared to tolcapone, e.g., increased half-life, improved clearance and/or improved elimination.
  • the improvement may be, for example, about 10%, about 20%, about 35%, about 50%, about 75% or about 100% or more.
  • the methods disclosed provide a half-life that is increased compared to tolcapone by about 10%, about 20%, about 25%, about 50%, about 75% or about 100% or more. In another embodiment, the methods disclosed herein provide a half-life that is increased compared to tolcapone by about two-fold, about three-fold, about four-fold or about five-fold or more.
  • the half-life is greater than about 3, greater than about 3.5, greater than about 4.0, greater than about 4.5, greater than about 5.0, greater than about 5.5, greater than about 6.0, greater than about 6.5, greater than about 7.5, greater than about 8.0, greater than about
  • the half-life is greater than about 14, greater than about 16, greater than about 18, greater than about 20, greater than about 22 or greater than about 24 hours.
  • the half-life is between about 3 and about 24 hours, more particularly, about 4 and about 22 hours, about 6 and about 22 hours, about 8 and about 20 hours, about 10 and about 18 hours or between about 12 and about 16 hours.
  • the half-life is about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 5.5, about 6.0, about 6.5, about 7.0, about 7.5, about 8.0 about 8.5, about 9.0, about 9.5, about 10.0, about 10.5, about 11,0, about 11.5, or about 12.0 hours.
  • the half-life is about 12.5, about 13.5, about 14.0, about
  • the compounds described herein have reduced liver toxicity compared to tolcapone. In one embodiment, the liver toxicity is reduced by about 10%, about 20%, about 30%, about 40% or about 50% or more.
  • liver toxicity may be measured in any suitable manner, for example, by testing the subject’s cellular metabolite profiles obtained experimentally before and after treatment with at least one tolcapone analog described herein.
  • liver toxicity may be measured by testing the subject’s liver enzyme levels, e.g., alanine transaminase (ALT), aspartate transaminase (AST) or gamma-glutamyl-transferase (GGT) levels, before and after treatment.
  • ALT alanine transaminase
  • AST aspartate transaminase
  • GTT gamma-glutamyl-transferase
  • the compounds described herein provide improved permeability through the blood brain barrier or other tissues, for example tissues of the eye.
  • the method of treatment disclosed herein reduces or eliminates one or more symptoms of the amyloid-associated disease. In a particular embodiment, the method of treatment reduces or eliminates one or more symptoms of hATTR-PN, hATTR-CM, wtATTR, or hATTR-Lepto.
  • the subject treated according to the method disclosed herein exhibits at least one therapeutic response as a result.
  • the subject treated according to the method described herein exhibits a slowing of disease progression or an improvement in disease as measured by the subject’s Neuropathic Impairment Score (NIS) or modified Neuropathic Impairment Score (mNIS).
  • NIS Neuropathic Impairment Score
  • mNIS modified Neuropathic Impairment Score
  • the subject treated according to the method described herein exhibits a slowing of disease progression or an improvement in disease as measured by the subject’s Norfolk Quality of Life-Diabetic Neuropathy (QOL-DN) score.
  • QOL-DN Norfolk Quality of Life-Diabetic Neuropathy
  • the Norfolk QOL-DN patient-reported questionnaire that comprises domains for physical functioning/large-fiber neuropathy, symptoms, activities of daily life, small-fiber neuropathy, and autonomic neuropathy.
  • the subject treated according to the methods described herein exhibits an absence of clinically significant changes in most clinical, biochemical, electrocardiographic, and echocardiographic parameters, consistent with delayed cardiac disease progression.
  • the subject treated according to the method described herein exhibits an improvement, compared to baseline, in the subject’s modified body mass index (mBMI).
  • the subject’s mBMI is improved by an amount between about 1% and about 20%, more particularly, between about 1 and about 10%, more particularly about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% , about 9% or about 10%.
  • the subject treated according to the method described herein exhibits an improvement in the subject’s modified body mass index (mBMI) compared to a reference subject treated with conventional tolcapone or other TTR stabilizer.
  • the subject’s mBMI is improved by an amount between about 1% and about 20%, more particularly, between about 1 and about 10%, more particularly about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% , about 9% or about 10%.
  • the subject treated according to the method described herein exhibits an improvement, compared to baseline, in the subject’s 6 minute walk test" or "6MWT”- a test that measures the distance that a patient can quickly walk on a flat, hard surface in a period of 6 minutes (the 6MWD).
  • the subject’s 6 minute walk test is improved by an amount between about 1% and about 20%, more particularly, between about 1 and about 10%, more particularly about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% , about 9% or about 10%.
  • the subject treated according to the method described herein exhibits an improvement, in the subject’s 6 minute walk test" compared to a reference subject treated with conventional tolcapone or other TTR stabilizer.
  • the subject’ s 6 minute walk test is improved by an amount between about 1% and about 20%, more particularly, between about 1 and about 10%, more particularly about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about 7%, about 8% , about 9% or about 10%.
  • the subject treated according to the methods disclosed herein exhibits an improvement in stabilization of the TTR tetramer (i.e., non-amyloidgenic TTR) following administration compared to baseline.
  • the stability of the TTR tetramer can be analyzed using a validated immunoturbidimetric assay performed on a subject’s plasma sample.
  • the improvement in stability is between about 10% and about 100%, more particularly, about 10%, about 20%, about 30%, about 40% or about 50% or more.
  • the subject treated according to the methods disclosed herein exhibits an improvement in stabilization of TTR tetramers following administration compared to a reference subject treated with conventional tolcapone or other TTR stabilizer.
  • the improvement in stability is between about 10% and about 100%, more particularly, about 10%, about 20%, about 30%, about 40% or about 50% or more.
  • the subject treated according to the method disclosed herein exhibits one or more of the following characteristics following administration, compared to baseline: (i) an increase in the level of tetrameric TTR, (ii) a decrease the level of monomeric TTR, and/or (iii) an increase the ratio of tetrameric to monomeric TTR.
  • the subject treated according to the method disclosed herein exhibits one or more of the following characteristics following administration, compared to a reference subject treated with conventional tolcapone or other TTR stabilizer: (i) an increase in the level of tetrameric TTR, (ii) a decrease the level of monomeric TTR, and/or (iii) an increase the ratio of tetrameric to monomeric TTR.
  • the subject treated according to the method disclosed herein exhibits a decrease in the rate of TTR fibril formation, as well as a decrease in the yield of fibril formation.
  • the decrease is between about 5% and about 50%, more particularly, about 10%, about 20%, about 30%, about 40% about 50% or more
  • the method disclosed herein further comprises administration of at least one additional therapeutic agent to the subject, i.e., in addition to the at least one compound described herein.
  • the one or more additional therapeutic agents are anti-amyloid agents selected from the group consisting of TTR stabilizers, TTR gene silencers, TTR amyloid destabilizing agents, TTR amyloid clearing agents and combinations thereof.
  • the one or more additional therapeutic agent may be, e.g., a small molecule, a peptide, a protein, an oligonucleotide, an antibody or an antibody fragment.
  • the at least one additional therapeutic agent is a TTR stabilizer, and more particularly, a small molecule TTR stabilizer. It is believed that TTR stabilizers block tetramer dissociation, the rate-limiting step in the amyloidogenic process, and reduce de novo deposition of amyloid.
  • the small molecule TTR stabilizer is selected from tafamidis, diflunisal or AGIO
  • the TTR stabilizer is an antibody or antibody fragment.
  • the antibody may be a chimeric and humanized monoclonal antibodies, a polyclonal antibody, a humanized antibody, a human antibody or a chemic antibody.
  • the antibody may be from recombinant sources and/or produced in transgenic animals.
  • the at least one additional therapeutic agent is a TTR gene silencer, and more particularly, is an antisense oligonucleotide or RNAi that inhibit translation of mRNA encoding mutant and/or wild-type TTR protein.
  • the at least one additional therapeutic agent is a TTR disaggregation agent.
  • the method of treatment reduces (vs. inhibits) amyloid deposition.
  • the TTR disaggregation agent is a protease inhibitor.
  • the one or more additional therapeutic agents is selected from 4'- iodo-4'-deoxydoxorubicin (I-DOX), tauro-ursodeoxycholic acid and a tetracycline.
  • the at least one additional therapeutic agent is an agent used to treat neuropathy or a symptom of neuropathy.
  • the agent is selected from the group consisting of anti-convulsants, anti-depressants (e.g., SSRIs, tricyclic antidepressants), pain relievers (e.g., system or topical pain relievers), anti-hypotensives (e.g. droxidopa, midodrine) and the like.
  • the at least one additional therapeutic agent is an agent used to treat cardiomyopathy or a symptom of cardiomyopathy.
  • the agent is selected from the group consisting of anti-arrhythmics, ACE inhibitors, beta-blockers, calcium channel blockers, digoxen, sympathomimetic agents, vasodilators, vasoconstrictors and the like.
  • administration of the at least one tolcapone analog described herein (or a pharmaceutical composition comprising the same) in combination with the at least one additional therapeutic agent results in a synergistic response.
  • a method for reducing the formation of oligomers or fibers of amyloidogenic peptides (e.g., TTR) in vivo by administering at least one compound described herein, either alone or in the form of a pharmaceutical composition to a cell.
  • amyloidogenic peptides e.g., TTR
  • the cell is located within an animal model.
  • the cell is located within a hTTR V30M HSF 1 ⁇ mouse model. (Santos SD, et al. Neurobiol Aging. 2010;31 :280-9). In one embodiment, the cell is located inside a mammal.
  • the presence of oligomers or fibers of amyloidogenic proteins is reduced by about 5%, about 10%, about 15%, about 20%, about 25%, about 30% about 35%, about 40% about 50% or more compared to baseline after the subject is treated with the at least one tolcapone analog disclosed herein or a pharmaceutical composition comprising the same.
  • a method for stabilizing TTR in vivo by administering at least one compound described herein, either alone or in the form of a pharmaceutical composition to a cell.
  • the cell is located within an animal model.
  • the cell is located within a hTTR V30M HSF1 ⁇ mouse model
  • the cell is located inside a mammal.
  • a method for stabilizing TTR in vitro by administering at least one compound described herein, either alone or in the form of a pharmaceutical composition to an in vitro assay.
  • the tolcapone analogs disclosed herein slow urea-mediated dissociation and acid-mediated TTR denaturation in vitro.
  • a Kinetic Turbidity Assay may be carried out according to the following protocol The assay is performed according to the procedure described in Dolado et al (Dolado I, Nieto J, Saraiva M J, Arsequell G, Valencia G, Planas A. “Kinetic Assay for High-Throughput Screening of In Vitro Transthyretin Amyloid Fibrillogenesis Inhibitors”. J. Comb. Chem., 2005, vol. 7, p. 246-252).
  • Recombinant Y78F TTR protein is a Tyr78Phe highly amyloidogenic variation of human TTR.
  • the assay comprises two stages, one stage where the Y78F protein is incubated together with the inhibitor during 30 minutes, and a second stage where fibril formation is induced by a change in pH and absorbance is measured along 1.5 h.
  • the assay is performed as follows: First, the following solutions are prepared: Protein Y78F stock: 4 mg/mL in 20 mM phosphate, 100 mM KC1, pH 7.6. Incubation buffer: 10 mM phosphate, 100 mM KC1, 1 mM EDTA, pH 7.6.
  • Dilution buffer 400 mM sodium acetate, 100 mM KC1, 1 mM EDTA, pH 4.2.
  • Exact protein concentration of the stock solution is determined by Abs2so and according to this value, the volume of Y78F stock to be added to have a final protein well concentration of 0.4 mg/mL is calculated and dispensed into 6 wells of a 96 well microplate. Different volumes of working inhibitor solution are added to give final concentrations ranging from 0 to 40 pM, and the final DMSO content of each well is adjusted to 5% by adding the corresponding volume of a H2O/DMSO (1 : 1) solution. Incubation buffer is then added up to a volume of 100 pL. The plate is incubated at 37° C. in a thermostated microplate reader 30 with orbital shaking 15 s every minute for 30 min.
  • a 100 portion of dilution buffer is dispensed to each well, and the mixture is incubated at 37° C. with shaking (15 s every min) in the microplate reader. Absorbance at 340 nm is monitored for 1.5 h at 1 min intervals. Data are collected and analyzed using, for example, Microsoft Excel software. All assays are done at least in duplicate.
  • An End-Point Turbity Assay may be carried out according to the following protocol.
  • Recombinant VI 221 TTR protein which is an amyloidogenic variation of human TTR associated with Familial Amyloid Cardiomyopathy (FAC) is produced by following the same procedure described for the Y78F variant used in Example 1. Plasmid DNA expressing the V122I mutant is prepared by site-directed mutagenesis as reported for Y78F in Dolado et al (supra) but using the following primers: 5'-GGATTGGTGATGACAGCCGT-3' (SEQ ID NO: 001) and 5'-ACGGCTGTCATCACCAATCC-3'(SEQ ID NO: 002).
  • V122I TTR is incubated with the inhibitor under the same conditions described above for the kinetic turbidity assay (Example 1), using V122I protein at a concentration of 0.4 mg/mL and three different concentrations of inhibitor: 3.6, 7.2 and 21.8 pM, corresponding to 0.5 x [protein], lx[protein], and 3* [protein].
  • samples are incubated without shaking for 72 h at 37° C. and then homogenized by mixing to resuspend any fibrils present. Turbidity is measured at 340 nm and normalized to amyl oidogene sis in the absence of inhibitor.
  • the inhibitory potency of the tested compounds is evaluated as the percentage of absorbance reduction of the inhibitor-containing samples when compared with the inhibitor-free control sample.
  • Example 3 Assay of Competition with Thyroxine (T4) for the Binding to TTR Wild Type (WT) by Gel Filtration
  • T4 Thyroxine
  • WT TTR Wild Type
  • TTR WT TTR tetramer binding sites
  • competition of test compounds with T4 (Sigma- Aldrich) for binding to TTR WT is assayed quantitatively by a gel filtration procedure, using a constant amount of TTR (100 pL of 60 nM solution) incubated with a trace amount of radiolabeled [ 125I]T4 (corresponding to 50.000 cpm; 125I-T4 specific activity 1250 pCi/pg from Perkin-Elmer, M A, USA) and with 100 pL of solution of either test compounds or T4 (positive control) at different concentrations, namely 0, 20, 60, 200, 600, 2000 6000 and 20000 nM (0-10 pM final concentration) (Ferreira et al, 2011, FEBSLett., vol.
  • the negative control is prepared with the protein, plus labelled T4 plus 100 pL of TNE (absence of competitor). All solutions are prepared in TNE buffer (Tris 0.1 M, NaCl 0.1 M, EDTA 1 mM). All samples are prepared in duplicate. Radioactivity is measured in each sample, in a gamma scintillation counter Wizard 14701, Wallac. The samples are then incubated overnight at 4° C. After incubation, T4 bound to TTR is separated from unbound T4 by filtration through a P6DG gel filtration column (1 mb, BioRad). Radioactivity is measured in the eluted samples.
  • the results can be presented as dose-response curves of T4 displacement from TTR WT by the different compounds. From each dose-response curve, the EC so value (inhibitor concentration at which half of the bound T4 is displaced) for each compound is determined. Further, the relative potency for the inhibition of binding of T4, defined as the ratio ECso (T4)/ECso (tested compound), is also calculated.
  • Example 4 Assessment of TTR Tetrameric Stability by Isoelectric Focusing (IEF) An Assessment of TTR Tetrameric Stability by Isoelectric Focusing (IEF) may be carried out according to the following protocol.
  • TTR stability is assessed by IEF in semi-denaturing conditions as previously described (Ferreira et al, 2009, FEBSLett, vol. 583, p. 3569-76).
  • Samples are prepared as follows: 30 pL of human plasma from controls and TTR V30M carriers are incubated with 5 pl of 10 mM solution of test compounds and control (EGCG) compounds overnight at 4° C. followed by a 1 h incubation at RT. The preparations are subjected to native PAGE (5% acrylamide) and the gel band containing TTR is excised and applied to an IEF gel (5% acrylamide).
  • IEF is carried out in semi-denaturing conditions (4 M urea), containing 5% (v/v) ampholytes pH 4-6.5 (GE Healthcare), at 1200 V for 6 hours. Proteins are stained with Coomassie Blue, the gels are scanned and subjected to densitometry using the ImageQuant program (HP Scanjet 4470c, Hewlett Packard). In the absence of any compound, plasma TTR presented a characteristic band pattern, composed of monomer, an oxidized monomer and several lower isoelectric point (pl) bands corresponding to different forms of tetramers. A total of 12 plasma samples (5 controls and 7 carriers TTR V30M) are analyzed in 3 IEF gels. For each treatment condition, a minimum of 4 samples from different donors are processed.
  • TTR tetramer+monomer The ratio of TTR tetramer over Total TTR (TTR tetramer+monomer) is calculated for each plasma sample. This ratio is normally higher for plasma from normal individuals than for the plasma from heterozygotic TTR V30M carriers plasma. Treatment with the exemplary compounds may increase the amount of TTR tetramer over the monomeric forms compared to the non-treated control plasmas of both normal or mutant TTR. The increase of the tetramer/total TTR ratio induced by the treatment with test compounds is pooled for all samples and represented as % of stabilization.
  • % stabilization 100x((ratio sample-ratio nt)/ratio nt).
  • ratio sample is tetramer/total TTR ratio in the presence of compound
  • ratio nt is tetramer/total TTR ratio of non-treated plasma from same donor.
  • Example 5 Cell Toxicity Assays A Cell Toxicity Assay may be carried out according to the following protocol.
  • Rat Schwannoma cells (RN22, obtained from American Type Cell Collection ATCC), 80% confluent cells in Dulbecco's minimal essential medium with 10% fetal bovine serum, are exposed for 24 hours to 2 pM of TTR Y78F oligomers. These oligomers are obtained by incubation of soluble TTR Y78F either in the absence or presence of a 1 Ox molar excess (final concentration is 20 pM) of test compounds or control (EGCG) at 37° C. for 6 days.
  • RN22 obtained from American Type Cell Collection ATCC
  • 80% confluent cells in Dulbecco's minimal essential medium with 10% fetal bovine serum are exposed for 24 hours to 2 pM of TTR Y78F oligomers. These oligomers are obtained by incubation of soluble TTR Y78F either in the absence or presence of a 1 Ox molar excess (final concentration is 20 pM) of test compounds or control (EGCG) at 37° C. for 6 days.
  • cells are trypsinized and cell lysates are used for determination of caspase-3 activation with the CaspACE fluorimetric 96-well plate assay system (Sigma). Protein concentration in lysates is determined with the Bio-Rad protein assay kit.
  • TTR preformed fibrils prepared by incubation of a filtered (0.2 pm filters) solution of TTR L55P (2 mg/ml in PBS 3.6 pM) for 15 days at 37° C. Subsequently, the samples are incubated either in the absence (control) or presence of a 10x molar excess (36 pM) (final concentration) of the test compounds for 4 days at 37° C.
  • the disruption effect is evaluated by Transmission Electron Microscopy (TEM) and Dynamic Light Scattering (DLS) as previously described (Ferreira et al, 2009, FEBSLett, vol. 583, p. 3569-76).
  • control sample of TTR pre-formed fibrils is mainly composed by big aggregates and fibrils (particles with a diameter higher than 1000 nm) and just a small amount of the protein is in soluble form (particles of 10 nm diameter). As the fibrils are being disrupted by the tested compounds the relative amount of big aggregates decrease and the small aggregates and soluble protein increase.
  • the fibril disruption activity is quantified from the DLS analysis as the relative intensity (%) of aggregates and soluble particles after 4 days treatment with 36 pM of compounds.

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Abstract

L'invention concerne des composés associés à la tolcapone et son métabolite, 3-OMT, ainsi qu'à la 3-désoxytolcapone et des compositions pharmaceutiques les comprenant. L'invention concerne également des procédés d'utilisation de tels composés et compositions, y compris l'utilisation pour le traitement ou la prévention de maladies ou de troubles associés aux amyloïdes.
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Publication number Priority date Publication date Assignee Title
WO2019195761A2 (fr) * 2018-04-05 2019-10-10 Calasia Pharmaceuticals, Inc. Agents pharmacologiques pour le traitement de maladies oculaires

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* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, 19 May 2015, Columbus, Ohio, US; abstract no. RN 1707369-12-7, ANONYMOUS : "Methanone, (4-methoxy-3-nitrophenyl)(4-methylphenyl)-" XP055928539 *
CHEMICAL ABSTRACTS, 2 September 2020, Columbus, Ohio, US; abstract no. RN 2469274-07-3, ANONYMOUS: "(3-Bromo-4-methylphenyl)(4-methoxy-3-nitrophenyl)methanone" XP055928541 *
CHEMICAL ABSTRACTS, 2020902, Columbus, Ohio, US; abstract no. RN 2469274-07-3, ANONYMOUS : "RN 2469274-07-3" XP055928534 *
STANLEY SHAWN, VAN DEN BERG KOOS, FOO HSIAO CHING, DENG DEREK: "Metabolism and elimination of the catechol‐ o ‐methyltransferase inhibitor tolcapone in the horse", DRUG TESTING AND ANALYSIS, JOHN WILEY & SONS LTD., GB, vol. 11, no. 4, 1 April 2019 (2019-04-01), GB , pages 578 - 585, XP055928538, ISSN: 1942-7603, DOI: 10.1002/dta.2531 *

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