Tramiprosate for treating APOE4-related disorders

Abstract

Provided herein is the use of tramiprosate, a prodrug of tramiprosate, a tramiprosate analog, a prodrug of a tramiprosate analog, a pharma- ceutically acceptable salt of any of the foregoing, or an isotopically enriched form of any of the foregoing, for treating an ApoE4-related non-amyloid disease or condition.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 336,210, filed April 28, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] Apolipoprotein E4 (apoE4) is a major genetic risk factor for late-onset Alzheimer's disease (AD) and increases the risk of developing AD early in its onset. Human ApoE has 299 amino acids and has three common isoforms (apoE2, apoE3, and apoE4) that differ at residues 112 or 158. ApoE3 contains a cysteine ​​at residue 112 and an arginine at residue 158, whereas apoE4 has arginines at both positions and apoE2 has a cysteine. These small changes result in major differences in tertiary protein structure and thus function. ApoE4 exhibits intramolecular domain interactions between its amino- and carboxyl-terminal domains, resulting in a compact, or "closed" structure. The domain interaction in apoE4 is induced by Arg-112, which promotes the formation of a salt bridge between Arg-61 in the amino-terminal domain and Glu-255 in the carboxyl-terminal domain. The Cys-112 residue in apoE2 and apoE3 weakens the domain interaction, resulting in a more open structure (see Figure 1). By disrupting the interaction of the apoE4 domain with small molecules, the so-called apoE4 structural correctors, apoE4 is converted into an apoE3-like conformation, reversing the apoE4-specific adverse effects. Most correctors known to date are highly hydrophobic small molecules that do not appear to have high specificity for ApoE4 and therefore may result in undesirable off-target effects that hinder their development or limit their usefulness as leads for the development of new therapeutic agents.

[0003] In addition to playing a role in Alzheimer's disease and other amyloid-related disorders, apoE is also involved in cholesterol homeostasis and lipid metabolism, and apoE4 isozyme appears to have a negative effect on lipid profile and cardiovascular disease. Thus, apoE4 plays an important contributing role in hypercholesterolemia, coronary heart disease, cardiovascular disease, cerebral atherosclerosis, small vessel disease, and blood-brain barrier leakage. In contrast, apoE3 does not cause the same side effects. ApoE4 is also associated with nephrotic syndrome, cholelithiasis, increased risk of breast cancer, high susceptibility to infections, and subnormal immune response. The risk of these aforementioned disorders is more increased in subjects with two copies or alleles of apoE4 (homozygous) than one copy of apoE4, and the risk is lower in apoE4 non-carriers.

[0004] Tramiprosate (also chemically known as homotaurine) is being investigated in human clinical trials for the treatment of Alzheimer's disease (AD). Although tramiprosate was not approved, trial results suggested efficacy in at least some patients, and a valine prodrug of tramiprosate, ALZ-801, is currently in human clinical trials for AD in ApoE4 homozygous subjects. Tramiprosate and its prodrugs are believed to act by binding to amyloid-beta multimers, preventing the formation of oligomers that are directly neurotoxic and are the main components of the plaques found in AD brains. Both tramiprosate and ALZ-801 have been found to be safe in human subjects.

[0005] Despite the identification of several small molecule apoE4 correctors, there remains a need for more potentially therapeutic apoE4 correctors that are safe and well tolerated, bind more specifically to apoE4, and induce conformational changes or modifications (i.e., a "corrector" effect), resulting in a more open structure that mimics apoE3 or apoE2. Summary of the Invention

[0006] The present disclosure solves the above problems by demonstrating that tramiprosate also binds directly to ApoE4 at the site that binds to heparin and other glycosaminoglycans (amino acids 141-150) and interacts with amino acid Asp107 (see Figures 2 and 3). The location of these interactions is close to Arg112 and may disrupt the salt bridge between Arg61 and Glu255 induced by Arg112 (Figure 1). This suggests for the first time that tramiprosate, as well as its derivatives, and prodrugs and salts of tramiprosate or its derivatives, may be useful for ApoE4-related treatments that do not require amyloid or beta-amyloid.

[0007] Thus, provided herein are methods of using tramiprosate, as well as derivatives thereof, and prodrugs and salts of tramiprosate or its derivatives, for treating ApoE4-related conditions that do not involve amyloid or beta-amyloid. [Brief description of the drawings]

[0008] [Figure 1] Ribbon diagram of the ApoE4 and ApoE3 structures, showing the role of Arg-112 in forming a salt bridge between Arg-61 and Glu-225 in ApoE4. In ApoE3, Cys-112 replaces Arg-112 and there is no salt bridge between Arg-61 and Glu-225, resulting in a more open structure. [Diagram 2] Binding of tramiprosate to ApoE4 at the site that binds to heparin and other glycosaminoglycans (amino acids 141-150) and interactions with neighboring amino acids of that bond are shown. [Diagram 3] The sulfonic acid group of tramiprosate interacts in a bidentate manner via an additional salt bridge to the side chain of Arg150 (2.78 Å and 3.07 Å), as well as with Asp-151 and Asp-107. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] In one aspect, a method of treating an ApoE4-related non-amyloid disease or condition is provided, comprising administering to a subject in need thereof an effective amount of an agent selected from tramiprosate, a prodrug of tramiprosate, a tramiprosate analog, a prodrug of a tramiprosate analog, a pharma- ceutically acceptable salt of any of the foregoing, or an isotopically enriched form of any of the foregoing.

[0010] Also provided is an effective amount of an agent selected from tramiprosate, a prodrug of tramiprosate, a tramiprosate analog, a prodrug of a tramiprosate analog, a pharma- ceutically acceptable salt of any of the foregoing, or an isotopically enriched form of any of the foregoing, for treating an ApoE4-related non-amyloid disease or condition.

[0011] Also provided is the use of an effective amount of an agent selected from tramiprosate, a prodrug of tramiprosate, a tramiprosate analog, a prodrug of a tramiprosate analog, a pharma- ceutically acceptable salt of any of the foregoing, or an isotopically enriched form of any of the foregoing, for the manufacture of a medicament for the treatment of an ApoE4-related non-amyloid disease or condition.

[0012] Further provided is a composition comprising an effective amount of an agent selected from tramiprosate, a prodrug of tramiprosate, a tramiprosate analog, a prodrug of a tramiprosate analog, a pharma- ceutically acceptable salt of any of the foregoing, or an isotopically enriched form of any of the foregoing, for treating an ApoE4-related non-amyloid disease or condition.

[0013] "Tramiprosate" (homotaurine, 3-amino-1-propanesulfonic acid (3-APS), or Alzhemed™) has the following chemical structure: [ka] It refers to a compound having the formula:

[0014] In one embodiment, "tramiprosate prodrug" or "prodrug of tramiprosate" includes, but is not limited to, a compound that is metabolized to tramiprosate after administration to a subject. Tramiprosate prodrugs and analogs are known in the art and include those described in WO2009 / 019534, WO2017 / 027582, WO2004 / 113275, WO2006 / 085149, WO1994 / 022437, WO2000 / 064420, WO1999 / 040909, WO1999 / 059571, WO2004 / 112762, and WO2018 / 156845.

[0015] In one embodiment, the tramiprosate prodrug has the formula: 1 -aa 2 -NH-CH2-CH2-CH2-S(O)2-OH, 1 is a natural or unnatural amino acid, aa 2 is a natural or unnatural amino acid or is absent, and any hydrogen atom is optionally replaced with a deuterium atom. Other prodrugs include those of the formula: [ka] where R is -(AA 1 )-(AA 2 ) t and A.A. 1 and A.A. 2are each independently selected from alanine (Ala), cysteine ​​(Cys), aspartic acid (Asp), glutamic acid (Glu), phenylalanine (Phe), glycine (Gly), histidine (His), isoleucine (Ile), lysine (Lys), leucine (Leu), methionine (Met), asparagine (Asn), proline (Pro), glutamine (Gln), arginine (Arg), serine (Ser), threonine (Thr), valine (Val), tryptophan (Trp), tyrosine (Tyr), β-alanine (β-ALA), and γ-aminobutyric acid (GABA); and t is 0 or 1. Additional prodrugs can be found, for example, in WO2015 / 143447.

[0016] In certain embodiments, the tramiprosate prodrug is ALZ-801 (valyl-3-amino-1-propanesulfonic acid), represented by the following chemical structure: [ka] or a pharma- ceutically acceptable salt thereof.

[0017] "Tramiprosate analog" refers to a compound that is a modification of tramiprosate by one or more of the following: addition of one or more additional substituents, insertion or deletion of one or more methylene groups, replacement of the SO3H group with an equivalent, and cyclization, while maintaining the ability to bind to β-amyloid. In some embodiments, the tramiprosate analog is a compound described or disclosed in any of WO2009 / 019534, WO2017 / 027582, WO2004 / 113275, WO2006 / 085149, WO1994 / 022437, WO2000 / 064420, WO1999 / 040909, WO1999 / 059571, WO2004 / 112762, and WO2018 / 156845.

[0018] One example of such a tramiprosate analog is of the formula: [ka] where D is a carbonyl or substituted methylene group and X is selected from -O-, -NH-, or -S-.

[0019] Another example of a tramiprosate analog is a compound of the formula: [ka] In particular, the compound has the formula 7 is C1~C 12 Alkyl, C2-C 12 Alkenyl, C2-C 12 Alkynyl, C3-C 15 Cycloalkyl, C3-C 15 Heterocycloalkyl, C6-C 15 Aryl, C5-C 15 Heteroaryl, C7-C 12 Aryl alkyl, C7-C 12 heteroaryl, arylalkyl, and combinations thereof.

[0020] Yet another example of a tramiprosate analog is represented by the formula: [ka] or the expression: [ka] or a pharma- ceutically acceptable salt of any of the foregoing, wherein: R a1 is selected from the group consisting of hydrogen and C1-C3 alkyl optionally substituted with one or more hydroxyls; R b1is selected from the group consisting of hydrogen; C1-C3 alkyl substituted with one or more substituents independently selected from carboxy, amino, optionally substituted heteroaryl, optionally substituted aryl, alkylthio, aminocarbonyl, hydroxy, dialkylamino, alkylamino, and arylalkylamino; cycloalkyl optionally substituted with amino; and heterocyclyl optionally substituted with amino; Each R 7 and each R 8 is hydrogen, Ring A is selected from optionally substituted pyrrolidinyl, piperidinyl, morpholinyl, or piperazinyl.

[0021] The term "alkyl," used alone or as part of a larger moiety, e.g., "haloalkyl," means, unless otherwise specified, a saturated, monovalent, straight or branched hydrocarbon radical of 1 to 10 carbon atoms, including, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, n-decyl, and the like.

[0022] The term "alkenyl," used alone or as part of a larger moiety, e.g., "haloalkenyl," means, unless otherwise specified, a monovalent group derived from a straight- or branched-chain aliphatic moiety having at least one carbon-carbon double bond, having 1 to 10 carbon atoms. Representative alkenyl groups include, but are not limited to, ethenyl ("vinyl"), propenyl ("allyl"), butenyl, 1-methyl-2-buten-1-yl, and the like.

[0023] The term "alkynyl," used alone or as part of a larger moiety, e.g., "haloalkynyl," means, unless otherwise specified, a monovalent group derived from a straight- or branched-chain aliphatic moiety having 1 to 10 carbon atoms and at least one carbon-carbon triple bond. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl ("propargyl"), 1-propynyl, and the like.

[0024] The term "aryl" used alone or as part of a larger moiety, such as "aralkyl", refers to monocyclic and bicyclic carbocyclic ring systems having a total of 5-10 ring members, where at least one ring of the ring system is aromatic. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments, "aryl" refers to aromatic ring systems, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like. In one embodiment, "aryl" is phenyl. It is understood that optional substituents on an aryl group, when specified, may be present at any substitutable position.

[0025] The term "heteroaryl" used alone or as part of a larger moiety, such as "heteroarylalkyl", refers to a 5-12 membered fully aromatic ring system containing 1-4 heteroatoms selected from N, O and S. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic". Heteroaryl groups may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, and pyrazinyl. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, benzoxazolyl, benzoxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, naphthyridinyl and pteridinyl. When specified, it will be understood that optional substituents on a heteroaryl group may be present at any substitutable position, including, for example, the position at which the heteroaryl is attached.

[0026] The term "heterocyclyl" refers to a 4-12 membered ring system that is saturated or partially unsaturated (not aromatic) and contains 1-4 heteroatoms independently selected from N, O, and S. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", and "heterocyclic moiety" are used interchangeably herein. A heterocyclyl ring may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A heterocyclyl group may be monocyclic or bicyclic. Examples of monocyclic saturated or partially unsaturated heterocyclic groups include, but are not limited to, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, and tetrahydropyrimidinyl. Bicyclic heterocyclyl groups include, for example, a heterocyclic ring fused to another unsaturated heterocyclic ring, a cycloalkyl, an aromatic ring, or a heteroaryl ring, such as benzodioxolyl, dihydrobenzodioxinyl, 6,7-dihydro-5H-pyrrolo[2,1-c][1,2,4]triazolyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyridinyl, 1,2-dihydroquinolinyl, dihydrobenzofuranyl, tetrahydronaphthyridine, indolinone, dihydropyrrolotriazole, quinolinone, dioxaspirodecane, etc. It will be understood that, when specified, the optional substituents on a heterocyclyl group may be present at any substitutable position, including, for example, the position at which the heterocyclyl is attached.

[0027] The term "cycloalkyl" refers to a monocyclic or bicyclic hydrocarbon that is fully saturated.

[0028] The compounds described herein may have chiral and / or geometric centers (E- and Z-isomers). It is understood that the present disclosure encompasses all stereoisomers and geometric isomers. Tautomeric forms of the compounds described herein are also part of the present disclosure.

[0029] The term "pharmaceutically acceptable salt" refers to a salt of a basic group (eg, amino group) or an acidic group (eg, sulfonic acid) on the compounds described herein. Exemplary salts of basic groups include, but are not limited to, sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, hydrogen sulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucuronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorsulfonate, and pamoate (i.e., 1,1′-methylene-bis-(2-hydroxy-3-naphthoate)) salts. Exemplary salts of acidic groups include, but are not limited to, lithium, sodium, potassium, calcium, magnesium, aluminum, chromium, iron, copper, zinc, cadmium, ammonium, guanidinium, pyridinium, and organic ammonium salts.

[0030] "Pharmaceutically acceptable" refers to drugs, agents, inactive ingredients, etc., that the term describes that are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, incompatibility, instability, irritation, allergic response, etc., commensurate with a reasonable benefit / risk ratio. In one aspect, pharma- ceutically acceptable refers to compounds or compositions that are approved or approvable by a federal or state government regulatory agency or that are listed in the United States Pharmacopeia or other generally recognized pharmacopoeias for use in animals, and more particularly in humans.

[0031] The method of administration may use dosages and routes of administration effective to treat or reduce the severity of the diseases described herein. The exact amount required will vary from subject to subject depending on the race, age, and general condition of the subject, the severity of the infection, the particular drug, its mode of administration, and the like. The compounds provided are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. For example, the compounds provided may be formulated so that a dosage of the compound of 0.01-100 mg / kg of body weight per day may be administered to the patient receiving these compositions. However, it is understood that the total daily usage of the compounds and compositions of the present disclosure will be determined by the attending physician within the scope of reasonable medical judgment. The specific effective dosage level for a particular patient or organism will depend on a variety of factors, including the disorder and severity of the disorder being treated, the activity of the specific compound used, the specific composition used, the age, weight, general health, sex, and diet of the patient, the time of administration, route of administration, and rate of excretion of the specific compound used, the duration of treatment, drugs used or to be used simultaneously with the specific compound used, and similar factors well known in the medical arts.

[0032] It should also be understood that the specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including age, weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the particular disease being treated.

[0033] As used herein, the terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as, for example, companion animals (e.g., dogs, cats, etc.), farm animals (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0034] As used herein, the terms "treatment", "treat" and "treating" refer to reversing, alleviating, delaying the onset or inhibiting the progression of a disease described herein or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed, i.e., after therapeutic treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual before the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors), i.e., before prophylactic treatment. Treatment may also be continued after symptoms have disappeared, e.g., to prevent or delay the recurrence of symptoms.

[0035] ApoE4-related non-amyloid disease or condition refers to diseases and conditions that are not known to be associated with amyloid deposition, such as those that grow in the presence of beta-amyloid plaques.ApoE4-related non-amyloid disease or condition includes, but is not limited to, hypercholesterolemia, coronary heart disease, cardiovascular disease, high susceptibility to infection, subnormal immune response, gallstones, cerebral atherosclerosis, small vessel disease, or blood-brain barrier leakage. EXAMPLES

[0036] Example 1. Docking of Tramiprosate into an ApoE4 crystal model. The 1.70 Å resolution crystal structure of human ApoE4 (PDB code: 1GS9) was used in the following study to investigate the possible binding mode of homotaurine. A 22 kD fragment of ApoE4 was first processed by Maestro's protein preparation wizard (Schrodinger, "Maestro," LLC, New York, NY, 2009), where all crystallographic waters were removed, explicit hydrogen atoms were added, and various conformational states of hydrogen-bonding side chains were analyzed for their ability to form internal hydrogen bonds. The processed structure of ApoE4 was then "relaxed" by constrained minimization of all atoms present in the OPLS_2005 force field. The relaxed ApoE4 protein structure was used to generate a grid for pose evaluation by glide docking without any constraints. RAFriesner, JLBanks, RBMurphy et al., "Glide: a new approach for rapid,accurate docking and scoring.1.Method and assessment of docking accuracy," J.Med.Chem.2004,47,1739-1749. TAHalgren, RBMurphy, RAFriesner et al., "Glide: a new approach for rapid,accurate docking and scoring.2.Enrichment See “factors in database screening,” J.Med.Chem.2004, 47, 1750-1759.

[0037] The structure of homotaurine was docked using Glide in ultra-precise mode (XP) and up to three poses were saved for further optimization. Each of the docked poses was then energy minimized in the bound state using the GBSA continuum solvation model (MM-GBSA). See Nu, H.; Kalyanaraman, C.; Irwin, JJ; Jacobson, MP Physics based scoring of protein-ligand complexes: enrichment of known inhibitors in large-scale virtual screening. J. Chem. Inf. Model. 2006, 46, 243-253. In the energy minimization step, no constraints were applied to residues within 5 Å of the center of the homotaurine pose. The latter step was used to allow for some protein flexibility.

[0038] The top scoring pose is a region of the heparin-binding domain of ApoE4 (residues 141-150) that was found to interact with the consensus sequence LRKLRKRLLR. See Datta, G., DW Garber, BH Chung, M. Chaddha, N. Dashti, WA Bradley, SHGianturco, GM Anantharamaiah. The cationic domain 141-150 of apoE covalently linked to a class A amphipathic helix enhances atherogenic lipoprotein metabolism in vitro and in vivo. J. Lipid Res. 2001, 42, 959-966. The primary interaction of homotaurine with ApoE4 is through a pair of salt bridges (3.05 Å and 2.80 Å, respectively) between the protonated amine of homotaurine and the carboxylate side chains of Asp107 and Asp151. In addition, the sulfonate group of homotaurine interacts in a bidentate manner through an additional salt bridge to the side chain of Arg150 (2.78 Å and 3.07 Å). These interactions are shown in Figures 1-3.

[0039] Having described a number of embodiments of the present disclosure, it is apparent that our basic examples may be modified to provide other embodiments that utilize the compounds and methods of the present disclosure. It will therefore be appreciated that the scope of the present disclosure should be defined by the appended claims rather than by the specific embodiments that have been represented by way of example.

[0040] The contents of all references cited in this application (including literature references, issued patents, published patent applications, and co-pending patent applications) are expressly incorporated herein by reference in their entirety. Unless otherwise defined, all technical and scientific terms used herein are accorded the meaning commonly known to one of ordinary skill in the art.

Claims

1. A pharmaceutical composition for treating an ApoE4-related non-amyloid disease or condition, comprising an effective amount of an agent selected from tramiprosate, a prodrug of tramiprosate, a tramiprosate analog, a prodrug of a tramiprosate analog, a pharmaceutically acceptable salt of any of the foregoing, or any isotopic enriched form of any of the foregoing.

2. The pharmaceutical composition according to claim 1, wherein the disease or condition is hypercholesterolemia, coronary heart disease, cardiovascular disease, high susceptibility to infection, subnormal immune response, gallstones, cerebral atherosclerosis, small vessel disease, or blood-brain barrier leakage.

3. The pharmaceutical composition according to claim 1 or 2, wherein the drug is tramiprosate or a prodrug of tramiprosate.

4. The prodrug of tramiprosate is given by formula (I): aa １ -aa ２ -NH-CH ２ -CH ２ -CH ２ -S(O) ２ -OH amino acid prodrug, in the formula aa １ However, it is a natural or non-natural amino acid, aa ２ The pharmaceutical composition according to claim 3, wherein the amino acids are natural or non-natural, or are not present, and any hydrogen atom is optionally replaced with a deuterium atom.

5. The pharmaceutical composition according to claim 1 or 2, wherein the drug is formulated into an oral dosage form.

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