Small molecule peptidomimetics for the treatment of tauopathies

Abstract

The present disclosure provides novel methods for treating, preventing, ameliorating, inhibiting and / or delaying the onset of tauopathy, comprising administering to a subject an effective amount of a small molecule peptidomimetic, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 298,024, filed January 10, 2022, the entire contents of which are incorporated herein by reference.

[0002] Parties to the Joint Research Agreement The claimed inventions were made on behalf of and / or in conjunction with one or more of the following parties to a Collaborative Research Agreement: Stealth BioTherapeutics Corp, Stealth BioTherapeutics, Inc., and The General Hospital Corporation, d / b / a Massachusetts General Hospital. The Collaborative Research Agreement was in effect on or before the date on which the claimed invention was made, and the claimed invention was made as a result of activities conducted within the scope of the Collaborative Research Agreement.

[0003] The present technology generally relates to compositions and methods for treating, preventing, ameliorating, inhibiting and / or delaying the onset of tauopathies, which are neurodegenerative disorders associated with the presence of abnormal tau protein in the brain, which leads to the intracellular formation of tau aggregates, filaments and tangles. In general, the present technology relates to administering to a subject suffering from a tauopathy an effective amount of a small molecule peptidomimetic compound, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (hereinafter referred to as Compound 1 or Comp. 1), or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate and / or solvate thereof.

[0004] Introduction The following explanation is provided to aid the understanding of the reader. None of the information provided or references cited are admitted to be prior art to the compositions and methods disclosed herein.

[0005] Neurodegenerative diseases and disorders affect the body's activities, such as balance, movement, speech, breathing, and / or heart function. Neurodegenerative diseases and disorders are generally incurable and debilitating conditions that result in the progressive degeneration and / or death of nerve cells. As the condition progresses, it can often lead to the death of the affected subject. Some examples of neurodegenerative diseases related to tauopathy include: Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, familial Danish dementia, and primary age-related tauopathy, including neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tau astrogliopathy. Clinical symptoms include frontotemporal dementia, corticobasal syndrome, Richardson's syndrome, Parkinsonism, pure akinesia with gait freezing, and rarely motor neuron symptoms or cerebellar ataxia. There is currently a strong need for suitable drugs to treat subjects who are affected or expected to be affected based on genetic, lifestyle or environmental considerations with tauopathies associated with the disease state. Summary of the Invention

[0006] In one aspect, the disclosure of the present technology provides a method for treating, preventing, ameliorating, inhibiting and / or delaying the onset of a tauopathy in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of a small molecule peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0007] In some embodiments, administration of the small molecule peptidomimetic reduces tau species levels and / or reduces toxicity associated with cellular tau accumulation, hi some embodiments, administration of the small molecule peptidomimetic reduces cellular oxidative stress caused by cellular accumulation of tau protein.

[0008] In some embodiments, the subject is diagnosed with Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia. In some embodiments, the subject is diagnosed with primary age-related tauopathy. In some embodiments, the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tauastrogliopathy.

[0009] In some embodiments, the peptidomimetic is administered daily for 2 weeks or more. In some embodiments, the peptidomimetic is administered daily for 12 weeks or more, 24 weeks or more, 48 weeks or more, 1 year or more, 2 years or more, or 5 years or more. In some embodiments, the peptidomimetic is administered immediately after diagnosis for the remainder of the subject's life or until administration of the peptidomimetic is no longer effective.

[0010] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0011] In some embodiments, the peptidomimetic is administered orally. In some embodiments, the peptidomimetic is administered subcutaneously. In some embodiments, the peptidomimetic is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmologically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

[0012] In some embodiments, the method further comprises administering to the subject an additional treatment, either separately, sequentially, or simultaneously. In some embodiments, the additional treatment comprises administration of a therapeutic agent or multiple therapeutic agents. In some embodiments, the therapeutic agent is a small molecule selected from the group consisting of a regulator of tau phosphorylation, a regulator of tau acylation, a histone deacetylase (HDAC) inhibitor, a regulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor), a regulator of tau cleavage (e.g., a capsase inhibitor), a tau aggregation inhibitor, a proteasome stimulator, a USP14 inhibitor, a phosphodiesterase inhibitor, an autophagy activator, a chaperone modulator, a co-chaperone modulator, and a tau-directed multitarget specific ligand.

[0013] In some embodiments, the combination of the peptidomimetic and the additional therapeutic agent has a synergistic effect in treating a tauopathy.

[0014] In some embodiments, pharma- ceutically acceptable salts include tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate. In some embodiments, the peptidomimetic is formulated as a tris-HCl, bis-HCl, or mono-HCl salt.

[0015] In one aspect, the disclosure of the present technology provides for the use of a composition in the preparation of a medicament for treating, preventing, ameliorating, inhibiting and / or delaying the onset of a tauopathy in a subject in need thereof, the composition comprising a therapeutically effective amount of a small molecule peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0016] In some embodiments, use of the compositions reduces tau species levels and / or reduces toxicity associated with cellular tau accumulation, hi some embodiments, use of the compositions reduces cellular oxidative stress caused by cellular accumulation of tau protein.

[0017] In some embodiments, the subject is diagnosed with Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia. In some embodiments, the subject is diagnosed with primary age-related tauopathy. In some embodiments, the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tauastrogliopathy.

[0018] In some embodiments, the composition / agent is administered daily for 2 weeks or more. In some embodiments, the composition / agent is administered daily for 12 weeks or more, 24 weeks or more, 48 weeks or more, 1 year or more, 2 years or more, or 5 years or more. In some embodiments, the composition / agent is administered immediately after diagnosis for the remainder of the subject's life or until administration of the peptidomimetic is no longer effective.

[0019] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0020] In some embodiments, the composition / agent is formulated for oral administration. In some embodiments, the composition / agent is formulated for subcutaneous administration. In some embodiments, the composition / agent is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intraventricular, iontophoretic, transmucosal, intravitreal, or intramuscular administration.

[0021] In some embodiments, the composition / medicament is intended to be used separately, sequentially, or simultaneously with an additional treatment. In some embodiments, the additional treatment comprises the further use of a therapeutic agent or agents. In some embodiments, the therapeutic agent is selected from the group consisting of a regulator of tau phosphorylation, a regulator of tau acylation, a histone deacetylase (HDAC) inhibitor, a regulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor), a regulator of tau cleavage (e.g., a capsase inhibitor), a tau aggregation inhibitor, a proteasome stimulator, a USP14 inhibitor, a phosphodiesterase inhibitor, an autophagy activator, a chaperone modulator, a co-chaperone modulator, and a tau-directed multitarget specific ligand.

[0022] In some embodiments, the combination of the composition / medicament and the additional treatment / therapeutic agent has a synergistic effect in treating a tauopathy.

[0023] In some embodiments, the small molecule peptidomimetic used in formulating the composition / medicament is a pharma- ceutically acceptable salt selected from the group consisting of tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, and tritosylate. In some embodiments, the peptidomimetic used in formulating the composition / medicament is a trisHCl, bisHCl, or monoHCl salt.

[0024] In one aspect, the disclosure of the present technology provides a small molecule peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, for use in treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide.

[0025] In some embodiments, the use of small molecule peptidomimetics reduces tau species levels and / or reduces toxicity associated with cellular tau accumulation, hi some embodiments, the use of small molecule peptidomimetics reduces cellular oxidative stress caused by cellular accumulation of tau protein.

[0026] In some embodiments, the subject is diagnosed with Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia. In some embodiments, the subject is diagnosed with primary age-related tauopathy. In some embodiments, the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tauastrogliopathy.

[0027] In some embodiments, the peptidomimetic is administered daily for 2 weeks or more. In some embodiments, the peptidomimetic is administered daily for 12 weeks or more, 24 weeks or more, 48 weeks or more, 1 year or more, 2 years or more, or 5 years or more. In some embodiments, the peptidomimetic is administered immediately after diagnosis for the remainder of the subject's life or until administration of the peptidomimetic is no longer effective.

[0028] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0029] In some embodiments, the peptidomimetic is formulated for oral administration. In some embodiments, the peptidomimetic is formulated for subcutaneous administration. In some embodiments, the peptidomimetic is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intraventricular, iontophoretic, transmucosal, intravitreal, or intramuscular administration.

[0030] In some embodiments, the peptidomimetics are intended to be used separately, sequentially, or simultaneously with additional treatments. In some embodiments, the additional treatments include the use of a therapeutic agent or agents. In some embodiments, the therapeutic agent is selected from the group consisting of regulators of tau phosphorylation, regulators of tau acylation, histone deacetylase (HDAC) inhibitors, regulators / inhibitors of tau glycosylation (e.g., O-GlcNAcase inhibitors), regulators of tau cleavage (e.g., capsase inhibitors), tau aggregation inhibitors, proteasome stimulators, USP14 inhibitors, phosphodiesterase inhibitors, autophagy activators, chaperone modulators, co-chaperone modulators, and tau-directed multitarget specific ligands.

[0031] In some embodiments, the combination of the peptidomimetic and the additional therapy has a synergistic effect in treating, preventing, ameliorating, inhibiting and / or delaying the onset of a tauopathy.

[0032] In some embodiments, pharma- ceutically acceptable salts include tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate. In some embodiments, the peptidomimetic is formulated as a tris-HCl, bis-HCl, or mono-HCl salt.

[0033] In one aspect, the disclosure of the present technology provides for the use of a small molecule peptidomimetic, or a composition comprising a small molecule peptidomimetic, in the preparation of a medicament for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof. In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0034] In some embodiments, the use of the agent reduces tau species levels and / or reduces toxicity associated with cellular tau accumulation, hi some embodiments, the use of the agent reduces cellular oxidative stress caused by cellular accumulation of tau protein.

[0035] In some embodiments, the subject is diagnosed with Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia. In some embodiments, the subject is diagnosed with primary age-related tauopathy. In some embodiments, the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tauastrogliopathy.

[0036] In some embodiments, the agent is administered daily for 2 weeks or more. In some embodiments, the agent is administered daily for 12 weeks or more, 24 weeks or more, 48 weeks or more, 1 year or more, 2 years or more, or 5 years or more. In some embodiments, the agent is administered immediately after diagnosis for the remainder of the subject's life or until administration of the peptidomimetic is no longer effective.

[0037] In some embodiments, the subject is a mammal. In some embodiments, the mammalian subject is a human.

[0038] In some embodiments, the agent is formulated for oral administration. In some embodiments, the agent is formulated for subcutaneous administration. In some embodiments, the agent is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intraventricular, iontophoretic, transmucosal, intravitreal, or intramuscular administration.

[0039] In some embodiments, pharma- ceutically acceptable salts include tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate. In some embodiments, the peptidomimetic is formulated as a tris-HCl, bis-HCl, or mono-HCl salt. [Brief description of the drawings]

[0040] [Figure 1] FIG. 1 is a diagram of the structures of small molecule phosphatase activators, kinase inhibitors, and acetylation inhibitors that may prove useful in the treatment of tauopathies. [Diagram 2] FIG. 1 is a diagram of the structures of small molecule histone deacetylase (HDAC) inhibitors and O-GlcNAcase inhibitors that may prove useful in the treatment of tauopathies. [Diagram 3]FIG. 1 is a diagram of the structures of small molecule modulators of tau cleavage and tau aggregation inhibitors that may prove useful in the treatment of tauopathies. [Figure 4] FIG. 1 is a diagram of the structures of additional small molecule tau aggregation inhibitors that may prove useful in the treatment of tauopathies. [Diagram 5] FIG. 1 is a diagram of the structures of small molecule proteasome stimulators, USP14 inhibitors, phosphodiesterase inhibitors, and PROTACs that may prove useful in the treatment of tauopathies. [Figure 6] FIG. 1. Structures of small molecule autophagy activators that may prove useful in the treatment of tauopathies. [Figure 7] FIG. 1 is a diagram of the structures of small molecule Hsp70 modulators that may prove useful in the treatment of tauopathies. [Figure 8] FIG. 1 is a diagram of the structures of small molecule Hsp90 and co-chaperone modulators that may prove useful in the treatment of tauopathies. [Figure 9] FIG. 1 is a diagram of the structure of a tau-directed multitarget specific ligand that may prove useful in the treatment of tauopathies. [Figure 10A-H] FIG. 1 is a chart showing the effect of the peptidomimetic (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide ("Compound 1" or "Comp. 1") on tauopathy neuronal cell viability and protection against stress-induced cell death in an iPSC-derived neuronal model derived from a patient with a MAPT P301L mutation (tau-P301L neurons). [Figure 10A] 1 is a chart showing the dose effect of Compound 1 on the viability of Tau-P301L neurons (iPSC-derived neuronal cells derived from a human subject harboring the MAPT P301L mutation). [Figure 10B]FIG. 1 is a schematic diagram providing an overview of a stress rescue assay to test the protective effect of Compound 1 against mitochondrial stressor-induced loss of viability in neurons from patients with frontotemporal dementia (FTD). Tau-P301L neurons at 8 weeks of differentiation are pretreated with Compound 1 at doses of 1 nM, 10 nM, 100 nM, 1 μM, 10 μM, 50 μM, and 100 μM for 8 hours, followed by addition of stressors, rotenone (2 μM and 5 μM) or piericidin A (5 μM and 10 μM) for 16 hours to promote mitochondrial stress and loss of neuronal viability. Neuronal viability is then measured by Alamar Blue HS assay (i.e., 16 hours after stressor addition; 24 hours total treatment with Compound 1). [Figure 10C] 10 is a chart showing the effect of various concentrations of the mitochondrial stressors, rotenone (10C) and piaricidin A (10D), on the viability of tau-P301L neurons. [Figure 10D] 10 is a chart showing the effect of various concentrations of the mitochondrial stressors, rotenone (10C) and piaricidin A (10D), on the viability of tau-P301L neurons. [Figure 10E] 1 is a chart showing the protective effect of Compound 1 against 2 μM rotenane (10E) and 5 μM rotenane (10F) on tau-P301L neurons in a stress rescue assay. Vulnerability to rotenone is manifested by a greater than 50% loss of neuronal viability. n=2 biological replicates; 3 technical replicates each. [Figure 10F] 1 is a chart showing the protective effect of Compound 1 against 2 μM rotenane (10E) and 5 μM rotenane (10F) on tau-P301L neurons in a stress rescue assay. Vulnerability to rotenone is manifested by a greater than 50% loss of neuronal viability. n=2 biological replicates; 3 technical replicates each. [Figure 10G]1 is a chart showing the protective effect of Compound 1 against 5 μM Piericidin A (10G) and 10 μM Piericidin A (10H) on Tau-P301L neurons using a stress rescue assay. Vulnerability to Piericidin A is manifested by a greater than 70% loss of neuronal viability. n=2 biological replicates; 3 technical replicates each. [Figure 10H] 1 is a chart showing the protective effect of Compound 1 against 5 μM Piericidin A (10G) and 10 μM Piericidin A (10H) on Tau-P301L neurons using a stress rescue assay. Vulnerability to Piericidin A is manifested by a greater than 70% loss of neuronal viability. n=2 biological replicates; 3 technical replicates each. [Figure 11A] FIG. 11B shows the dose effect of Compound 1 ("Comp.1") on total tau (tau5) and phosphorylated tau at sites Ser396 (P-tauS396) and Ser202 / Thr205 (P-tauAT8), including high molecular weight (MW) oligomeric P-tau detected by S396 antibody, in tau-P301L neurons. A rotenone dose of 5 μM was used as a control for mitochondrial stress. FIG. 11C shows the Western blot and densitometric charts showing the effect of Compound 1 on total tau (tau5) and phosphorylated tau P-tauS396 (detection of monomeric and oligomeric tau) and P-tauAT8 levels, respectively, in tau-P301L neurons. [Figure 11B] 1 shows the dose effect of Compound 1 ("Comp.1") on total tau (tau5) and phosphorylated tau at sites Ser396 (P-tauS396) and Ser202 / Thr205 (P-tauAT8), including high molecular weight (MW) oligomeric P-tau detected by S396 antibody, in tau-P301L neurons. A rotenone dose of 5 μM was used as a control for mitochondrial stress. [Figure 11C]FIG. 11D shows the dose effect of Compound 1 ("Comp.1") on total tau (tau5) and phosphorylated tau at sites Ser396 (P-tauS396) and Ser202 / Thr205 (P-tauAT8), including high molecular weight (MW) oligomeric P-tau detected by S396 antibody, in tau-P301L neurons. A rotenone dose of 5 μM was used as a control for mitochondrial stress. FIG. 11C shows the Western blot and densitometric charts showing the effect of Compound 1 on total tau (tau5) and phosphorylated tau P-tauS396 (detection of monomeric and oligomeric tau) in tau-P301L neurons and P-tauAT8 levels in tau-P301L neurons co-treated with 0.1 μM rotenone, respectively. [Figure 11D] 1 shows the dose effect of Compound 1 ("Comp.1") on total tau (tau5) and phosphorylated tau at sites Ser396 (P-tauS396) and Ser202 / Thr205 (P-tauAT8), including high molecular weight (MW) oligomeric P-tau detected by S396 antibody, in tau-P301L neurons. A rotenone dose of 5 μM was used as a control for mitochondrial stress. [Figure 11E] FIG. 11D shows the dose effect of Compound 1 ("Comp.1") on total tau (tau5) and phosphorylated tau at sites Ser396 (P-tauS396) and Ser202 / Thr205 (P-tauAT8), including high molecular weight (MW) oligomeric P-tau detected by S396 antibody, in tau-P301L neurons. A rotenone dose of 5 μM was used as a control for mitochondrial stress. FIG. 11F shows the Western blot and densitometric charts showing the effect of Compound 1 on total tau (tau5) and phosphorylated tau P-tauS396 (detection of monomeric and oligomeric tau) in tau-P301L neurons and P-tauAT8 levels in tau-P301L neurons co-treated with 0.5 μM rotenone, respectively. [Figure 11F]1 shows the dose effect of Compound 1 ("Comp.1") on total tau (tau5) and phosphorylated tau at sites Ser396 (P-tauS396) and Ser202 / Thr205 (P-tauAT8), including high molecular weight (MW) oligomeric P-tau detected by S396 antibody, in tau-P301L neurons. A rotenone dose of 5 μM was used as a control for mitochondrial stress. [Figure 11G] FIG. 1 shows the dose effect of Compound 1 ("Comp.1") on total tau (tau5) and phosphorylated tau at sites Ser396 (P-tauS396) and Ser202 / Thr205 (P-tauAT8), including high molecular weight (MW) oligomeric P-tau detected by S396 antibody, in tau-P301L neurons. A rotenone dose of 5 μM was used as a control for mitochondrial stress. FIG. 1 shows the effect of rotenone doses used throughout the experiment on total tau (tau5) and phosphorylated tau (P-tauS396; P-tauAT8) levels in tau-P301L neurons. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0041] It should be understood that certain aspects, modes, embodiments, variations and features of the present technology are described below at various levels of detail to provide a substantial understanding of the present technology. Definitions of certain terms used in this specification are provided below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which the present technology belongs.

[0042] The practice of the present technology employs many conventional techniques in molecular biology, protein biochemistry, cell biology, immunology, microbiology, and recombinant DNA, which are well known and described, for example, in: Current Protocols in Molecular Biology, Vols. I-III, Ausubel, Ed. (1997), Sambrook et al., Molecular Cloning: A Laboratory Manual, Second Ed. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY, 1989), DNA Cloning: A Practical Approach, Vols. I and II, Glover, Ed. (1985), Oligonucleotide, respectively. Synthesis, Gait, Ed. (1984), Nucleic Acid Hybridization, Hames & Higgins, Eds. (1985), Transcription and Translation, Hames & Higgins, Eds. (1984), Animal Cell Culture, Freshney, Ed. (1986), Immobilized Cells and Enzymes (IRL Press, 1986), Perbal, A Practical Guide to Molecular Cloning, the series, Meth. Enzymol., (Academic Press, Inc., 1984), Gene Transfer Vectors for Mammalian Cells, Miller & Calos, Eds. (Cold Spring Harbor Laboratory, NY, 1987), and Meth. Enzymol., Vols. 154 and 155, Wu & Grossman, and Wu, Eds.

[0043] I. Chemical substance definition: Definitions of specific functional groups and chemical terms are described in more detail below. Chemical elements are identified according to the Periodic Table of the Elements, GAS version, Handbook of Chemistry and Physics, 7Sh Ed., inside cover. Additionally, general rules of organic chemistry, as well as specific functional moieties and reactivities, are described in Thomas Sorrell, Organic Chemistry, University Science Books, Sausalito, 1999; Smith and March, March's Advanced Organic Chemistry, 5th Edition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989; and Carruthers, Some Modern Methods of Organic Synthesis, 3rd Edition, Cambridge University Press, Cambridge, 1987.

[0044] Abbreviations used herein have their conventional meanings within the chemical and biological arts. Chemical structures and formulas described herein are intended to follow the standard rules of chemical valency known in the chemical arts. When a range of values ​​is listed, it is intended to encompass each value and subrange within the range. For example, "C1-C6 alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-C6, C1-C5, C1-C4, C1-C3, C1-C2, C2-C6, C2-C5, C2-C4, C2-C3, C3-C5, C3-C4, C4-C6, C4-C5, and C5-C6 alkyl.

[0045] Certain compounds of the present application can exist in unsolvated forms as well as solvated forms, including hydrated forms. Solvated forms may exist, for example, because it is difficult or impossible to remove all of the solvent from the compound after synthesis. In general, solvated forms are equivalent to unsolvated forms and are included within the scope of the present application. Certain compounds of the present application may exist in multiple crystalline or amorphous forms. Certain compounds of the present application may exist in various tautomeric forms. Certain compounds of the present application may exist in various salt forms. In general, all physical forms are equivalent to the uses contemplated by the present application and are intended to be within the scope of the present disclosure.

[0046] As used herein, the term "hydrate" refers to a compound associated with water. The number of water molecules contained in a hydrate of a compound may (or may not) be in a definite ratio to the number of compound molecules in the hydrate.

[0047] As used herein, the term "pharmaceutical acceptable salts" refers to salts of therapeutically active compounds that can be prepared with relatively non-toxic acids or bases, depending on the specific substituents found in the compounds described herein. When a compound contains a relatively acidic functional group, a base addition salt can be obtained by contacting a neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired base. Examples of pharmaceutical acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salts, or similar salts. When a compound contains a relatively basic functional group, an acid addition salt can be obtained by contacting a neutral form of such a compound, either neat or in a suitable inert solvent, with a sufficient amount of the desired acid. Salts derived from pharmaceutical acceptable inorganic bases include ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, and zinc salts, and the like. Salts derived from pharma- ceutically acceptable organic bases include the protonated forms of organic bases (e.g., [HNEt3]), such as arginine, betaine, caffeine, choline, N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-methylmorpholine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperadine, polyamine resins, procaine, purines, theobromine, trimethylamine (NEt3), trimethylamine, tripropylamine, tromethamine, and the like. +), including salts of primary, secondary, and tertiary amines, including substituted amines, cyclic amines, naturally occurring amines, etc. Salts derived from pharma-ceutically acceptable inorganic acids include salts of boric acid, carbonic acid, hydrohalic acids (hydrobromic, hydrochloric, hydrofluoric, or hydroiodic acids), nitric acid, phosphoric acid, sulfamic acid, and sulfuric acid. Salts derived from pharma- ceutically acceptable organic acids include salts derived from aliphatic hydroxyl acids (e.g., citric acid, gluconic acid, glycolic acid, lactic acid, lactobionic acid, malic acid, and tartaric acid), aliphatic monocarboxylic acids (e.g., acetic acid, butyric acid, formic acid, propionic acid, and trifluoroacetic acid), amino acids (e.g., aspartic acid and glutamic acid), aromatic carboxylic acids (e.g., benzoic acid, p-chlorobenzoic acid, diphenylacetic acid, gentisic acid, hippuric acid, and triphenylacetic acid), aromatic hydroxyl acids (e.g., o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxynaphthalene acid, 1-hydroxyphenylacetic ... Examples of suitable carboxylic acids include naphthalene-2-carboxylic acid and 3-hydroxynaphthalene-2-carboxylic acid), ascorbic acid, dicarboxylic acids (e.g., fumaric, maleic, oxalic, and succinic acids), glucuronic, mandelic, mucilaginous, nicotinic, orotic, pamoic, pantothenic, sulfonic acids (e.g., benzenesulfonic, camphorsulfonic, edisylic, ethanesulfonic, isethionic, methanesulfonic, naphthalenesulfonic, naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic, p-toluenesulfonic acid (PTSA)), xinafoic acid, and the like.In some embodiments, the pharma- ceutically acceptable counterion is selected from the group consisting of acetate, benzoate, besylate, bromide, camphorsulfonate, chloride, chlorotheophyllinate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucoronate, hippurate, iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, mesylate, methylsulfate, naphthoate, sapsylate, nitrate, octadecanoate, oleate, oxalate, pamoate, phosphate, polygalacturonate, succinate, sulfate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate. In some embodiments, the salt is a tartrate, fumarate, citrate, benzoate, succinate, suberate, lactate, oxalate, phthalate, methanesulfonate, benzenesulfonate, maleate, trifluoroacetate, hydrochloride, or tosylate. Also included are salts of amino acids such as arginates, and salts of organic acids such as glucuronic acid or galacturonic acid (see, for example, Berge et al, Journal of Pharmaceutical Science 66:1-19 (1977)). Certain compounds of the present application may contain both basic and acidic functional groups that allow the compounds to be converted into either base or acid addition salts, or may exist in zwitterionic form. These salts can be prepared by methods known to those skilled in the art. Other pharma-ceutically acceptable carriers known to those skilled in the art are also suitable for the present technology.

[0048] As used herein, the term "peptidomimetic" refers to a compound of formula (I): [ka] , or the pharma- ceutically acceptable salts, stereoisomers, tautomers, hydrates, and / or solvates thereof, as more fully described and / or claimed in WIPO Published Application: WO2019 / 118878 (referred to as the variables AA1, AA2, R1, R 2a , R 2b (See below for definitions of R, R and X). In some embodiments, the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (Compound 1 as exemplified below), or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0049] As used herein, the term "small molecule" refers to any organic compound that affects biological processes having a molecular weight of less than 900 Daltons. For purposes of this definition, it should be understood that molecular weight is calculated without reference to any associated (i.e., non-covalently bound) molecules such as salts, water, or other solvent molecules. As used herein, a "small molecule peptidomimetic" is a peptidomimetic having a free base molecular weight of less than 900 Daltons. An example of such a small molecule peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide (CAS number 2356106-71-1: free base molecular weight of 607.76), or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

[0050] As used herein, the term "solvate" refers to a form of a compound associated with a solvent, possibly through a solvolysis reaction. This physical association may include hydrogen bonding. Conventional solvents include water, methanol, ethanol, isopropanol, acetic acid, ethyl acetate, acetone, hexane(s), DMSO, THF, diethyl ether, and the like.

[0051] As used herein, the term "tautomers" refers to compounds that are interchangeable forms of a particular compound structure, with changes in the displacement of hydrogen atoms and electrons. Thus, two structures can be in equilibrium through the movement of π electrons and atoms (usually H). For example, enols and ketones are tautomers because they are rapidly interconverted by treatment with either acid or base. Tautomeric forms can be relevant to achieving optimal chemical reactivity and biological activity of a compound of interest.

[0052] II. Other Definitions: It should be understood that certain aspects, modes, embodiments, variations and features of the present technology are described below at various levels of detail to provide a substantial understanding of the present technology. Definitions of certain terms used in this specification are provided below. Unless otherwise defined, all technical and scientific terms used herein generally have the same meaning as commonly understood by one of ordinary skill in the art to which the present technology belongs.

[0053] As used in this specification and the accompanying embodiments, the singular forms "a," "an," and "the" include plural referents unless the content clearly dictates otherwise. For example, reference to "a cell" includes a combination of two or more cells, and the like.

[0054] As used herein, "administering" or "administration" of an agent (i.e., a therapeutic agent) or compound / drug product (including a composition) to a subject includes any route of introducing or delivering the compound / drug product to a subject to perform its intended function. Administration may be by any suitable route, such as oral administration. Administration may be subcutaneous. Administration may be intravenous. Administration may be intraocular. Administration may be systemic. Alternatively, administration may be topical, intranasal, intraperitoneal, intradermal, ophthalmic, intrathecal, intracerebroventricular, iontophoretic, transmucosal, intravitreal, or intramuscular. Administration includes self-administration, administration by another, or administration by use of a device (e.g., an infusion pump).

[0055] As used herein, "ameliorating" or "ameliorating" a disease, disorder, or condition (e.g., a tauopathy) in a statistical sample or a particular subject refers to the result of making the occurrence of the disease, disorder, or condition (or a sign, symptom, or condition thereof) better or more tolerable in a sample or subject administered a therapeutic agent compared to a control sample or subject.

[0056] As used herein, the terms "carrier" and "pharmaceutical acceptable carrier" refer to a diluent, adjuvant, excipient, or vehicle with which a compound / drug product / composition (including a drug) is administered or formulated for administration. Non-limiting examples of such pharmaceutical acceptable carriers include liquids such as water, saline, and oils, and solids such as gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, silica particles (nanoparticles or microparticles), urea, and the like. In addition, auxiliary agents, stabilizers, thickeners, lubricants, flavoring agents, and coloring agents can be used. Other examples of suitable pharmaceutical carriers are described in Remington's Pharmaceutical Sciences by EW Martin, which is incorporated herein by reference in its entirety.

[0057] As used herein, the phrase "delaying the onset of" refers to postponing, preventing the onset of, or causing one or more signs or symptoms of, a disease, disorder, or condition to occur later than normal in a statistical sample in a sample or subject administered a therapeutic agent compared to a control sample or subject.

[0058] As used herein, the term "effective amount" refers to a sufficient amount of a compound / composition / drug product to achieve the desired therapeutic and / or prophylactic effect, e.g., an amount that treats, prevents, inhibits, ameliorates, or delays the onset of a disease, disorder, or condition, or physiological signs, symptoms, or pathology of a disease or condition. In the context of therapeutic or prophylactic use, in some embodiments, the amount of a compound / composition / drug product administered to a subject will depend on the type and severity of the disease, as well as individual characteristics such as general health, age, sex, weight, and tolerance to drugs. In some embodiments, it will also depend on the extent, severity, and type of disease. Those skilled in the art will be able to determine appropriate dosages depending on these and other factors. The compound / composition / drug product can also be administered in combination with one or more additional therapeutic compounds / agents (so-called "co-administration", e.g., the additional therapeutic agents can be administered simultaneously, sequentially, or by separate administration). The one or more additional therapeutic agents may be, for example, a small molecule therapeutic agent selected from the group consisting of activators / modulators of tau phosphorylation, kinase inhibitors, modulators of tau acylation, histone deacetylase (HDAC) inhibitors, modulators / inhibitors of tau glycosylation (e.g., O-GlcNAcase inhibitors), modulators of tau cleavage (e.g., capsase inhibitors), tau aggregation / fibrillization inhibitors, proteasome stimulators, USP14 inhibitors, phosphodiesterase inhibitors, protein degradation targeting chimeras (PROTACs), autophagy activators, Hsp70 modulators, Hsp90 modulators, co-chaperone modulators, and tau-directed multitarget specific ligands (review article: Wang, L., et al. "Small molecule therapeutics for tauopathy in Alzheimer's disease: Walking the path of most resistance", European Journal of Medicinal See Chemistry, 209(2021)112915).The one or more additional therapeutic agents can be, for example, a Szeto-Schiller peptide, such as SS-20 or SS-31 (also known as elamipretide or bendavia).

[0059] In some of the methods described herein, (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, tautomer, hydrate, and / or solvate thereof, may be administered to a subject having one or more signs, symptoms, or conditions associated with a tauopathy. For example, a "therapeutically effective amount" of a small molecule peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide includes a level at which the presence, frequency, or severity of one or more signs, symptoms, or conditions (e.g., risk factors) of a disease or disorder associated with a tauopathy is treated, prevented, inhibited, ameliorated, or delayed in a subject. In some embodiments, administration of a therapeutically effective amount of a small molecule peptidomimetic such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide treats, inhibits, ameliorate, prevents or delays the physiological effects of a disease, disorder or condition associated with a tauopathy.

[0060] As used herein, "inhibit" or "inhibiting" refers to a reduction in a sign, symptom, or condition (e.g., a risk factor) associated with a disease, disorder, or condition by an objectively measurable amount or extent compared to a control. In one embodiment, inhibit or inhibiting refers to a reduction to at least a statistically significant amount compared to a control (or control subject). In one embodiment, inhibit or inhibiting refers to a reduction to at least a 5 percent reduction compared to a control (or control subject). In various individual embodiments, inhibit or inhibiting refers to a reduction to at least 1, 2, 3, 4, 5, 10, 15, 20, 25, 30, 33, 40, 50, 60, 67, 70, 75, 80, 90, 95, or 99 percent reduction compared to a control (or control subject).

[0061] As used herein, the term "simultaneous" therapeutic use refers to the administration of at least two active ingredients by the same route and at the same time or substantially the same time.

[0062] As used herein, the term "separate" therapeutic use refers to the administration of at least two active ingredients by different routes at the same time or substantially the same time.

[0063] As used herein, the term "sequential" therapeutic use refers to the administration of at least two active ingredients at different times, and the administration route is the same or different. More specifically, sequential use refers to the administration of one of the active ingredients entirely before the administration of the other or multiple other ingredients is started. Thus, one of the active ingredients can be administered minutes, hours, or days before the administration of the other active ingredient or active ingredients. In this definition, there is no simultaneous treatment.

[0064] As used herein, "subject" refers to a living animal. In various embodiments, the subject is a mammal. In various embodiments, the subject is a non-human mammal, including, but not limited to, a mouse, rat, hamster, guinea pig, rabbit, sheep, goat, cat, dog, pig, mini pig, horse, cow, or non-human primate. In certain embodiments, the subject is a human.

[0065] As used herein, the term "treating" or "treatment" refers to a therapeutic treatment, the purpose of which is to reduce, alleviate, or delay (attenuate) an existing disease or disorder, or its associated signs, symptoms, or conditions. By way of example, and not by way of limitation, a subject is successfully "treated" for a disease (e.g., a tauopathy) if, after receiving an effective amount of a compound / composition / drug product, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, the subject shows an observable and / or measurable reduction, or absence, of one or more signs, symptoms, or conditions associated with the disease, disorder, or condition. For example, treating a subject may reduce tau species levels and / or reduce toxicity associated with cellular tau accumulation in the subject. Treatment may also reduce cellular oxidative stress, for example, caused by cellular accumulation of tau protein. It should also be recognized that the various modes of treatment of the described medical conditions are intended to mean "substantial," including the overall alleviation of the state, signs, or symptoms of the disease or disorder, as well as "partial," in which some biologically or medically relevant result is achieved.

[0066] As used herein, "prevention" or "preventing" of a disease, disorder, or condition associated with a tauopathy refers to a result in a statistical sample that shows a reduction in the occurrence of the disease, disorder, or condition in a sample or subject administered a therapeutic agent compared to a control sample or subject, or a delay in the onset of one or more symptoms of the disease, disorder, or condition relative to a control sample or subject. Such prevention is sometimes referred to as prophylactic treatment.

[0067] III. Chiral / Stereochemical Considerations The compounds described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers (i.e., stereoisomers). Chiral centers in the depicted structures (including embodiments) may be identified herein by the use of an asterisk (*). Unless otherwise indicated, the compounds described herein may be in the form of individual enantiomers, diastereomers, or geometric isomers, or in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, for example, Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen et al., Tetrahedron 33:2725 (1977); Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); and Wilen, Tables of Resolving Agents and Optical Resolutions p.268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). The disclosure of this application may additionally encompass the compounds described herein as individual isomers substantially free of other isomers, and alternatively, as mixtures of various isomers.

[0068] As used herein, a pure enantiomer compound is substantially free of the other enantiomer or stereoisomer of the compound (i.e., in enantiomeric excess): purity is a relative term in the sense that 100% purity is very difficult to achieve. In other words, the "S" form of the compound is substantially free of the "R" form of the compound, and is therefore in enantiomeric excess of the "R" form. With respect to amino acids (more commonly described in terms of "D" and "L" enantiomers), it should be understood that in most cases, for "D" amino acids, the configuration is "R" and for "L" amino acids, the configuration is "S". In some embodiments, "substantially free" refers to: (i) an aliquot of the "S" form of the compound that contains less than 2% of the "R" form, or (ii) an aliquot of the "R" form of the compound that contains less than 2% of the "S" form. The term "enantiomerically pure" or "pure enantiomer" means that a compound contains more than 90%, more than 91%, more than 92%, more than 93%, more than 94%, more than 95%, more than 96%, more than 97%, more than 98%, more than 99%, more than 99.5%, or more than 99.9% by weight of a specifically identified enantiomer (e.g., compared to the other enantiomer). In certain embodiments, the relative weights are based only on the R and S configurations for a particular stereocenter of the compound of interest. In certain embodiments, the relative weights are based on the total weight of all enantiomers, diastereomers, or stereoisomers of the compound.

[0069] In the compositions provided herein, the enantiomerically pure compounds can be present together with other active or inactive ingredients. For example, a pharmaceutical composition containing an enantiomerically pure "S" compound can contain, for example, about 90% of an excipient and about 10% of an enantiomerically pure "S" compound. In certain embodiments, the enantiomerically pure "S" compound in such a composition can contain, for example, at least about 95% by weight of the "S" compound and up to about 5% by weight of the "R" compound, based on the total weight of the compound. In certain embodiments, the active ingredient can be formulated with little or no excipients or carriers.

[0070] IV. Pharmaceutical Compositions, Routes of Administration, and Dosages: In some embodiments, the present application relates to a pharmaceutical composition. In some embodiments, the composition comprises a compound of the present application and a pharma- ceutically acceptable carrier. In certain embodiments, the pharmaceutical composition comprises a plurality of compounds of the present application (e.g., small molecule peptidomimetics) and a pharma- ceutically acceptable carrier. The pharmaceutical composition may be a drug.

[0071] In certain embodiments, the pharmaceutical compositions of the present application may further comprise at least one additional therapeutic agent other than the small molecule peptidomimetic. The at least one additional therapeutic agent may be an agent useful in the treatment of mitochondrial disease or tauopathy. Thus, in some embodiments, the pharmaceutical compositions of the present application may be prepared, for example, by combining one or more compounds of the present application (e.g., small molecule peptidomimetics) with a pharma- ceutically acceptable carrier and, optionally, one or more additional therapeutic agents.

[0072] The pharmaceutical compositions of the present application may contain an effective amount of a therapeutic compound / agent (or compounds / agents) described herein, optionally dispensed (e.g., dissolved, suspended, or otherwise) in a pharma- ceutically acceptable carrier. The components of the pharmaceutical composition(s) also are capable of being mixed with the compounds of the present application, and with each other, in a manner such that there is no interaction which would substantially impair the desired pharmaceutical efficiency.

[0073] As stated above, an "effective amount" refers to any amount of an active compound (or compounds; alone or formulated) sufficient to achieve a desired biological effect. By selecting from among various active compounds and metering factors, such as potency, relative bioavailability, patient weight, severity of adverse side effects, and method of administration, in combination with the teachings provided herein, an effective prophylactic (i.e., preventative) or therapeutic treatment regimen can be designed that is effective in treating a particular condition or disease in a particular subject while not causing substantial undesirable toxicity. The effective amount for any particular indication may vary depending on factors such as the disease, disorder, or condition being treated, the particular compound or compounds being administered, the size of the subject, or the severity of the disease, disorder, or condition. The effective amount may be determined by methods familiar to physicians and clinicians during preclinical and clinical trials. Those skilled in the art may empirically determine the effective amount of a particular compound and / or other therapeutic agent(s) without the need for undue experimentation. A maximum dose, i.e., the highest safe dose, may be used according to some medical judgment. Multiple administrations per day may be contemplated to achieve adequate systemic levels of the compound. Appropriate systemic levels can be determined, for example, by measuring the patient's peak or sustained plasma levels of the drug. "Dose" and "administration" are used interchangeably herein. A dose can be administered by oneself, by another, or by a device (e.g., a pump).

[0074] For any compound described herein, the therapeutically effective amount can be determined, for example, first from animal models. Therapeutically effective doses can also be determined from human data of compounds tested in humans and compounds known to exhibit similar pharmacological activity, such as other related active agents. Parenteral administration may require higher doses. The applied dose can be adjusted based on the relative bioavailability and potency of the administered compound. It is well within the capabilities of a person skilled in the art to adjust the dose to achieve maximum efficacy in humans based on the above methods and other methods as known in the art.

[0075] Compounds for use in therapy or prevention (alone or formulated in pharmaceutical compositions) can be tested in suitable animal model systems. Suitable animal model systems include, but are not limited to, rats, mice, chickens, cows, monkeys, rabbits, pigs, minipigs, etc., before testing in human subjects. For in vivo testing, any of the animal model systems known in the art can be used before administration to human subjects. In some embodiments, dosage can be tested directly in humans.

[0076] The dosage, toxicity and therapeutic efficacy of any therapeutic compound / agent, composition (e.g., formulation or drug), other therapeutic agent, or mixture thereof can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, for example, to determine the LD50 (the dose lethal to 50% of the population) and the ED50 (the dose therapeutically effective in 50% of the population). The dose ratio between the toxic effect and the therapeutic effect is the therapeutic index, which can be expressed as the ratio LD50 / ED50. Compounds that exhibit high therapeutic indices are advantageous. Compounds that exhibit toxic side effects may be used, but in such cases it may be prudent and careful to design a delivery system that targets such compounds to the site of the affected tissue in order to minimize potential damage to uninfected cells, thereby reducing side effects.

[0077] In some embodiments, an effective amount of a therapeutic compound / agent disclosed herein sufficient to achieve a therapeutic or prophylactic effect may range from about 0.000001 mg per kilogram of body weight per day to about 10,000 mg per kilogram of body weight per day. Suitably, the dosage range is from about 0.0001 mg per kilogram of body weight per day to about 100 mg per kilogram of body weight per day. For example, dosages may range from 1 mg / kg body weight or 100 mg / kg body weight daily, every 2 or 3 days, or from 1 to 100 mg / kg weekly, every 2 or 3 weeks. In some embodiments, a single dosage of a therapeutic compound / agent disclosed herein ranges from 0.001 to 10,000 micrograms per kg of body weight. In some embodiments, a therapeutic compound / agent disclosed herein dissolved or suspended in a carrier ranges from 0.2 to 2000 micrograms per milliliter delivered. In some embodiments, the dosage regimen meets pharmacokinetic target concentrations in the target tissue to achieve the desired therapeutic outcome.

[0078] Exemplary treatment regimen may involve administration once a day, twice a day, three times a day, once a week, or once a month.In treatment applications, relatively high dosages may be required at relatively short intervals until disease progression is reduced or terminated, or until subject shows partial or complete improvement of disease symptoms.Then, patient may be administered a prophylactic regimen.

[0079] In some embodiments, the therapeutically effective amount of the therapeutic compound / agent disclosed herein is 10 -12 ~10 -4 Molar, e.g., about 10 -7 The therapeutic concentration may be defined as the concentration of compound present in a target tissue in moles. This concentration may be delivered by a systemic dose of 0.001-100 mg / kg or equivalent by body surface area. The dosing schedule will be optimized to maintain a therapeutic concentration in the target tissue, such as by a single daily or weekly administration, but also includes continuous administration (e.g., oral, systemic, topical, subcutaneous, intranasal, parenteral injection, or transdermal application).

[0080] In some embodiments, intravenous or subcutaneous administration of the compound (alone or as formulated) may typically be from 0.01 μg / kg / day to 80 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of the compound (alone or as formulated) may typically be from 0.01 μg / kg / day to 100 μg / kg / day. In some embodiments, intravenous or subcutaneous administration of the compound (alone or as formulated) may typically be from 0.1 μg / kg / day to 10 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of the compound (alone or as formulated) may typically be from 10 μg / kg / day to 2 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of the compound (alone or as formulated) may typically be from 500 μg / kg / day to 5 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of the compound (alone or formulated) can typically be from 1 mg / kg / day to 100 mg / kg / day. In some embodiments, intravenous or subcutaneous administration of the compound (alone or formulated) can typically be from 1 mg / kg / day to 50 mg / kg / day.

[0081] In general, the daily oral dose of the compound (alone or as formulated) will be about 0.01 micrograms / kg to 250 micrograms / kg / day for a human subject. In some embodiments, the daily oral dose of the compound (alone or as formulated) will be about 1 milligrams / kg to 100 milligrams / kg per day for a human subject, or about 10 milligrams / kg to 75 milligrams / kg per day, or an oral dose of the compound (alone or as formulated) in the range of 0.1 to 50 milligrams / kg in one or more administrations per day will provide therapeutic results. Dosages can be appropriately adjusted to achieve desired local or systemic drug levels depending on the mode of administration. For example, intravenous administration is expected to be one to several orders of magnitude lower in doses per day. If the response in the subject is insufficient at such doses, even higher doses (or effective higher doses by different, more localized delivery routes) may be used, as tolerated by the patient. Multiple doses per day are contemplated to achieve adequate systemic levels of the compound.

[0082] For use in therapy, an effective amount of the compound (alone or formulated) can be administered to a subject by any mode that delivers the compound to the desired surface. Administration of pharmaceutical compositions can be achieved by any means known to those skilled in the art. Routes of administration include, but are not limited to, oral, topical, intranasal, systemic, intravenous, subcutaneous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intraventricular, iontophoretic, transmucosal, intravitreal, or intramuscular administration. Administration includes self-administration, administration by another person, and administration by a device.

[0083] The therapeutic compounds / agents disclosed herein can be delivered to a subject in a formulation or medicament (i.e., a pharmaceutical composition). Formulations and medicaments can be prepared, for example, by dissolving or suspending the therapeutic compounds / agents disclosed herein in water, a pharma- ceutically acceptable carrier, a salt (e.g., NaCl or sodium phosphate), a buffer, a preservative, a compatible carrier, an adjuvant, and optionally other therapeutically acceptable ingredients.

[0084] The pharmaceutical composition (e.g., formulation or agent) may contain a carrier (a pharma- ceutically acceptable carrier), which may be a solvent or dispersion medium, for example, containing water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof. Proper fluidity may be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. Prevention of microbial action may be achieved by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, ascorbic acid, thiomerazole, and the like. Glutathione and other antioxidants may be included to prevent oxidation. In many cases, it is advantageous to include an isotonic agent, for example, a sugar (e.g., trehalose), a polyalcohol such as mannitol, sorbitol, or sodium chloride in the composition. Prolonged absorption of an injectable composition may be achieved by including an agent that delays absorption in the composition, for example, aluminum monostearate or gelatin.

[0085] Solutions or suspensions (e.g., formulations or medicaments) used for parenteral, intradermal, subcutaneous, or intraocular application can contain the following components: sterile diluents such as water for injection, saline solution, fixed oils, polyethylene glycols, glycerin, propylene glycol, or other synthetic solvents, antibacterial agents such as benzyl alcohol or methylparabens, antioxidants such as ascorbic acid or sodium bisulfite, chelating agents such as ethylenediaminetetraacetic acid, buffers such as acetates, citrates, or phosphates, and agents for adjusting tonicity such as sodium chloride or dextrose. pH can be adjusted with acids or bases such as hydrochloric acid or sodium hydroxide. Parenteral preparations can be enclosed in ampoules, disposable syringes, or multiple dose vials made of glass or plastic. For the convenience of the patient or treating physician, the formulation to be administered can be provided alone or in a kit that includes all the supplies needed during a course of treatment (e.g., 1, 2, 3, 4, 5, 6, 7 or more days of treatment) (e.g., vials of drug, vials of diluent, syringes, and needles).

[0086] The therapeutic compounds / agents or pharmaceutical compositions, when it is desired to deliver them systemically, can be formulated for parenteral administration by injection, e.g., bolus injection or continuous infusion (e.g., by IV injection or via a pump to meter the dose over a defined period of time). Formulations for injection can be provided in unit dosage form, e.g., in ampoules or in multi-dose containers, with added preservatives. The compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as suspending, stabilizing, and / or dispersing agents. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.

[0087] Systemic formulations include those designed for administration by injection, e.g., subcutaneous, intravenous, intramuscular, intrathecal, or intraperitoneal injection, as well as those designed for transdermal, transmucosal oral, or pulmonary administration.

[0088] For intravenous and other parenteral routes of administration, the compounds may be formulated as lyophilized preparations, as lyophilized preparations of liposome-intercalated or encapsulated active compounds, as lipid complexes in aqueous suspension, or as salt complexes. Lyophilized preparations are generally reconstituted in a suitable aqueous solution, such as sterile water or saline, immediately prior to administration.

[0089] Pharmaceutical compositions (e.g., formulations or medicaments) suitable for injection can include sterile aqueous solutions (if water soluble), or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor EL™ (BASF, Parsippany, NJ), or phosphate buffered saline (PBS). Compositions for administration by injection generally must be sterile and fluid to the extent that they are easily syringable. They must be stable under the conditions of manufacture and storage and can be preserved against the contaminating action of microorganisms such as bacteria and fungi.

[0090] Sterile injectable solutions (e.g., formulations or medicaments) can be prepared by incorporating the required amount of active compound into a suitable solvent containing one or a combination of the above-listed ingredients as required, followed by filtration sterilization.Generally, dispersions are prepared by incorporating active compound into a sterile vehicle that contains a basic dispersion medium and other ingredients required from those listed above.In the case of sterile powders for preparing sterile injectable solutions, typical preparation methods include vacuum drying and freeze-drying, which can obtain a powder of active ingredient plus any additional desired ingredients from the solution that has been previously sterile-filtered.

[0091] For oral administration, the compound can be easily formulated by combining the active compound(s) with pharma- ceutically acceptable carriers well known in the art. Such carriers allow the compound of the present application to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the subject to be treated. Tablets, pills, capsules, troches, etc. can contain the following ingredients: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel®, or corn starch; lubricants such as magnesium stearate or sterates; flow agents such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavoring, or any of the compounds of a similar nature.

[0092] Pharmaceutical preparations for oral use can be obtained as solid excipients, optionally milling the resulting mixture, adding suitable auxiliaries if desired, and then processing the mixture of granules to obtain tablets or dragee cores.Suitable excipients are in particular fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP).If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid, or its salts, for example, sodium alginate, can be added.Optionally, oral preparations can be formulated in saline or buffer, for example, EDTA to neutralize internal acid conditions, or can be administered without any carrier.

[0093] Also specifically contemplated are the above oral dosage forms that can be chemically modified to effect oral delivery of the derivative. In general, the contemplated chemical modification is the attachment of at least one moiety to the therapeutic agent(s), ingredient(s), and / or excipient(s), which (a) inhibits acid hydrolysis and (b) allows uptake into the bloodstream from the stomach or intestine. Also desired is an increase in the overall stability of the therapeutic agent(s), ingredient(s), and / or excipient(s), as well as an increase in circulation time in the body. Examples of such moieties include polyethylene glycol, copolymers of ethylene glycol and propylene glycol, carboxymethylcellulose, dextran, polyvinyl alcohol, polyvinylpyrrolidone, and polyproline. Abuchowski and Davis, "Soluble Polymer-Enzyme Adducts", In: Enzymes as Drugs, Hocenberg and Roberts, eds. Wiley-Interscience, New York, NY, pp. 367-383 (1981); Newmark et al. J Appl Biochem 4:185-9 (1982). Other polymers that can be used are poly-1,3-dioxolane and poly-1,3,6-tioxocane. For pharmaceutical use, as mentioned above, polyethylene glycol (PEG) moieties of various molecular weights are suitable.

[0094] For formulations of therapeutic agent(s), ingredient(s), and / or excipient(s), the location of release may be the stomach, the small intestine (duodenum, jejunum, or ileum), or the large intestine. Those skilled in the art have formulations available that do not dissolve in the stomach, but release the material in the duodenum or elsewhere in the intestine. Preferably, this release avoids the deleterious effects of the stomach environment, either by protection of the compound (or derivative) of the present application, or by release of the biologically active material beyond the stomach environment, such as in the intestine.

[0095] Coatings or mixtures of coatings may also be used on tablets that are not intended for protection against the stomach. This includes sugar coatings, or coatings that make the tablet easier to swallow. Capsules may consist of a hard shell (such as gelatin) for delivery of dry therapeutics (e.g., powders), or for liquid forms, a soft gelatin shell may be used. The shell material for cachets may be thick starch or other edible paper. For pills, lozenges, molded tablets, or tablet triturates, wet mashing techniques may be used.

[0096] The therapeutic compound / agent or pharmaceutical composition may be included in the formulation as fine multiparticulates in the form of granules or pellets of about 1-2 mm particle size. The formulation of the material for capsule administration may also be as a powder, lightly compressed plugs, or even tablets. The therapeutic compound / agent or pharmaceutical composition may be prepared by compression.

[0097] Colorants and flavoring agents may all be included. For example, the compounds or pharmaceutical compositions (or derivatives) of the present application may be formulated and then further contained within an edible product, such as a refrigerated beverage, that includes colorants and flavoring agents.

[0098] One can dilute or increase the volume of the therapeutic compound / agent or pharmaceutical composition with inert materials. These diluents can include carbohydrates, especially mannitol, lactose, anhydrous lactose, cellulose, sucrose, modified dextrans, and starch. Certain inorganic salts, including calcium triphosphate, magnesium carbonate, and sodium chloride, can also be used as bulking agents. Some commercially available diluents are Fast-Flo®, Emdex®, STARCH 1500®, Emcompress®, and Avicel®.

[0099] Disintegrants may be included in the formulation of the therapeutic compound / agent or composition into solid dosage form. Materials used as disintegrants include, but are not limited to, starch, including Explotab, a commercial disintegrant based on starch. Sodium starch glycolate, Amberlite®, sodium carboxymethylcellulose, ultramylopectin, sodium alginate, gelatin, orange peel, acid carboxymethylcellulose, natural sponge and bentonite may all be used. Another form of disintegrant is the insoluble cation exchange resin. Powdered gums may be used as disintegrants and binders, and these may include powdered gums such as agar, Karaya gum or tragacanth. Alginic acid and its sodium salt are also useful as disintegrants.

[0100] Binders are used to hold the compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof together with inert materials to form a hard tablet, and may include materials derived from natural products such as acacia, tragacanth, starch, and gelatin. Others include methylcellulose (MC), ethylcellulose (EC), and carboxymethylcellulose (CMC). Polyvinylpyrrolidone (PVP) and hydroxypropylmethylcellulose (HPMC) can both be used in alcoholic solutions to granulate the therapeutic agent.

[0101] Antifriction agents may be included in the formulation of the compound, therapeutic agent, peptide, peptidomimetic, or mixture thereof to prevent adhesion during the formulation process. Lubricants may be used as a layer between the therapeutic agent and the wall of the die, and these may include, but are not limited to, stearic acid, including magnesium and calcium salts, polytetrafluoroethylene (PTFE), liquid paraffin, vegetable oils, and waxes. Soluble lubricants such as sodium lauryl sulfate, magnesium lauryl sulfate, polyethylene glycol (PEG) of various molecular weights, Carbowax™ 4000 and 6000 may also be used.

[0102] Glidants may be added during formulation to improve the flow properties of the drug and aid in rearrangement during compression. Glidants may include starch, talc, pyrogenic silica, and hydrated silicoaluminate.

[0103] Surfactants may be added as wetting agents to aid in dissolving the therapeutic compound / agent or composition (e.g., drug) in an aqueous environment. Surfactants may include anionic detergents such as sodium lauryl sulfate, dioctyl sodium sulfosuccinate, and dioctyl sodium sulfonate. Cationic detergents may be used and may include benzalkonium chloride and benzethonium chloride. Potential non-ionic detergents that may be included in the formulation as surfactants include lauromacrogol 400, polyoxyl 40 stearate, polyoxyethylene hydrogenated castor oil 10, 50, and 60, glycerol monostearate, polysorbate 40, 60, 65, and 80, sucrose fatty acid esters, methylcellulose, and carboxymethylcellulose. These surfactants may be present in the formulation of the compounds or derivatives of the present application either alone or as a mixture in different ratios.

[0104] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft sealed capsules made of gelatin and plasticizers such as glycerol or sorbitol. Push-fit capsules can contain active ingredients mixed with fillers such as lactose, binders such as starch, and / or lubricants such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, active compounds can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers may be added. Microspheres formulated for oral administration can also be used. Such microspheres are well defined in the art. All formulations for oral administration should be in dosages suitable for such administration.

[0105] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0106] For topical administration, the compounds may be formulated as solutions, gels, ointments, creams, suspensions, and the like, as is well known in the art. Solutions, gels, ointments, creams, or suspensions may be administered topically. The compounds may be formulated in rectal or vaginal compositions, such as suppositories or retention enemas, for example, containing conventional suppository bases, such as cocoa butter or other glycerides.

[0107] For administration of a compound or composition (e.g., a drug) by inhalation for use according to the present application, it may be conveniently delivered in the form of an aerosol spray presentation from a pressurized pack or nebulizer using a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In some embodiments, the formulation, drug, or therapeutic compound / agent may be delivered in the form of an aerosol spray from a pressurized container or dispenser or nebulizer containing a suitable propellant, e.g., a gas such as carbon dioxide. Such methods include those described in U.S. Pat. No. 6,468,798. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. For example, capsules and cartridges of, e.g., gelatin, for use in an inhaler or insufflator may be formulated containing a powder mix of the therapeutic compound / agent and a suitable powder base, such as lactose or starch. Alternatively, the active compounds may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0108] Nasal delivery of the therapeutic compound / agent or pharmaceutical composition of the present application is also contemplated. Nasal delivery allows the therapeutic compound / agent or pharmaceutical composition to pass into the bloodstream immediately after administration of the therapeutic compound / agent or pharmaceutical composition to the nose, without the need for the product to be deposited in the lungs. Formulations for nasal delivery include those with dextran or cyclodextran.

[0109] For nasal administration, a useful device is a small, hard bottle fitted with a metered dose sprayer. In some embodiments, a metered dose is delivered by drawing the pharmaceutical composition of the present application into a chamber of a defined volume, which has an opening dimensioned to aerosolize and aerosolize the aerosol formulation by forming a spray when the liquid in the chamber is compressed. The chamber is compressed to administer the therapeutic compound / agent or pharmaceutical composition. In certain embodiments, the chamber is a piston arrangement. Such devices are commercially available.

[0110] Alternatively, a plastic squeeze bottle is used that has an opening or aperture sized to aerosolize the aerosol formulation by forming a spray when squeezed. The aperture is usually found at the top of the bottle, and the top is generally tapered to partially fit into the nasal passages for efficient administration of the aerosol formulation. Preferably, the nasal inhaler provides a metered amount of the aerosol formulation for administration of a measured dose of the therapeutic compound / agent or pharmaceutical composition.

[0111] Pulmonary delivery of the compounds disclosed herein is also contemplated herein. The compounds or pharmaceutical compositions can be delivered to the lungs of a mammal during inhalation and can cross the lung epithelial lining into the bloodstream. Other reports of inhaled molecules include Adjei et al., Pharm Res 7:565-569(1990); Adjei et al., Int J Pharmaceutics 63:135-144(1990) (leuprolide acetate); Braquet et al., J Cardiovasc Pharmacol 13(suppl.5):143-146(1989) (endothelin-1); Hubbard et al., Annal Int Med 3:206-212(1989) (α1-antitrypsin); Smith et al., 1989, J Clin Invest 84:1145-1146 (α-1-proteinase); Oswein et al., 1990, “Aerosolization of Proteins”, Proceedings of Symposium on Respiratory Drug Delivery. II, Keystone, Colorado, March, (recombinant human growth hormone), Debs et al., 1988, J Immunol 140:3482-3488 (interferon gamma and tumor necrosis factor alpha) and Platz et al., U.S. Patent No. 5,284,656 (granulocyte colony stimulating factor, incorporated by reference). Methods and compositions for pulmonary delivery of drugs for systemic effect are described in U.S. Patent No. 5,451,569, issued September 19, 1995 to Wong et al., incorporated by reference.

[0112] Contemplated for use in the practice of the present technology are a wide range of devices designed for pulmonary delivery of therapeutic products, including, but not limited to, nebulizers, metered dose inhalers, and powder inhalers, all of which are familiar to those of skill in the art.

[0113] Some specific examples of commercially available devices suitable for the practice of the present technology are the Ultravent™ nebulizer manufactured by Mallinckrodt, Inc., St. Louis, Mo., the Acorn II nebulizer manufactured by Marquest Medical Products, Englewood, Colo., the Ventolin metered dose inhaler manufactured by Glaxo, Inc., Research Triangle Park, North Carolina, and the Spinhaler powder inhaler manufactured by Fisons Corp., Bedford, Mass.

[0114] All such devices require the use of a formulation suitable for dispensing the compound(s) / therapeutic agent(s). Typically, each formulation is specific to the type of device used and may include the use of appropriate propellant materials in addition to the usual diluents, adjuvants, and / or carriers useful in therapy. Also contemplated is the use of liposomes, microcapsules, microspheres, nanoparticles, nanospheres, inclusion complexes, or other types of carriers. The chemically modified compounds of the present application may also be prepared in different formulations depending on the type of chemical modification or the type of device used.

[0115] Formulations suitable for use with either jet or ultrasonic nebulizers may include, for example, a compound / therapeutic agent (or derivative) of the present application dissolved in water at a concentration of about 0.01-50 mg of biologically active compound per mL of solution. The formulation may also include a buffer and a simple sugar (e.g., for inhibitor stabilization and regulation of osmotic pressure). Nebulizer formulations may also contain a surfactant to reduce or prevent surface-induced aggregation of the compound of the present application caused by atomization of the solution in forming an aerosol.

[0116] Formulations for use with metered dose inhaler devices may generally comprise a finely divided powder containing the compound (or derivative) of the present application suspended in a propellant with the aid of a surfactant. The propellant may be any conventional material used for this purpose, such as chlorofluorocarbons, hydrochlorofluorocarbons, hydrofluorocarbons, or hydrocarbons, including trichlorofluoromethane, dichlorodifluoromethane, dichlorotetrafluoroethanol, and 1,1,1,2-tetrafluoroethane, or combinations thereof. Suitable surfactants include sorbitan trioleate and soy lecithin. Oleic acid may also be useful as a surfactant.

[0117] Formulations for dispensing from a powder inhaler device may comprise a finely divided dry powder containing the compound (or derivative) of the present application and may also contain a bulking agent such as lactose, sorbitol, sucrose, or mannitol in an amount to facilitate dispersion of the powder from the device, e.g., 50-90% by weight of the formulation. The compound(s) / therapeutic agent(s) (or derivatives) of the present application may advantageously be prepared in particulate or nanoparticle form having an average particle size of less than 10 micrometers (μm), most preferably 0.5-5 μm, for most effective delivery to the deep lung.

[0118] For ophthalmic or intraocular indications, any suitable mode of delivering the therapeutic compound / agent or pharmaceutical composition to the eye or area near the eye can be used. For ophthalmic formulations, see generally Mitra (ed.), Ophthalmic Drug Delivery Systems, Marcel Dekker, Inc., New York, NY (1993) and also Havener, WH, Ocular Pharmacology, CV Mosby Co., St. Louis (1983). Non-limiting examples of pharmaceutical compositions suitable for administration in or near the eye include, but are not limited to, ocular inserts, minitablets, and topical formulations such as eye drops, ointments, and in situ gels. In one embodiment, contact lenses are coated with a pharmaceutical composition comprising the therapeutic compound / agent disclosed herein. In some embodiments, a single dose comprises 0.1 ng to 5000 μg, 1 ng to 500 μg, or 10 ng to 100 μg of the therapeutic compound / agent or pharmaceutical composition administered to the eye.

[0119] Eye drops can include sterile liquid formulations that can be administered directly to the eye. In some embodiments, eye drops include at least one therapeutic compound / agent disclosed herein and may further include one or more preservatives. In some embodiments, the optimal pH of eye drops is equal to the pH of tears, which is about 7.4. For eye drops, the therapeutic compound / agent can be present in the drop solution at about 0.1% to about 5% (w / v or v / v, depending on the physical nature of the active ingredient (i.e., solid or liquid)). In some embodiments, the therapeutic compound / agent can be present in the drop solution at about 1% to about 3% (w / v or v / v, as appropriate).

[0120] In-situ gels are viscous liquids that exhibit the ability to transition from sol to gel when influenced by external factors such as appropriate pH, temperature, and the presence of electrolytes. This property slows drug efflux from the ocular surface and increases the bioavailability of the active ingredient. Polymers commonly used in in-situ gel formulations include, but are not limited to, gellan gum, poloxamer, silicone-containing formulations, silicon-based formulations, and cellulose acetate phthalate. In some embodiments, therapeutic compounds / agents are formulated into the in-situ gel (as pharmaceutical compositions / agents).

[0121] For local ocular administration, the therapeutic compound / agent or pharmaceutical composition may be formulated as a solution, gel, ointment, cream, suspension, etc., as is well known in the art. An ointment is a semi-solid dosage form for external use, such as topical use on the eye or skin. In some embodiments, an ointment comprises a solid or semi-solid hydrocarbon base with a melting or softening point close to the core temperature of the human body. In some embodiments, an ointment applied to the eye breaks down into small droplets, which remain in the conjunctival sac for a longer period of time, thus increasing bioavailability.

[0122] Ophthalmic inserts are solid or semi-solid dosage forms that do not have the drawbacks of conventional ophthalmic drug forms. They are less susceptible to defense mechanisms such as outflow through the nasolacrimal duct, exhibit the ability to remain in the conjunctival sac for extended periods, and are more stable than conventional dosage forms. They also offer advantages such as accurate dosing of one or more therapeutic compounds / agents, slow release of one or more therapeutic compounds / agents at a constant rate, and limited systemic absorption of one or more therapeutic compounds / agents. In some embodiments, the ophthalmic inserts comprise one or more therapeutic compounds / agents and one or more polymeric materials as disclosed herein. The polymeric materials can include, but are not limited to, methylcellulose and its derivatives (e.g., hydroxypropylmethylcellulose (HPMC)), ethylcellulose, polyvinylpyrrolidone (PVP K-90), polyvinyl alcohol, chitosan, carboxymethylchitosan, gelatin, and various mixtures of the aforementioned polymers. The ophthalmic inserts can include silica. The ophthalmic inserts can include liposomes, nanoparticles, or microparticles of degradable or biodegradable polymers (as described in more detail below).

[0123] Minitablets are biodegradable solid drug forms that migrate into a gel after application to the conjunctival sac, thereby extending the contact period between the active ingredient (i.e., the therapeutic compound / agent disclosed herein) and the ocular surface, which in turn increases the bioavailability of the therapeutic compound / agent. Advantages of minitablets include easy application to the conjunctival sac, resistance to defense mechanisms such as tears or runoff through the nasolacrimal duct, longer contact with the cornea caused by the presence of mucoadhesive polymers, and gradual release of the active ingredient from the formulation at the application site due to swelling of the outer carrier layer. Minitablets can include one or more of the therapeutic compounds / agents disclosed herein and one or more polymers. Non-limiting examples of polymers suitable for use in minitablet formulations include, for example, cellulose derivatives such as hydroxypropylmethylcellulose (HPMC), hydroxyethylcellulose (HEC), sodium carboxymethylcellulose, ethylcellulose, acrylates (e.g., polyacrylic acid and its crosslinked forms), Carbopol® or carbomer, chitosan, and starch (e.g., drum-dried waxy corn starch). In some embodiments, the minitablets further comprise one or more excipients. Non-limiting examples of excipients include mannitol and magnesium stearate.

[0124] Ophthalmic or intraocular preparations and medicaments may contain antimicrobial components that are non-harmful during use, e.g., non-toxic auxiliary substances such as thimerosal, benzalkonium chloride, methyl and propylparabens, benzyldodecinium bromide, benzyl alcohol, or phenylethanol; buffer components such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffer; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitylate, ethylenediaminetetraacetic acid, etc.

[0125] In some embodiments, the viscosity of the ophthalmic formulation containing one or more therapeutic compounds / agents is increased to improve contact with the cornea of ​​the eye and bioavailability. Viscosity can be increased by adding high molecular weight hydrophilic polymers that do not diffuse through biological membranes and form three-dimensional networks in water. Non-limiting examples of such polymers include polyvinyl alcohol, poloxamer, hyaluronic acid, carbomer, and polysaccharides, cellulose derivatives, gellan gum, and xanthan gum.

[0126] In addition to the above formulations, the therapeutic compounds / agents disclosed herein can also be formulated as depot preparations. Such long-acting preparations can be formulated with suitable polymeric or hydrophobic materials (e.g., as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, e.g., as a sparingly soluble salt.

[0127] In some embodiments, the therapeutic agent(s) are administered as a depot formulation, where the active therapeutic agent(s) are encapsulated by or disposed within silica-based microparticles. In some embodiments, the ophthalmic formulation may be injected into the eye, for example, as a sol-gel (e.g., silica sol-gel). In some embodiments, the ophthalmic formulation is a depot formulation, such as a controlled release formulation (see below). Such controlled release formulations may include particles, such as microparticles or nanoparticles.

[0128] The pharmaceutical compositions may also include suitable solid or gel phase carriers or excipients, examples of which include, but are not limited to, calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, silica / silicones, and polymers such as polyethylene glycols.

[0129] Suitable liquid or solid pharmaceutical preparation forms include, for example, aqueous or saline solutions for inhalation, microencapsulated, cochleated, coated on fine gold particles, encapsulated in liposomes, nebulized, aerosolized, pellets embedded in the skin, or dry forms on sharps for scratching the skin. Pharmaceutical compositions also include granules, powders, tablets, coated tablets, (micro)capsules, suppositories, syrups, emulsions, suspensions, creams, drops, or preparations in which active compounds are sustainedly released, in which excipients and additives, and / or auxiliaries, such as disintegrants, binders, coating agents, swelling agents, lubricants, flavoring agents, sweetening agents, or solubilizers, are conventionally used as described above. Pharmaceutical compositions may be suitable for use in various drug delivery systems. For a brief overview of methods for drug delivery, see Langer R, Science 249:1527-33 (1990).

[0130] The therapeutic agent(s), specifically including but not limited to the therapeutic compounds / agents disclosed herein, may be provided within the particles. As used herein, particle refers to nanoparticles or microparticles (or in some instances larger particles) that may consist in whole or in part of the therapeutic compounds / agents or other therapeutic agent(s) described herein. The particles may contain the therapeutic compound(s) / agent(s) within a core surrounded by a coating, including but not limited to an enteric coating. The therapeutic compound(s) / agent(s) may also be dispersed throughout the particle. The therapeutic compound(s) / agent(s) may also be adsorbed within the particle. The particles may have any order of release kinetics, including zero order release, first order release, second order release, delayed release, sustained release, immediate release, and any combination thereof. In addition to the therapeutic compound(s) / agent(s), the particles may contain any of those materials conventionally used in the pharmaceutical and medical fields, including, but not limited to, erodible, non-erodible, biodegradable, or non-biodegradable materials, or combinations thereof. The particles may be microcapsules containing the therapeutic compound(s) / agent(s) in solution or in a semi-solid state. The particles may be of virtually any shape.

[0131] Both non-biodegradable and biodegradable polymeric materials may be used in the manufacture of particles for delivering therapeutic compound(s) / agent(s). Such polymers may be natural or synthetic. The polymer is selected based on the period over which release is desired. Bioadhesive polymers of particular interest include the bioerodible hydrogels described in Sawhney HS et al. (1993) Macromolecules 26:581-7, the teachings of which are incorporated herein. These include polyhyaluronic acid, casein, gelatin, glutin, polyanhydrides, polyacrylic acid, alginates, chitosan, polyethylene glycol (PEG), polyvinyl alcohol (PVA), poly(methyl methacrylate), poly(ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), polylactic acid (PLA), poly(lactic-co-glycolic) acid (PLGA), poly(hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly(phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), poly(isobutyl acrylate), poly(octadecyl acrylate), and poly(ε-caprolactone), or a mixture of two or more of the foregoing.

[0132] The therapeutic compound / agent or other therapeutic agent(s), or mixtures thereof, can be formulated in a carrier system. The carrier can be a colloidal system. The carrier or colloidal system can be a liposome, a phospholipid bilayer vehicle. In one embodiment, the therapeutic compound(s) / agent(s) or other therapeutic agent(s) or mixtures thereof can be encapsulated in a liposome while maintaining the integrity of the therapeutic compound(s) / agent(s) or other therapeutic agent(s) or mixtures thereof. Those skilled in the art will appreciate that there are various methods for preparing liposomes. (See Lichtenberg, et al., Methods Biochem. Anal., 33:337-462 (1988); Anselem, et al., Liposome Technology, CRC Press (1993)). Liposomal formulations can delay clearance and increase cellular uptake (see Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). For example, active agents can also be loaded into particles prepared from pharma- ceutically acceptable components, including, but not limited to, soluble, insoluble, permeable, impermeable, biodegradable, or digestion-promoting polymers or liposomes. Such particles include, but are not limited to, nanoparticles, biodegradable nanoparticles, microparticles, biodegradable microparticles, nanospheres, biodegradable nanospheres, microspheres, biodegradable microspheres, capsules, emulsions, liposomes, micelles, and viral vector systems.

[0133] The carrier can also be a polymer, for example, a biodegradable, biocompatible polymer matrix. In one embodiment, the therapeutic compound or other therapeutic agent or mixtures thereof can be embedded in the polymer matrix while maintaining the integrity of the composition. The polymer can be a microparticle or nanoparticle that encapsulates the therapeutic agent or agents. The polymer can be natural, such as a polypeptide, protein, or polysaccharide, or synthetic, such as poly-alpha-hydroxy acid. Examples include carriers made of, for example, collagen, fibronectin, elastin, cellulose acetate, cellulose nitrate, polysaccharides, fibrin, gelatin, and combinations thereof. In one embodiment, the polymer is polylactic acid (PLA), polylactic / glycolic acid (PLGA), or mixtures thereof. The polymer matrix can be prepared and isolated in a variety of forms and sizes, including microspheres and nanospheres. The polymer formulation can provide an extended duration of therapeutic effect. (See Reddy, Ann. Pharmacother., 34(7-8):915-923 (2000)). Polymeric formulations of human growth hormone (hGH) are in use in clinical trials (see Kozarich and Rich, Chemical Biology, 2:548-552 (1998)).

[0134] Examples of polymeric microsphere sustained release formulations are described in PCT Publication No. 99 / 15154 (Tracy et al.), U.S. Patent Nos. 5,674,534 and 5,716,644 (both Zale et al.), PCT Publication No. 96 / 40073 (Zale et al.), and PCT Publication No. 00 / 38651 (Shah et al.). U.S. Patent Nos. 5,674,534 and 5,716,644, and PCT Publication No. 96 / 40073, describe polymer matrices containing particles of erythropoietin stabilized against aggregation with salts.

[0135] In some embodiments, the nanoparticles or microparticles can be silica-based or silane-based (see, for example, WO 2002 / 080977 entitled "Biodegradable carrier and method for preparation thereof").

[0136] In some embodiments, the therapeutic compound(s) / agent(s) or other therapeutic agent(s) or mixtures thereof are prepared with a carrier that protects the therapeutic compound(s) / agent(s) or other therapeutic agent(s) or mixtures thereof from rapid elimination from the body, such as controlled release formulations, including implants and microencapsulated delivery systems. Biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid, can be used. Such formulations can be prepared using known techniques. Materials can also be obtained commercially, for example, from Alza Corporation and Nova Pharmaceuticals, Inc. Liposomal suspensions (including liposomes targeted to specific cells with monoclonal antibodies against cell-specific antigens) can also be used as pharma-ceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811.

[0137] The therapeutic compound(s) / agent(s) may be included in a controlled release system. The term "controlled release" is intended to refer to any drug-containing formulation in which the manner and profile of drug release from the formulation is controlled. It refers to immediate as well as non-immediate release formulations, which include, but are not limited to, sustained and delayed release formulations. The term "sustained release" (also referred to as "extended release") is used in its conventional sense to refer to a drug formulation that provides gradual release of drug over an extended period of time, preferably, but not necessarily, resulting in substantially constant blood levels of drug over an extended period of time. The term "delayed release" is used in its conventional sense to refer to a drug formulation in which there is a time delay between administration of the formulation and the release of the drug therefrom, thereby making it available to the subject. "Delayed release" may or may not involve gradual release of drug over an extended period of time, and therefore may or may not be a "sustained release".

[0138] The use of long-term sustained release implants or depot formulations may be particularly suitable for the treatment of chronic diseases. The terms "implant" and "depot formulation" are intended to include a single composition (such as a mesh), or a composition comprising multiple components (e.g., a fibrous mesh constructed from several individual mesh materials), or multiple individual compositions, where the multiple compositions remain localized and provide a long-term sustained release resulting from the aggregation of the multiple compositions. "Long-term" release, as used herein, means that the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 2 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 7 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 14 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 60 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 90 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least 180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for at least one year. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 15-30 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 30-60 days.In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 60 to 90 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 90 to 120 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for 120 to 180 days. In some embodiments, the implant or depot formulation is constructed and arranged to deliver therapeutic or prophylactic levels of the active ingredient(s) for up to one year. In some embodiments, long-term sustained release implants or depot formulations are well known to those skilled in the art and include some of the release systems described above. In some embodiments, such implants or depot formulations can be administered surgically. In some embodiments, such implants or depot formulations can be administered topically or by injection.

[0139] V. Compounds and Compositions Useful in the Practice of the Methods, Uses and Medicaments Disclosed herein Small Molecule Peptide Mimetics In some embodiments, the present disclosure provides a peptidomimetic compound of formula (I), or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, for practicing the methods disclosed herein: [ka] (In the formula, AA1 is [ka] is selected from AA2 is, [ka] is selected from R1 is, [ka] is selected from R 2a teeth, [ka] is selected from R 2b is H or Me, R3 and R 4 is independently selected from H and (C1-C6)alkyl; R 5 and R 6 are independently H, methyl, ethyl, propyl, cyclopropyl, or cyclobutyl, or R 5 and R 6 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; R 7 is selected from H, (C1-C6)alkyl, cycloalkyl, and aryl; R 8 and R 9 is independently selected from H, (C1-C6)alkyl, cycloalkyl, and aryl, or R 8 and R 9 together with the N atom to which they are attached form a 4- to 6-membered heterocyclyl; n is 1, 2, or 3; X is [ka] is selected from * represents the point of attachment of X to R1.

[0140] In some embodiments, AA1 is [ka] In some embodiments, AA1 is [ka] In some embodiments, AA1 is [ka] In some embodiments, AA1 is [ka] In some embodiments, AA1 is [ka] In some embodiments, AA1 is [ka] It is.

[0141] In some embodiments, AA2 is [ka] In some embodiments, AA2 is [ka] In some embodiments, AA2 is [ka] In some embodiments, AA2 is [ka] It is.

[0142] In some embodiments, R1 is [ka] or JPEG2025503652000020.jpg1425. In some embodiments, R1 is [ka] In some embodiments, R is [ka] In some embodiments, R is [ka] It is.

[0143] In some embodiments, R1 is [ka] In some embodiments, R is [ka] In some embodiments, R is [ka] , JPEG2025503652000027.jpg1221, or The image is JPEG2025503652000028.jpg1323.

[0144] In some embodiments, R1 is [ka] , JPEG2025503652000030.jpg1221, JPEG2025503652000031.jpg1421, or The image is JPEG2025503652000032.jpg1425.

[0145] In some embodiments, R1 is [ka] It is.

[0146] In some embodiments, R 2a teeth, [ka] In some embodiments, R 2a teeth, [ka] It is.

[0147] In some embodiments, R 2a teeth, [ka] or JPEG2025503652000037.jpg1918. In some embodiments, R 2a teeth, [ka] In some embodiments, R 2a teeth, [ka] or JPEG2025503652000040.jpg2518. In some embodiments, R 2a teeth, [ka] or JPEG2025503652000042.jpg2318. In some embodiments, R 2a teeth, [ka] , JPEG2025503652000044.jpg1621, or JPEG2025503652000045.jpg1817. In some embodiments, R2a teeth, [ka] , JPEG2025503652000047.jpg1917, or The file is JPEG2025503652000048.jpg2316.

[0148] In some embodiments, R 2b is H. In some embodiments, R 2b is methyl.

[0149] In some embodiments, R3 is H. In some embodiments, R3 is (C1-C6) alkyl. In some embodiments, R3 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. In some embodiments, R3 is methyl. In some embodiments, R3 is ethyl.

[0150] In some embodiments, R 4 is H. In some embodiments, R 4 is (C1-C6) alkyl. In some embodiments, R 4 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 4 is methyl. In some embodiments, R 4 is ethyl.

[0151] In some embodiments, R and R 4 In some embodiments, R and R 4 is different.

[0152] In some embodiments, R 5 is H. In some embodiments, R 5 is methyl.

[0153] In some embodiments, R 6 is H. In some embodiments, R 6 is methyl.

[0154] In some embodiments, R 5 and R 6 are the same. In some embodiments, R 5 and R 6 are different. In some embodiments, R 5 and R 6 is H.

[0155] In some embodiments, R 5 and R 6 together with the N atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-6 membered ring. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl.

[0156] In some embodiments, R 7 is H. In some embodiments, R 7 is (C1-C6) alkyl. In some embodiments, R 7 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 7 is methyl.

[0157] In some embodiments, R 7 is cycloalkyl. In some embodiments, R 7 is cyclopropyl, cyclobutyl, cyclopropyl, or cyclohexyl. In some embodiments, R 7 is aryl. In some embodiments, R 7 is phenyl.

[0158] In some embodiments, R8 is H. In some embodiments, R 8 is (C1-C6) alkyl. In some embodiments, R 8 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 8 is methyl.

[0159] In some embodiments, R 9 is H. In some embodiments, R 9 is (C1-C6) alkyl. In some embodiments, R 9 is methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl. 9 is methyl.

[0160] In some embodiments, R 8 and R 9 are the same. In some embodiments, R 8 and R 9 are different. In some embodiments, R 8 and R 9 is H.

[0161] In some embodiments, R 8 and R 9 together with the N atom to which they are attached form a 4-6 membered heterocyclyl. In some embodiments, the heterocyclyl is a 4-6 membered ring. In some embodiments, the heterocyclyl is azetidinyl, pyrrolidinyl, or piperidinyl.

[0162] In some embodiments, X is [ka] In some embodiments, X is [ka] In some embodiments, X is [ka] or JPEG2025503652000052.jpg1422. In some embodiments, X is [ka] In some embodiments, X is [ka] or JPEG2025503652000055.jpg1622. In some embodiments, X is [ka] , JPEG2025503652000057.jpg1622, JPEG2025503652000058.jpg1522, or The image is JPEG2025503652000059.jpg1522.

[0163] In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3.

[0164] In some embodiments, the peptidomimetic has a free base (i.e., not including any associated salt(s), water molecule(s), or solvent molecule(s)) molecular weight of less than 900 daltons, thereby making it a small molecule peptidomimetic.

[0165] The chiral centers of the peptidomimetics disclosed herein may be in either the R or S configuration. The peptidomimetics described herein may contain one or more asymmetric centers and therefore may exist in various isomeric forms, e.g., enantiomers and / or diastereomers. For example, the compounds described herein may be in the form of individual enantiomers, diastereomers or geometric isomers, or may be in the form of mixtures of stereoisomers, including racemic mixtures and mixtures enriched in one or more stereoisomers. Isomers may be isolated from mixtures by methods known to those skilled in the art, including chiral high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts, or preferred isomers may be prepared by asymmetric synthesis. See, e.g., Jacques et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981), Wilen et al., Tetrahedron 33:2725 (1977), Eliel, Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962), and Wilen, Tables of Resolving Agents and Optical Resolutions p. 268 (EL Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972). Additionally, peptidomimetics encompass the compounds described herein as individual isomers substantially free of other isomers, or alternatively as mixtures of various isomers.

[0166] In some embodiments, the small molecule peptidomimetic is compound 1) (having formula (II)), which is described in the literature as: (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, (2R)-2-amino No-N-[(1S)-1-{[(1S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl]carbamoyl}-2-(4-hydroxy-2,6-dimethylphenyl)ethyl]-5-carbamimidamidopentanamide, or known as “(D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pent-1-yl): [ka]

[0167] The term (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, (2R)-2-amino-N-[(1S)-1-{[(1S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino]-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl]-5-guanidinopentanamide

[0033] The term "(D-Arg-DMT-NH((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pent-1-yl)" is intended to include pharma- ceutically acceptable salt forms such as, for example, the tri-(or tris)-HCl salt of the formula (IIa) below: [ka]

[0168] Compound 1 (i.e., Formula (II) or (IIa)) has previously been shown to cross the blood-brain barrier, thereby making it a good candidate for the treatment of neurodegenerative diseases (see WO2021 / 016462, in particular Figure 5A and paragraph

[0238] ).

[0169] Synthesis of small molecule peptidomimetics The peptidomimetic compounds described herein can be prepared in whole or in part using well-known peptide synthesis methods, such as conventional liquid-phase (also known as solution-phase) or solid-phase peptide synthesis, or by peptide synthesis with an automated peptide synthesizer (Kelley et al., Genetics Engineering Principles and Methods, Setlow, JKeds., Plenum Press NY. (1990) Vol. 12, pp. 1 to 19; Stewart et al., Solid-Phase Peptide Synthesis (1989) WH; Houghten, Proc. Natl. Acad. Sci. USA (1985) 82: p. 5132). The peptidomimetics thus produced can be collected or purified by conventional methods, such as chromatography, such as gel filtration chromatography, ion exchange column chromatography, affinity chromatography, reversed-phase column chromatography, and HPLC, ammonium sulfate fractionation, ultrafiltration, and immunoadsorption.

[0170] In solid-phase peptide synthesis, peptides are typically synthesized from the carbonyl group (C-terminus) to the amino group (N-terminus) of the amino acid chain. In certain embodiments, an amino-protected amino acid is covalently attached to a solid support material through the carboxyl group of the amino acid, typically through an ester or amide bond, and optionally through a linking group. The amino group may be deprotected and reacted (i.e., "coupled") with the carbonyl group of a second amino-protected amino acid using a coupling reagent to generate a dipeptide bound to the solid support. After coupling, the resin is optionally treated with a capping reagent, thereby capping any unreacted amine groups (making them inactive toward the subsequent coupling step). These steps (i.e., deprotection, coupling, and optionally capping) may be repeated to form the desired peptide chain. Once the desired peptide chain is complete, the peptide may be cleaved from the solid support.

[0171] In certain embodiments, protecting groups used for amino groups of amino acid residues (peptides and / or peptidomimetics) include 9-fluorenylmethyloxycarbonyl (Fmoc) and t-butyloxycarbonyl (Boc). The Fmoc group is removed from the amino terminus with base and the Boc group is removed with acid. In an alternative embodiment, the amino protecting group is a substituted or unsubstituted group of the aralkyloxycarbonyl type, such as formyl, acrylyl (Acr), benzoyl (Bz), acetyl (Ac), trifluoroacetyl, benzyloxycarbonyl (Z), p-chlorobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, benzhydryloxycarbonyl, 2(p-biphenylyl)isopropyloxycarbonyl, 2-(3,5-dimethoxyphenyl)isopropyloxycarbonyl, p-phenylazobenzyloxycarbonyl, triphenylphosphonoethyloxycarbonyl or 9-fluorenylmethyloxycarbonyl group (Fmoc), tert-butyloxycarbonyl (BOC), tert-amyloxycarbonyl, tert-butyloxycarbonyl (BOC), tert-amyloxycarbonyl, tert-butyloxycarbonyl (BZ), ... It may be a substituted or unsubstituted radical of the alkyloxycarbonyl type, such as the oxycarbonyl, diisopropylmethyloxycarbonyl, isopropyloxycarbonyl, ethyloxycarbonyl, allyloxycarbonyl, 2-methylsulfonylethyloxycarbonyl or 2,2,2-trichloroethyloxycarbonyl radical, a radical of the cycloalkyloxycarbonyl type, such as the cyclopentyloxycarbonyl, cyclohexyloxycarbonyl, adamantyloxycarbonyl or isobornyloxycarbonyl radical, and a radical containing a heteroatom, such as the benzenesulfonyl, p-toluenesulfonyl, mesitylenesulfonyl, methoxytrimethylphenylsulfonyl, 2-nitrobenzenesulfonyl, 2-nitrobenzenesulfenyl, 4-nitrobenzenesulfenyl or 4-nitrobenzenesulfenyl radical.

[0172] Many amino acids have reactive functional groups in their side chains. In certain embodiments, such functional groups are protected to prevent the functional groups from reacting with the incoming amino acid. The protecting groups used with these functional groups must be stable to the conditions of peptide and / or peptidomimetic synthesis, but may be removed before, after, or concomitantly with cleavage of the peptide from the solid support (if support-bound), or during final deprotection in the case of solution-phase synthesis. See also: Isidro-Llobet, A., Alvarez, M., Albericio, F., “Amino Acid-Protecting Groups”; Chem. Rev., 109:2455-2504 (2009) for a comprehensive review of protecting groups commonly used in peptide synthesis (which protecting groups can also be used in peptidomimetic synthesis where the peptidomimetic contains functional groups found in peptides).

[0173] In certain embodiments, the solid support material used in solid phase peptide synthesis methods is a gel-type support such as polystyrene, polyacrylamide, or polyethylene glycol. Alternatively, materials such as controlled pore glass, cellulose fibers, or polystyrene can be functionalized on their surfaces to provide solid supports for peptide synthesis.

[0174] Coupling reagents that can be used in the solid-phase (or solution-phase) peptide synthesis described herein are typically carbodiimide reagents. Examples of carbodiimide reagents include, but are not limited to, N,N'-dicyclohexylcarbodiimide (DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC) and its HCl salt (EDC·HCl), N-cyclohexyl-N'-isopropylcarbodiimide (CIC), N,N'-diisopropylcarbodiimide (DIC), N-tert-butyl-N'-methylcarbodiimide (BMC), N-tert-butyl-N'-ethylcarbodiimide (BEC), bis[[4-[(2,2-dimethyl-1,3-dioxolyl)]-methyl]carbodiimide (BDDC), and N,N-dicylopentylcarbodiimide. DCC is a preferred coupling reagent. Other coupling agents include HATU and HBTU, generally used in combination with an organic base such as DIEA and a hindered pyridine-type base such as lutidine or collidine.

[0175] In some embodiments, amino acids can be activated for coupling to a peptide or peptidomimetic by forming an N-carboxyanhydride, as described in Fuller et al., Urethane-Protected α-Amino Acid N-Carboxyanhydrides and Peptide Synthesis, Biopolymers (Peptide Science), Vol. 40, 183-205 (1996) and WO2018 / 034901.

[0176] Representative methods for preparing small molecule peptidomimetics of general formula (I), more specifically compounds of formula (II) and (IIa), can be found in WO2019 / 118878, which is incorporated herein by reference. More specifically, the synthesis of compound 1a is specifically described in WO2019 / 118878 with respect to the synthesis of compound 7a described therein.

[0177] Preparations and drugs: The small molecule peptidomimetics disclosed herein (e.g., compounds of formula (I), (II), or (IIa)) can be used alone or in combination with other therapeutically active ingredients to address the needs of subjects suffering from tauopathy. In order to be administered to a subject in need thereof, the small molecule peptidomimetic generally needs to be formulated for a suitable route of administration. The formulated product can be considered as a composition or medicament comprising the small molecule peptidomimetic and optionally one or more additional active therapeutic agents. For example, when the small molecule peptidomimetic (alone or in combination with another active ingredient) is administered to a subject by injection, it is typically formulated in an injectable liquid or liquid suspension. For example, this can be achieved by dissolving or suspending the small molecule peptidomimetic in a suitable diluent, adjuvant, excipient, vehicle, or pharma- ceutically acceptable carrier, optionally with one or more, optionally with one or more, additional active therapeutic agents, as described herein above (see the sections entitled Pharmaceutical Compositions, Routes of Administration, and Dosing, above). In some embodiments, the diluent, adjuvant, excipient, vehicle, or pharma- ceutically acceptable carrier may be water, saline, or an aqueous buffer solution.

[0178] Similarly, if the small molecule peptidomimetic (alone or in combination with another active ingredient or ingredients) is to be administered to a subject in oral form, the selected active ingredient(s) may be formulated into a pill, tablet, capsule, or other vehicle for such administration, as described above in the section entitled "Pharmaceutical Compositions, Routes of Administration, and Dosing," or as otherwise known to one of skill in the art. Similarly, the molecular peptidomimetic (alone or in combination with another active ingredient or ingredients) may be formulated for ocular, buccal, topical, nasal, or any other mode of administration previously discussed herein or known to one of skill in the art.

[0179] In summary, any of the formulations (which may also be referred to as medicaments or compositions when formulated for administration to a subject having a certain affliction or condition requiring medical treatment) in "pharmaceutical compositions, routes of administration, and dosing" can be applied to produce a composition (i.e., formulation or medicament) suitable for administration to a subject in need thereof. Thus, in some embodiments, the present application relates to compositions, formulations, and medicaments suitable for administration to a subject suffering from or believed to suffer from a tauopathy.

[0180] VII. Treatment Methods and Related Uses Combination therapy Several small molecules are under investigation as possible therapeutic agents suitable for the treatment of tauopathies. # can be divided into different types of activators. Such categories include regulators of tau phosphorylation, kinase inhibitors, regulators of tau acylation, histone deacetylase (HDAC) inhibitors, regulators / inhibitors of tau glycosylation (e.g., O-GlcNAcase inhibitors), regulators of tau cleavage (e.g., capsase inhibitors), tau aggregation inhibitors, proteasome stimulators, USP14 inhibitors, phosphodiesterase inhibitors, autophagy activators, chaperone modulators, co-chaperone modulators, and tau-directed multi-target specific ligands (review article: Wang, L., et al. “Small molecule therapeutics for tauopathy in Alzheimer's disease: Walking the path of most resistance”, European Journal of Medicinal Chemistry, 209 (2021) 112915; #Some of the “small molecules” identified in this literature are comprised of molecular weights greater than 900 daltons, but are classified as such by Wang et al. and are therefore referred to herein as “small molecules”).

[0181] Some examples of suitable regulators of tau phosphorylation include memantine, fingolimod (FTY720), SEW2871, genistein, metformin, resveratrol, morroniside, and loganin (see Wang, L., et al. and FIG. 1).

[0182] Some examples of suitable kinase inhibitors include tideglusib and saracatinib / AZD0530 (see Wang, L., et al. and FIG. 1).

[0183] Some examples of suitable modulators of tauacylation include salsalate, salicylate, C646, CGP3466B (omigapil) and A03 (see Wang, L., et al. and FIG. 1).

[0184] Some examples of suitable histone deacetylase (HDAC) inhibitors include ACY-738, CKD-504, glycodeoxycholic acid, PubChem ID: 38028580, PubChem ID: 16399643, and RGFP-966 (see Wang, L., et al. and FIG. 2).

[0185] Some examples of suitable modulators / inhibitors of tau glycosylation (e.g., O-GlcNAcase inhibitors) include PUGNAc, NAG-thiazoline, NButGT, thiamet-G, MK-8719 and ASN120290 (see Wang, L., et al. and FIG. 2).

[0186] Some examples of suitable modulators of tau cleavage (e.g., capsase inhibitors) include Z-VAD-FMK, Z-VAD(OMe)-FMK, Q-VD-OPh, and minocycline (see Wang, L., et al. and FIG. 3).

[0187] Some examples of suitable tau aggregation inhibitors include methylene blue, LMTM, curcumin, PE859, TAI-1, TAI-2, curcumin-sugar-conjugates, N744, RH-1, TAI-3, TAI-4, TAI-5, TAI-6, TAI-7, cinnamaldehyde, epicatechin, crocin. ## , VB-008 and CL-NQTrp (see Wang, L., et al. and Figures 3 and 4; ## The mass of this compound is over 900 daltons, but is nevertheless characterized as a small molecule by Wang et al.).

[0188] Some examples of suitable proteasome stimulators include chlorpromazine and TCH-165 (see Wang, L., et al. and FIG. 5).

[0189] Some examples of suitable USP14 inhibitors include IU1, IU1-47 (see Wang, L., et al. and FIG. 5).

[0190] Some examples of suitable phosphodiesterase inhibitors and PROTACs include rolipram, BPN14770, cilostazol, sildenafil, and QC-01-175 (see Wang, L., et al. and FIG. 5).

[0191] Some examples of suitable autophagy activators include rapamycin. ##、 Temsirolimus ##、 These include trehalose, nilotinib, pimozide and lonafamib (see Wang, L., et al. and FIG. 6).

[0192] Some examples of suitable chaperone modulators include methylene blue (see above), Azure C, myricetin, HSP70 modulators such as MKT-077, YM-01, YM-08, JG-48, JG-98, VER-155008, 116-9E, ALSB-2970, and PES and Hsp90 modulators such as 17-AAG, EC102, PUDZ8, PU24FCl, LA1011, KU-32 and celastrol (see Wang, L., et al. and Figures 7 and 8).

[0193] Some examples of suitable co-chaperone modulators include sulforaphane and KU-177 (see Wang, L., et al. and FIG. 8).

[0194] Some examples of suitable tau-directed multi-target specific ligands include Ipomoea batatas-hypurin hybrid, levetiracetam-hypurin hydride, AChE / GSK3β dual inhibitor (tacrine-valmelin hybrid), BACE / GSK3β dual inhibitor, GSK3β / HDAC dual inhibitor, HDAC / PD5E dual inhibitor (CM-414), MTDL-1, LM-031 and MTDL-2 (see Wang, L., et al. and FIG. 9).

[0195] Thus, in some embodiments, the present application provides small molecule peptidomimetics, such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, as modulators of tau phosphorylation, kinase inhibitors, modulators of tau acylation, histone It is anticipated that the compounds may be co-administered to a subject in combination with deacetylase (HDAC) inhibitors, regulators of tau glycosylation, regulators of tau cleavage, tau aggregation inhibitors, proteasome stimulators, USP14 inhibitors, phosphodiesterase inhibitors and PROTACs, autophagy activators, chaperone modulators, co-chaperone modulators, and / or tau-directed multi-target specific ligands, each in an effective amount, to treat, inhibit, ameliorate, or delay the onset of a tauopathy. Such co-administration may be by simultaneous or sequential administration. Such co-administration may be by the same formulation or by different formulations. Such co-administration may be by the same route or administration, or by different routes of administration.

[0196] Literature suggests that hyperglycemia may play an important role in exacerbating neuroinflammation, and that oxidative stress may contribute to the development and progression of Alzheimer's disease. Peptides such as elamipretide (also known as SS-31, MTP-131, and Bendavia) and the Szeto-Schiller peptide SS-20 have been reported to exhibit or otherwise promote antioxidant activity. Thus, in some embodiments, the present application anticipates that small molecule peptidomimetics such as (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide can be co-administered to a subject in effective amounts of each with elamipretide and / or SS-20 to treat, prevent, inhibit, ameliorate or delay the onset of a tauopathy. Such co-administration may be by simultaneous or sequential administration. Such co-administration may be by the same formulation or by different formulations. Such co-administration may be by the same route or administration or by different routes of administration.

[0197] Treatment method In some embodiments, the present application relates to a method for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a small molecule peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, the small molecule peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, such administration of the small molecule peptidomimetic may reduce tau species levels. In some embodiments, such administration of a small molecule peptidomimetic may reduce toxicity associated with cellular tau accumulation, hi some embodiments, such administration of a small molecule peptidomimetic may reduce cellular oxidative stress caused by cellular accumulation of tau protein.

[0198] In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is Alzheimer's disease. In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is Pick's disease. In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is corticobasal degeneration. In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is progressive supranuclear palsy. In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is global glial tauopathy. In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is argyrophilic grain disease. In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is familial British dementia. In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is familial Danish dementia.

[0199] In some embodiments, the tauopathy addressed by administration of the small molecule peptidomimetic is a primary age-related tauopathy. For example, the primary age-related tauopathy may be selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tau astrogliopathy.

[0200] According to the disclosed methods, in some embodiments, the small molecule peptidomimetic is administered daily for 2 weeks or more. In some embodiments, the small molecule peptidomimetic is administered daily for 12 weeks or more. In some embodiments, the small molecule peptidomimetic is administered daily for 24 weeks or more. In some embodiments, the small molecule peptidomimetic is administered daily for 48 weeks or more. In some embodiments, the small molecule peptidomimetic is administered daily for 1 year or more. In some embodiments, the small molecule peptidomimetic is administered daily for 2 years or more. In some embodiments, the small molecule peptidomimetic is administered daily for 5 years or more. In some embodiments, the small molecule peptidomimetic is administered daily for 1 year or more. In some embodiments, the small molecule peptidomimetic is administered immediately after diagnosis for the remainder of the subject's life or until administration of the peptidomimetic is no longer effective.

[0201] According to the disclosed methods, in some embodiments, the subject is a mammal. In some embodiments, the subject is a human.

[0202] According to the disclosed methods, in some embodiments, the peptidomimetic is administered orally. In some embodiments, the peptidomimetic is administered subcutaneously. In some embodiments, the peptidomimetic is administered topically. In some embodiments, the peptidomimetic is administered intranasally. In some embodiments, the peptidomimetic is administered systemically. In some embodiments, the peptidomimetic is administered intravenously. In some embodiments, the peptidomimetic is administered intraperitoneally. In some embodiments, the peptidomimetic is administered transdermally. In some embodiments, the peptidomimetic is administered intraocularly. In some embodiments, the peptidomimetic is administered ocularly. In some embodiments, the peptidomimetic is administered intrathecally. In some embodiments, the peptidomimetic is administered intracerebroventricularly. In some embodiments, the peptidomimetic is administered iontophoretically. In some embodiments, the peptidomimetic is administered transmucosally. In some embodiments, the peptidomimetic is administered intravitreally. In some embodiments, the peptidomimetic is administered intramuscularly.

[0203] According to the above disclosed method, in some embodiments, the method includes administering to the subject an additional treatment, either separately, sequentially, or simultaneously, which may include administration of an additional therapeutic agent or multiple therapeutic agents (i.e., co-administration of a second therapeutic agent or multiple therapeutic agents in combination with a small molecule peptidomimetic). In some embodiments, the additional therapeutic agent is a small molecule selected from the group consisting of a regulator of tau phosphorylation, a regulator of tau acylation, a histone deacetylase (HDAC) inhibitor, a regulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor), a regulator of tau cleavage (e.g., a capsase inhibitor), a tau aggregation inhibitor, a proteasome stimulator, a USP14 inhibitor, a phosphodiesterase inhibitor, an autophagy activator, a chaperone modulator, a co-chaperone modulator, and a tau-directed multi-target specific ligand.

[0204] In some embodiments, the modulator of tau phosphorylation is selected from the group consisting of memantine, fingolimod (FTY720), SEW2871, genistein, metformin, resveratrol, morroniside and loganin (see Wang, L., et al. and FIG. 1).

[0205] In some embodiments, the kinase inhibitor is selected from the group consisting of tideglusib and saracatinib / AZD0530 (see Wang, L., et al. and Figure 1).

[0206] In some embodiments, the modulator of tauacylation is selected from the group consisting of salsalate, salicylate, C646, CGP3466B (omigapil), and A03 (see Wang, L., et al. and FIG. 1).

[0207] In some embodiments, the histone deacetylase (HDAC) inhibitor is selected from the group consisting of ACY-738, CKD-504, glycodeoxycholic acid, PubChem ID: 38028580, PubChem ID: 16399643, and RGFP-966 (see Wang, L., et al. and FIG. 2).

[0208] In some embodiments, the modulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor) is selected from the group consisting of PUGNAc, NAG-thiazoline, NButGT, thiamet-G, MK-8719, and ASN120290 (see Wang, L., et al. and FIG. 2).

[0209] In some embodiments, suitable modulators of tau cleavage (e.g., capsase inhibitors) include Z-VAD-FMK, Z-VAD(OMe)-FMK, Q-VD-OPh, and minocycline (see Wang, L., et al. and FIG. 3).

[0210] In some embodiments, the tau aggregation inhibitor is selected from the group consisting of methylene blue, LMTM, curcumin, PE859, TAI-1, TAI-2, curcumin-glyco-congugate, N744, RH-1, TAI-3, TAI-4, TAI-5, TAI-6, TAI-7, cinnamaldehyde, epicatechin, crocin##, VB-008, and CL-NQTrp (see Wang, L., et al. and Figures 3 and 4).

[0211] In some embodiments, the proteasome stimulatory agent is selected from the group consisting of chlorpromazine and TCH-165 (see Wang, L., et al. and FIG. 5).

[0212] In some embodiments, the USP14 inhibitor is selected from the group consisting of IU1, IU1-47 (see Wang, L., et al. and FIG. 5).

[0213] In some embodiments, the phosphodiesterase inhibitor and PROTAC is selected from the group consisting of rolipram, BPN14770, cilostazol, sildenafil, and QC-01-175 (see Wang, L., et al. and FIG. 5).

[0214] In some embodiments, the autophagy activator is selected from the group consisting of rapamycin, temsirolimus, trehalose, nilotinib, pimozide, and lonafamib (see Wang, L., et al. and FIG. 6).

[0215] In some embodiments, the chaperone modulator is an Hsp70 modulator such as PES methylene blue (see above), Azure C, myricetin, MKT-077, YM-01, YM-08, JG-48, JG-98, VER-155008, 116-9E, ALSB-2970, or an Hsp90 modulator such as 17-AAG, EC102, PUDZ8, PU24FCl, LA1011, KU-32, and celastrol (see Wang, L., et al. and Figures 7 and 8).

[0216] In some embodiments, the co-chaperone modulator is sulforaphane or KU-177 (see Wang, L., et al. and FIG. 8).

[0217] In some embodiments, the tau-directed multi-target specific ligand is selected from the group consisting of: Isogastrichum-hypurin hybrid, levetiracetam-hypurin hydride, AChE / GSK3β dual inhibitor (tacrine-valmelin hybrid), BACE / GSK3β dual inhibitor, GSK3β / HDAC dual inhibitor, HDAC / PD5E dual inhibitor (CM-414), MTDL-1, LM-031 and MTDL-2 (see Wang, L., et al. and FIG. 9).

[0218] According to the disclosed methods, in some embodiments, the combination of the small molecule peptidomimetic and the additional therapeutic treatment / agent has a synergistic effect in treating a tauopathy.

[0219] According to the disclosed method, in some embodiments, the small peptide is administered in the form of a pharma- ceutically acceptable salt, in some embodiments, the pharma- ceutically acceptable salt is tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate.

[0220] In some embodiments, the small molecule peptidomimetic is formulated as a Tris-HCl salt, a Bis-HCl salt, or a Mono-HCl salt.

[0221] Therapeutic Uses Related to Compositions and Medicaments: In some embodiments, the present application relates to the therapeutic use of a small molecule therapeutic agent disclosed herein, formulated into a composition and / or medicament suitable for administration to a subject in need thereof to treat, prevent, ameliorate, inhibit, and / or delay the onset of a tauopathy, the composition / medicament comprising a therapeutically effective amount of a small molecule peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. Thus, in some embodiments, the present application relates to the use of a composition in the preparation of a medicament for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof, the composition comprising a therapeutically effective amount of a small molecule peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, a small molecule peptidomimetic suitable for such use is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, such use of a composition / medication may reduce tau species levels in a subject. In some embodiments, such use of a composition / medication may reduce toxicity associated with cellular tau accumulation in a subject. In some embodiments, such use of a composition / medication may reduce cellular oxidative stress caused by cellular accumulation of tau protein in a subject.

[0222] In some embodiments, the tauopathy addressed by the use of compositions / medications comprising small molecule peptidomimetics is Alzheimer's disease. In some embodiments, the tauopathy addressed by the use of compositions / medications comprising small molecule peptidomimetics is Pick's disease. In some embodiments, the tauopathy addressed by the use of compositions / medications comprising small molecule peptidomimetics is corticobasal degeneration. In some embodiments, the tauopathy addressed by the use of compositions / medications comprising small molecule peptidomimetics is progressive supranuclear palsy. In some embodiments, the tauopathy addressed by the use of compositions / medications comprising small molecule peptidomimetics is global glial tauopathy. In some embodiments, the tauopathy addressed by the use of compositions / medications comprising small molecule peptidomimetics is argyrophilic grain disease. In some embodiments, the tauopathy addressed by the use of compositions / medications comprising small molecule peptidomimetics is familial British dementia. In some embodiments, the tauopathy addressed by the use of compositions / medicaments comprising small molecule peptidomimetics is Familial Danish Dementia.

[0223] In some embodiments, the tauopathy addressed by the use of compositions / medications comprising small molecule peptidomimetics is a primary age-related tauopathy. For example, the primary age-related tauopathy may be selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tau astrogliopathy.

[0224] According to the disclosed uses, in some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered daily for 2 weeks or more. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered daily for 12 weeks or more. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered daily for 24 weeks or more. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered daily for 48 weeks or more. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered daily for 1 year or more. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered daily for 2 years or more. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered daily for 5 years or more. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered daily for 1 year or more. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is administered immediately after diagnosis for the remainder of the subject's life or until administration of the peptidomimetic is no longer effective.

[0225] According to the disclosed uses, in some embodiments, the subject is a mammal. In some embodiments of the disclosed uses, the subject is a human.

[0226] According to the above disclosed uses, in some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for oral administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for subcutaneous administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for topical administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for intranasal administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for systemic administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for intravenous administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for intraperitoneal administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for intradermal administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for intraocular administration. In some embodiments, the composition / medication comprising the small molecule peptidomimetic is formulated for ophthalmic administration. In some embodiments, the composition / medicament comprising the small molecule peptidomimetic is formulated for intrathecal administration. In some embodiments, the composition / medicament comprising the small molecule peptidomimetic is formulated for intraventricular administration. In some embodiments, the composition / medicament comprising the small molecule peptidomimetic is formulated for iontophoretic administration. In some embodiments, the composition / medicament comprising the small molecule peptidomimetic is formulated for transmucosal administration. In some embodiments, the composition / medicament comprising the small molecule peptidomimetic is formulated for intravitreal administration. In some embodiments, the composition / medicament comprising the small molecule peptidomimetic is formulated for intramuscular administration.

[0227] According to the above disclosed use, in some embodiments, the use includes the use of an additional treatment separately, sequentially, or simultaneously, and the additional treatment may include the administration of an additional therapeutic agent or multiple therapeutic agents. In some embodiments, the additional therapeutic agent is a small molecule selected from the group consisting of a regulator of tau phosphorylation, a regulator of tau acylation, a histone deacetylase (HDAC) inhibitor, a regulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor), a regulator of tau cleavage (e.g., a capsase inhibitor), a tau aggregation inhibitor, a proteasome stimulator, a USP14 inhibitor, a phosphodiesterase inhibitor, an autophagy activator, a chaperone regulator, a co-chaperone regulator, and a tau-directed multi-target specific ligand.

[0228] In some embodiments, the modulator of tau phosphorylation is selected from the group consisting of memantine, fingolimod (FTY720), SEW2871, genistein, metformin, resveratrol, morroniside and loganin (see Wang, L., et al. and FIG. 1).

[0229] In some embodiments, the kinase inhibitor is selected from the group consisting of tideglusib and saracatinib / AZD0530 (see Wang, L., et al. and Figure 1).

[0230] In some embodiments, the modulator of tauacylation is selected from the group consisting of salsalate, salicylate, C646, CGP3466B (omigapil), and A03 (see Wang, L., et al. and FIG. 1).

[0231] In some embodiments, the histone deacetylase (HDAC) inhibitor is selected from the group consisting of ACY-738, CKD-504, glycodeoxycholic acid, PubChem ID: 38028580, PubChem ID: 16399643, and RGFP-966 (see Wang, L., et al. and FIG. 2).

[0232] In some embodiments, the modulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor) is selected from the group consisting of PUGNAc, NAG-thiazoline, NButGT, thiamet-G, MK-8719, and ASN120290 (see Wang, L., et al. and FIG. 2).

[0233] In some embodiments, modulators of tau cleavage (e.g., capsase inhibitors) include Z-VAD-FMK, Z-VAD(OMe)-FMK, Q-VD-OPh, and minocycline (see Wang, L., et al. and FIG. 3).

[0234] In some embodiments, the tau aggregation inhibitor is selected from the group consisting of methylene blue, LMTM, curcumin, PE859, TAI-1, TAI-2, curcumin-glyco-congugate, N744, RH-1, TAI-3, TAI-4, TAI-5, TAI-6, TAI-7, cinnamaldehyde, epicatechin, crocin##, VB-008, and CL-NQTrp (see Wang, L., et al. and Figures 3 and 4).

[0235] In some embodiments, the proteasome stimulatory agent is selected from the group consisting of chlorpromazine and TCH-165 (see Wang, L., et al. and FIG. 5).

[0236] In some embodiments, the USP14 inhibitor is selected from the group consisting of IU1, IU1-47 (see Wang, L., et al. and FIG. 5).

[0237] In some embodiments, the phosphodiesterase inhibitor and PROTAC is selected from the group consisting of rolipram, BPN14770, cilostazol, sildenafil, and QC-01-175 (see Wang, L., et al. and FIG. 5).

[0238] In some embodiments, the autophagy activator is selected from the group consisting of rapamycin, temsirolimus, trehalose, nilotinib, pimozide, and lonafamib (see Wang, L., et al. and FIG. 6).

[0239] In some embodiments, the chaperone modulator is an Hsp70 modulator such as PES methylene blue (see above), Azure C, myricetin, MKT-077, YM-01, YM-08, JG-48, JG-98, VER-155008, 116-9E, ALSB-2970, or an Hsp90 modulator such as 17-AAG, EC102, PUDZ8, PU24FCl, LA1011, KU-32, and celastrol (see Wang, L., et al. and Figures 7 and 8).

[0240] In some embodiments, the co-chaperone modulator is sulforaphane or KU-177 (see Wang, L., et al. and FIG. 8).

[0241] In some embodiments, the tau-directed multi-target specific ligand is selected from the group consisting of: Isogastrichum-hypurin hybrid, levetiracetam-hypurin hydride, AChE / GSK3β dual inhibitor (tacrine-valmelin hybrid), BACE / GSK3β dual inhibitor, GSK3β / HDAC dual inhibitor, HDAC / PD5E dual inhibitor (CM-414), MTDL-1, LM-031 and MTDL-2 (see Wang, L., et al. and FIG. 9).

[0242] According to the above disclosed uses, in some embodiments, the combination of a composition / agent comprising a small molecule peptidomimetic with an additional therapeutic treatment / agent has a synergistic effect in the treatment of a tauopathy.

[0243] According to the above disclosed uses, in some embodiments, the small molecule peptidomimetic used in formulating the composition / medicament is a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate.

[0244] In some embodiments, the small molecule peptidomimetic used in formulating the composition / medicament is a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.

[0245] In yet other embodiments, the present application relates to a small molecule peptidomimetic, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof, for use in treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof. In some embodiments, the small molecule peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, such use of the small molecule peptidomimetic reduces tau species levels in the subject. In some embodiments, the use of small molecule peptidomimetics reduces toxicity associated with cellular tau accumulation in a subject, hi some embodiments, the use of small molecule peptidomimetics reduces cellular oxidative stress caused by cellular accumulation of tau protein in a subject.

[0246] In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is Alzheimer's disease. In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is Pick's disease. In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is corticobasal degeneration. In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is progressive supranuclear palsy. In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is global glial tauopathy. In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is argyrophilic grain disease. In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is familial british dementia. In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is familial danish dementia.

[0247] In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics is a primary age-related tauopathy. For example, the primary age-related tauopathy may be selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tau astrogliopathy.

[0248] According to the above disclosed uses, in some embodiments, the small molecule peptidomimetic is administered daily for 2 weeks or more. In some embodiments, the small molecule peptidomimetic is administered daily for 12 weeks or more. In some embodiments, the small molecule peptidomimetic is administered daily for 24 weeks or more. In some embodiments, the small molecule peptidomimetic is administered daily for 48 weeks or more. In some embodiments, the small molecule peptidomimetic is administered daily for 1 year or more. In some embodiments, the small molecule peptidomimetic is administered daily for 2 years or more. In some embodiments, the small molecule peptidomimetic is administered daily for 5 years or more. In some embodiments, the small molecule peptidomimetic is administered daily for 1 year or more. In some embodiments, the small molecule peptidomimetic is administered immediately after diagnosis for the remainder of the subject's life or until administration of the peptidomimetic is no longer effective.

[0249] According to the disclosed uses, in some embodiments, the subject is a mammal. In some embodiments of the disclosed uses, the subject is a human.

[0250] According to the above disclosed uses, in some embodiments, the small molecule peptidomimetic is formulated for oral administration. In some embodiments, the small molecule peptidomimetic is formulated for subcutaneous administration. In some embodiments, the small molecule peptidomimetic is formulated for topical administration. In some embodiments, the small molecule peptidomimetic is formulated for intranasal administration. In some embodiments, the small molecule peptidomimetic is formulated for systemic administration. In some embodiments, the small molecule peptidomimetic is formulated for intravenous administration. In some embodiments, the small molecule peptidomimetic is formulated for intraperitoneal administration. In some embodiments, the small molecule peptidomimetic is formulated for intradermal administration. In some embodiments, the small molecule peptidomimetic is formulated for intraocular administration. In some embodiments, the small molecule peptidomimetic is formulated for ophthalmic administration. In some embodiments, the small molecule peptidomimetic is formulated for intrathecal administration. In some embodiments, the small molecule peptidomimetic is formulated for intracerebroventricular administration. In some embodiments, the small molecule peptidomimetic is formulated for iontophoretic administration. In some embodiments, the small molecule peptidomimetic is formulated for transmucosal administration. In some embodiments, the small molecule peptidomimetic is formulated for intravitreal administration. In some embodiments, the small molecule peptidomimetic is formulated for intramuscular administration.

[0251] According to the above disclosed use, in some embodiments, the use includes the use of an additional treatment separately, sequentially, or simultaneously, and the additional treatment may include the administration of an additional therapeutic agent or multiple therapeutic agents. In some embodiments, the additional therapeutic agent is a small molecule selected from the group consisting of a regulator of tau phosphorylation, a regulator of tau acylation, a histone deacetylase (HDAC) inhibitor, a regulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor), a regulator of tau cleavage (e.g., a capsase inhibitor), a tau aggregation inhibitor, a proteasome stimulator, a USP14 inhibitor, a phosphodiesterase inhibitor, an autophagy activator, a chaperone regulator, a co-chaperone regulator, and a tau-directed multi-target specific ligand.

[0252] In some embodiments, the modulator of tau phosphorylation is selected from the group consisting of memantine, fingolimod (FTY720), SEW2871, genistein, metformin, resveratrol, morroniside and loganin (see Wang, L., et al. and FIG. 1).

[0253] In some embodiments, the kinase inhibitor is selected from the group consisting of tideglusib and saracatinib / AZD0530 (see Wang, L., et al. and Figure 1).

[0254] In some embodiments, the modulator of tauacylation is selected from the group consisting of salsalate, salicylate, C646, CGP3466B (omigapil), and A03 (see Wang, L., et al. and FIG. 1).

[0255] In some embodiments, the histone deacetylase (HDAC) inhibitor is selected from the group consisting of ACY-738, CKD-504, glycodeoxycholic acid, PubChem ID: 38028580, PubChem ID: 16399643, and RGFP-966 (see Wang, L., et al. and FIG. 2).

[0256] In some embodiments, the modulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor) is selected from the group consisting of PUGNAc, NAG-thiazoline, NButGT, thiamet-G, MK-8719, and ASN120290 (see Wang, L., et al. and FIG. 2).

[0257] In some embodiments, the modulator of tau cleavage (e.g., a capsase inhibitor) is selected from the group consisting of Z-VAD-FMK, Z-VAD(OMe)-FMK, Q-VD-OPh and minocycline (see Wang, L., et al. and FIG. 3).

[0258] In some embodiments, the tau aggregation inhibitor is selected from the group consisting of methylene blue, LMTM, curcumin, PE859, TAI-1, TAI-2, curcumin-glyco-congugate, N744, RH-1, TAI-3, TAI-4, TAI-5, TAI-6, TAI-7, cinnamaldehyde, epicatechin, crocin##, VB-008, and CL-NQTrp (see Wang, L., et al. and Figures 3 and 4).

[0259] In some embodiments, the proteasome stimulatory agent is selected from the group consisting of chlorpromazine and TCH-165 (see Wang, L., et al. and FIG. 5).

[0260] In some embodiments, the USP14 inhibitor is selected from the group consisting of IU1, IU1-47 (see Wang, L., et al. and FIG. 5).

[0261] In some embodiments, the phosphodiesterase inhibitor and PROTAC is selected from the group consisting of rolipram, BPN14770, cilostazol, sildenafil, and QC-01-175 (see Wang, L., et al. and FIG. 5).

[0262] In some embodiments, the autophagy activator is selected from the group consisting of rapamycin, temsirolimus, trehalose, nilotinib, pimozide, and lonafamib (see Wang, L., et al. and FIG. 6).

[0263] In some embodiments, the chaperone modulator is an Hsp70 modulator such as PES methylene blue (see above), Azure C, myricetin, MKT-077, YM-01, YM-08, JG-48, JG-98, VER-155008, 116-9E, ALSB-2970, or an Hsp90 modulator such as 17-AAG, EC102, PUDZ8, PU24FCl, LA1011, KU-32, and celastrol (see Wang, L., et al. and Figures 7 and 8).

[0264] In some embodiments, the co-chaperone modulator is sulforaphane or KU-177 (see Wang, L., et al. and FIG. 8).

[0265] In some embodiments, the tau-directed multi-target specific ligand is selected from the group consisting of Ipomoea batatas-hypurin hybrid, levetiracetam-hypurin hydride, AChE / GSK3β dual inhibitor (tacrine-valmelin hybrid), BACE / GSK3β dual inhibitor, GSK3β / HDAC dual inhibitor, HDAC / PD5E dual inhibitor (CM-414), MTDL-1, LM-031 and MTDL-2 (see Wang, L., et al. and FIG. 9). According to the above disclosed uses, in some embodiments, the combination of small molecule peptidomimetic and additional therapeutic treatment / agent has a synergistic effect in the treatment of tauopathy.

[0266] According to the disclosed uses, in some embodiments, the small molecule peptidomimetic is a pharma- ceutically acceptable salt, in some embodiments, the pharma- ceutically acceptable salt is a tartrate, a fumarate, a monoacetate, a bisacetate, a triacetate, a monotrifluoroacetate, a bistrifluoroacetate, a tritrifluoroacetate, a monohydrochloride, a bishydrochloride, a trihydrochloride, a monotosylate, a bistosylate, or a tritosylate.

[0267] In some embodiments, the small molecule peptidomimetic is a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt.

[0268] In some embodiments, the present application relates to the use of a small molecule peptidomimetic, or a composition comprising a small molecule peptidomimetic, in the preparation of a medicament for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof. In some embodiments, a small molecule peptidomimetic suitable for such use is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharma- ceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof. In some embodiments, such use of the medicament may reduce tau species levels in the subject. In some embodiments, such use of the drug may reduce toxicity associated with cellular tau accumulation in the subject. In some embodiments, such use of an agent may reduce cellular oxidative stress caused by cellular accumulation of tau protein in a subject.

[0269] In some embodiments, the tauopathy addressed by the use of an agent comprising a small molecule peptidomimetic is Alzheimer's disease. In some embodiments, the tauopathy addressed by the use of an agent comprising a small molecule peptidomimetic is Pick's disease. In some embodiments, the tauopathy addressed by the use of an agent comprising a small molecule peptidomimetic is corticobasal degeneration. In some embodiments, the tauopathy addressed by the use of an agent comprising a small molecule peptidomimetic is progressive supranuclear palsy. In some embodiments, the tauopathy addressed by the use of an agent comprising a small molecule peptidomimetic is global glial tauopathy. In some embodiments, the tauopathy addressed by the use of an agent comprising a small molecule peptidomimetic is argyrophilic grain disease. In some embodiments, the tauopathy addressed by the use of an agent comprising a small molecule peptidomimetic is familial British dementia. In some embodiments, the tauopathy addressed by the use of an agent comprising a small molecule peptidomimetic is familial Danish dementia.

[0270] In some embodiments, the tauopathy addressed by the use of small molecule peptidomimetics / agents is a primary age-related tauopathy. For example, the primary age-related tauopathy may be selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tau astrogliopathy.

[0271] According to the above disclosed uses, in some embodiments, the agent comprising the small molecule peptidomimetic is administered daily for 2 weeks or more. In some embodiments, the agent comprising the small molecule peptidomimetic is administered daily for 12 weeks or more. In some embodiments, the agent comprising the small molecule peptidomimetic is administered daily for 24 weeks or more. In some embodiments, the agent comprising the small molecule peptidomimetic is administered daily for 48 weeks or more. In some embodiments, the agent comprising the small molecule peptidomimetic is administered daily for 1 year or more. In some embodiments, the agent comprising the small molecule peptidomimetic is administered daily for 2 years or more. In some embodiments, the agent comprising the small molecule peptidomimetic is administered daily for 5 years or more. In some embodiments, the agent comprising the small molecule peptidomimetic is administered daily for 1 year or more. In some embodiments, the agent comprising the small molecule peptidomimetic is administered immediately after diagnosis for the remainder of the subject's life or until administration of the peptidomimetic is no longer effective.

[0272] According to the disclosed uses, in some embodiments, the subject is a mammal. In some embodiments of the disclosed uses, the subject is a human.

[0273] According to the above disclosed uses, in some embodiments, the agent is formulated for oral administration. In some embodiments, the agent is formulated for subcutaneous administration. In some embodiments, the agent is formulated for topical administration. In some embodiments, the agent is formulated for oral administration. In some embodiments, the agent is formulated for systemic administration. In some embodiments, the agent is formulated for intravenous administration. In some embodiments, the agent is formulated for intraperitoneal administration. In some embodiments, the agent is formulated for intradermal administration. In some embodiments, the agent is formulated for intraocular administration. In some embodiments, the agent is formulated for ocular administration. In some embodiments, the agent is formulated for intrathecal administration. In some embodiments, the agent is formulated for intraventricular administration. In some embodiments, the agent is formulated for iontophoretic administration. In some embodiments, the agent is formulated for transmucosal administration. In some embodiments, the agent is formulated for intravitreal administration. In some embodiments, the agent is formulated for intramuscular administration.

[0274] According to the above disclosed uses, in some embodiments, the small molecule peptidomimetic used in the formulation of the medicament is a pharmaceutically acceptable salt. In some embodiments, the pharmaceutically acceptable salt is tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, tritrifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate.

[0275] In some embodiments, the small molecule peptidomimetic used in formulating the medicament is a tris-HCl salt, a bis-HCl salt, or a mono-HCl salt. EXAMPLES

[0276] The present technology is further illustrated by the following examples, which should not be construed as limiting in any way.

[0277] Example 1 - Effect of Compound 1 on Tauopathy Neuronal Cell Viability and Protection Against Stress-Induced Cell Death This example demonstrates the neuroprotective effects of Compound 1 in an iPSC-derived neuronal model derived from a patient with the MAPT P301L mutation (tau-P301L neurons) when exposed to a mitochondrial stressor.

[0278] method Culture and Differentiation of Human Neural Progenitor Cells. Approval for research with human subjects and induced pluripotent stem cells (iPSCs) was obtained under Massachusetts General Hospital / MGB approved IRB protocol #2010P001611 / MGH. The primary cell line used in this study was derived from a female individual in her 50s with an autosomal dominant mutation P301L (c.C1907T NCBI NM_001123066, rs63751273) diagnosed with FTD and classified as cell line MGH2046-RC1 (DOI:10.1038 / s41467-020-16984-1, DOI:10.7554 / eLife.45457). Two independent clonal lines have been generated, designated Tau-P301L line 1 and line 2 (if not mentioned, line 1 is the one utilized). Briefly, fibroblasts were reprogrammed into iPSCs by a non-integrative method, which were then converted into cortical enriched neural progenitor cells (NPCs) (DOI:10.1016 / j.stemcr.2016.08.001, DOI:10.1002 / cphg.33). NPCs were cultured in DMEM / F12-B27 cell medium [70% DMEM (Gibco), 30% Ham's-F12 (Fisher Scientific Corning), 2% B27 (Gibco), 1% penicillin-streptomycin (Gibco)] in 6-well (Fisher Scientific Corning) or black 96-well clear bottom (Fisher Scientific Corning) plates coated with polyornithine (20 μg / mL in water, Sigma) and laminin (5 μg / mL in PBS), referred to as POL-coated plates. The medium was supplemented with EGF (20 ng / mL, Sigma), FGF (20 ng / mL, Stemgent) and heparin (5 μg / mL, Sigma) to promote NPC proliferation. For NPC differentiation, growth factors were omitted from the cell medium and cells were cultured for several weeks, with half the medium changed twice a week (DOI:10.1038 / s41467-020-16984-1; DOI:10.7554 / eLife.45457; DOI:10.1016 / j.stemcr.2016.08.001).

[0279] Neuronal viability. NPCs were plated at 110,000 cells / cm in 200 μL of DMEM / F12-B27 medium in black POL-coated 96-well clear-bottom plates (Fisher Scientific Corning). 2 Neurons were plated at a starting density of 100 μL / well and allowed to differentiate for 8 weeks. After 8 weeks, 100 μL of medium / well was aspirated and neurons were treated with Compound 1 or vehicle alone (DMSO, i.e., 0 μM compound), added directly to the cell medium (final volume 100 μL). After 24 h of incubation, viability was measured after 4 h of incubation at 37° C. using a 1:10 dilution with Alamar Blue cell viability reagent (Life Technologies) according to the manufacturer's instructions and as previously published (DOI:10.1038 / s41467-020-16984-1; DOI:10.7554 / eLife.45457; DOI:10.1016 / j.stemcr.2016.08.001). Readings were performed on an EnVision multilabel plate reader (Perkin Elmer). Calculations were performed using Microsoft Excel and graphs were plotted in GraphPad Prism 9.

[0280] Stress vulnerability assay. NPCs were cultured at 110,000 cells / cm in 200 μL of DMEM / F12-B27 medium in black POL-coated 96-well clear-bottom plates (Fisher Scientific Corning). 2Neurons were plated at a density of 100 μL / well and allowed to differentiate for 8 weeks. At that time, 100 μL of medium was aspirated from each well (treatment in a final volume of 100 μL of medium) and the stressors rotenone (Sigma) or piericidin A (Enzo Lifesciences) were added directly to the cell medium at concentrations ranging from 1 nM to 5 μM. DMSO alone (0 μM stressor) was used as a 100% viability control. Neurons were incubated at 37 °C for 16 h (overnight) and then viability was measured with Alamar Blue cell viability reagent (Life Technologies) using an EnVision multilabel plate reader (Perkin Elmer) (DOI:10.1038 / s41467-020-16984-1; DOI:10.7554 / eLife.45457; DOI:10.1016 / j.stemcr.2016.08.001). Calculations were performed in Microsoft Excel and graphs were plotted in GraphPad Prism 9.

[0281] Additional cell lines were included in the control studies with rotenan and piericidin as follows (DOI:10.1038 / s41467-020-16984-1; DOI:10.7554 / eLife.45457; DOI:10.1016 / j.stemcr.2016.08.001): Cell line Control-1, Control line 1, or 8330-8-RC1, derived from a male individual in his 60s with disease unaffected control tau-WT; unaffected control tau-WT derived from a female individual in her 40s, classified as cell line control-2, control line 2, or MGH2069-RC1; and unaffected control tau-WT derived from a male individual in his 50s, classified as cell line control-3, control line 3, or CTR2-L17-RC2 (DOI: 10.1016 / j.celrep.2012.09.007). MAPT-Kd line: a neuronal cell line in which human tau is knocked down (DOI: 10.1016 / j.stemcr.2016.08.001).

[0282] Mitochondrial stress vulnerability rescue assay. NPCs were cultured at 110,000 cells / cm in 200 μL of DMEM / F12-B27 medium in black POL-coated 96-well clear bottom plates (Fisher Scientific Corning). 2 Cells were plated at a density of 100 μL per well and allowed to differentiate. At 8 weeks, 100 μL of medium was aspirated from each well and compound treatments were performed in a final volume of 100 μL of medium. Increasing concentrations of compound 1 between 1 nM and 100 μM, as well as vehicle (DMSO) alone, were added directly to the medium and incubated for 8 hours at 37° C. (4 replicates per biological replicate). The stressors rotenone (2 μM or 5 μM) or piericidin A (5 μM or 10 μM), as well as DMSO alone, were then added to groups of wells representing a dose range of compound 1 from 1 nM to 100 μM, respectively, and incubated for an additional 16 hours. At 24 hours, viability was measured with Alamar Blue cell viability reagent (Life Technologies) and an EnVision multilabel plate reader (Perkin Elmer). Calculations and statistics were performed in Microsoft Excel and graphs were plotted in GraphPad Prism 9. A schematic diagram providing an overview of the stress rescue assay to test the protective effect of compound 1 against mitochondrial stressor-induced loss of viability of neurons from patients with frontotemporal dementia (FTD) is shown in Figure 10B.

[0283] result Neuronal viability. As shown in Figure 10A, Compound 1 alone does not adversely affect the viability of Tau-P301L neurons, except at higher concentrations (e.g., 100 μM).

[0284] Stress vulnerability assay. As shown in Figures 10C and 10D, compared to the control neuronal lines (control lines 1, 2, and 3, and MAPT-Kd), Tau-P301L neurons exhibit high sensitivity to relatively low concentrations of the mitochondrial stressors, rotenone (Figure 10C) and piaricidin A (Figure 10D).

[0285] Mitochondrial Stress Vulnerability Rescue Assay As shown in Figures 10E-10H, compound 1 exhibits neuroprotective effects on tau-P301L neurons when added to the neuronal culture medium prior to the addition of mitochondrial stressors, rotenone (Figures 10E and 10F) and piericidin A (Figures 10G and 10H).

[0286] Thus, these results demonstrate that Compound 1 is useful in methods for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of tauopathy in subjects in need thereof.

[0287] Example 2 - Effect of Compound 1 on Tau Protein Accumulation This example shows that Compound 1 reduces the levels of a pathological form of tau protein in an iPSC-derived neuronal model derived from a patient with the MAPT P301L mutation (tau-P301L neurons).

[0288] method Neuronal treatment and tau protein analysis. NPCs were plated at 75,000 cells / cm on 6-well POL plates with DMEM / F12-B27 medium for differentiation. 2Neurons were plated at an average density of 1000 x g. At 8 weeks, neurons were treated with compound 1 alone, at doses ranging from 1 nM to 10 μM, or in addition to a low dose of rotenone (0.1 μM or 0.5 μM) for 24 h. After incubation, neurons were washed, collected in PBS (Corning) and pelleted at 3000 x g. Cell pellets were resuspended and lysed with SDS sample loading buffer (NEB) in 5x pellet volume, incubated at room temperature for 15 min and boiled for 15 min. Tau protein analysis by Western blot followed a previously developed assay (DOI:10.1038 / s41467-020-16984-1; DOI:10.7554 / eLife.45457; DOI:10.1016 / j.stemcr.2016.08.001). Prior to analysis, lysates were spun down and then loaded onto SDS-PAGE gels. Electrophoresis was performed using a Novex NuPAGE SDS-PAGE gel system (Invitrogen). Proteins were transferred from the gel to PVDF membranes (EMD Millipore) using standard procedures. Membranes were blocked in 5% (w / v) BSA (Sigma) in Tris-buffered saline with Tween-20 (TBST, Boston Bio-Products) and incubated overnight with primary antibodies (below) at 4°C, followed by incubation with the corresponding HRP-conjugated secondary antibodies at 1:4000 dilution (Cell Signaling Technology). Blots were developed using SuperSignal West Pico Chemiluminescent Substrate (ThermoFisher) according to the manufacturer's instructions, exposed to autoradiography film (LabScientific by ThermoFischer), and scanned with an Epson Perfection V800 photoscanner. Densitometry of protein bands, i.e., the pixel average intensity in arbitrary units (au) of each protein band on the X-ray film scan, was measured with the Adobe Photoshop 2021 histogram function and normalized to the respective intensity of the internal control β-actin band (calculation in Microsoft Excel).For compound treatments, the intensity of the bands for each condition was then normalized to DMSO. Graphs were prepared in GraphPad Prism 9.

[0289] Antibodies used: total tau tau5 (Invitrogen catalog no. AHB0042), P-tau S396 (Invitrogen / Thermo catalog no. 44752G), P-tau AT8 (Thermo Scientific catalog no. MN1020), and β-actin (Sigma catalog no. A1978).

[0290] result As shown in Figure 11A (vehicle lane), Tau-P301L neurons have significant oligomer and phosphorylated tau protein load. As shown in Figures 11A and 11B, treatment with Compound 1 reduces the pathological forms of tau protein (P-tau S396; P-tau AT8) in Tau-P301L neurons. In addition, as shown in Figures 11C-11F, Compound 1 reduced pathological tau protein levels when neurons were independently stressed with low concentrations of rotenone. Figure 11G shows the effect of rotenone alone on tau protein levels.

[0291] These results demonstrate that Compound 1 is useful in methods for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of tauopathy in subjects in need thereof.

[0292] Example 3 - Use of Compound 1 in a method for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a human subject This example demonstrates the use of an effective amount of Compound 1 in a subject in need of treatment, prevention, amelioration, inhibition, and / or delay of the onset of a tauopathy, where the subject has been diagnosed with, is at risk of developing, or is suspected of having a tauopathy.

[0293] method Subjects suspected of having or diagnosed with a tauopathy are administered Compound 1 (e.g., 0.5-5.0 mg / kg / day) via any suitable route of administration (e.g., subcutaneous, intravenous, etc.) for any suitable period of time. Subjects are evaluated periodically (e.g., weekly, biweekly, monthly, monthly, etc.) for the presence and / or severity of signs and symptoms of tauopathy, including, but not limited to, frontotemporal dementia, corticobasal syndrome, Richardson's syndrome, parkinsonism, pure dyskinesia with freezing of gait, and motor neuron symptoms or cerebellar ataxia. Treatment is maintained at least until one or more signs or symptoms of tauopathy are improved or eliminated.

[0294] result Subjects suspected of or diagnosed as having a tauopathy and receiving a therapeutically effective amount of Compound 1 are predicted to show a reduction in severity or elimination of one or more signs or symptoms of the tauopathy.

[0295] Thus, these results would demonstrate that Compound 1 is useful in methods for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in subjects suspected of having a tauopathy, subjects at risk of developing a tauopathy, or subjects diagnosed with a tauopathy.

[0296] Example 4 - Effect of Compound 1 in FTD neuron model and mouse tauopathy model This example will demonstrate the effects of Compound 1 as assessed by various assays in FTD neuron models and mouse tauopathy models.

[0297] FTD neuron model and mouse tauopathy model This experiment uses an FTD patient iPSC-derived cell line (e.g., MGH2046-RC1) that expresses tau-P301L.

[0298] Neurons are allowed to differentiate for 8 weeks, a pre-determined time point to reveal mutant tau-specific phenotypes, specifically tau-mediated toxicity, at which point neurons are treated with Compound 1 and the intended assay(s) described below are performed. Brain tissue samples taken from PS19 mice expressing full-length human tau-P301S (1N4R isoform) under the control of the mouse prion (Prnp) promoter are analyzed.

[0299] Compound treatment phenotypic assays Assay 1: Examine cardiolipin (CL) levels in FTD neurons from human and mouse models. This assay determines whether FTD (Tau-P301L) patient iPSC-derived neurons show altered levels of cardiolipin (CL) compared to control (Tau-WT) neurons, as previously described in the FTD clinical biomarker study (Angelique Camilleri et al. 2020 Biomembranes). Implement a cardiolipin (CL) ELISA assay (antibody catalogue no. ABIN6954370), as well as protocols for enrichment and lysis of neuronal mitochondrial fractions. In parallel, measure CL levels in brain tissue isolated from the Tau-P301S mouse tauopathy model.

[0300] Assay 2: Identify mitochondrial stressors that reveal tau or other FTD-associated toxicity that can be rescued by Compound 1. This assay evaluates mitochondrial stressors (e.g., rotenone, paraquat, hydrogen peroxide, hydroquinone or BSO / buthionine sulfoximine) and their exacerbation of mutant tau-mediated neurotoxicity.

[0301] Eight week differentiated neurons are treated overnight (18 hours) with stressors (minimum of three doses). Stress effects are measured by: ● 2.1.Changes in CL levels (ELISA); ●2.2. Changes in neuronal viability (vulnerability to stress assay using Alamar Blue HS, already implemented) ● 2.3. Changes in mitochondrial number, morphology and localization by microscopic imaging and use of mitochondrial specific dyes such as mitoTracker, mitoView, and / or JC1 (a voltage-dependent mitochondrial dye).

[0302] Assay 3: Testing effects of Compound 1 treatment on FTD neuronal CL levels. 8 week differentiated tau-P301L neurons are treated with Compound 1 at dose range 1 nM-10 µM for 24 h ± mitostressors from Assay 2. • 3.1. Measure compound 1 concentration effects on CL levels in FTD neurons using a CL ELISA assay. • 3.2. Utilize the most optimized Mitochondrial dye from Assay 2 for compound 1-induced microscopic image alteration / rescue.

[0303] Assay 4: Examining compound 1 changes in mitochondrial homeostasis as a readout for mode of action. 8-week differentiated tau-P301L neurons are treated with compound 1 at doses that showed phenotypic effects / rescue (24 h) in assays 1-2 and changes in mitochondrial metabolic state are investigated by implementing commercially available assays that measure changes in glycolytic pathway activity, oxygen consumption and ATP levels.

[0304] Equivalent The present technology is not limited with respect to the specific embodiments described in this application, but is intended as a single illustration of each aspect of the technology. As will be apparent to those skilled in the art, many modifications and variations of the present technology can be made without departing from its spirit and scope. In addition to those enumerated herein, functionally equivalent methods and devices within the scope of the present technology will be apparent to those skilled in the art from the foregoing description. Such modifications and variations are intended to fall within the scope of the appended embodiments. It should be understood that the present technology is not limited to specific methods, reagents, compound compositions, or biological systems, which, of course, may vary. It should also be understood that the terminology used herein is for the purpose of describing specific embodiments only, and is not intended to be limiting.

[0305] Additionally, where features or aspects of the disclosure are described in terms of a Markush group, those skilled in the art will recognize that the disclosure is also thereby described in terms of any individual members or subgroups of members of the Markush group.

[0306] As would be understood by one of ordinary skill in the art, for any or all purposes, especially in terms of providing a written description, all ranges disclosed herein also encompass any and all possible subranges and combinations of those subranges. Any recited range can be readily recognized as fully descriptive and allowing for the same range to be broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, and upper third, etc. Also, as would be understood by one of ordinary skill in the art, all language such as "up to," "at least," "greater than," "less than," etc. refers to a range that includes the recited numbers and can then be broken down into the subranges described above. Finally, as would be understood by one of ordinary skill in the art, a range includes each individual member. Thus, for example, a group having 1-3 cells refers to a group having 1, 2, or 3 cells. Similarly, a group having 1-5 cells refers to a group having 1, 2, 3, 4, or 5 cells.

[0307] All patents, patent applications, provisional applications, and publications mentioned or cited in this specification are incorporated by reference in their entirety, including all figures and tables, to the extent they do not contradict the explicit teachings of this specification.

[0308] Other embodiments are within the scope of the following claims.

Claims

1. 1. A pharmaceutical composition for use in a method for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof, comprising: the pharmaceutical composition comprises a therapeutically effective amount of a small molecule peptidomimetic, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof; The method comprises administering to the subject a therapeutically effective amount of a small molecule peptidomimetic, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

2. 2. The pharmaceutical composition of claim 1, wherein the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

3. 3. The pharmaceutical composition of claim 1 or 2, wherein administration of the small molecule peptidomimetic reduces tau species levels and / or reduces toxicity associated with cellular tau accumulation.

4. 3. The pharmaceutical composition of claim 1 or 2, wherein administration of the small molecule peptidomimetic reduces cellular oxidative stress caused by cellular accumulation of tau protein.

5. 10. The pharmaceutical composition of claim 1, wherein the subject has been diagnosed with Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, global gliotauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia.

6. 2. The pharmaceutical composition of claim 1, wherein the subject has been diagnosed with a primary age-related tauopathy.

7. 7. The pharmaceutical composition of claim 6, wherein the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tauastrogliopathy.

8. The pharmaceutical composition of claim 1 , wherein the peptidomimetic is administered daily for two weeks or more.

9. 10. The pharmaceutical composition of claim 1, wherein the peptidomimetic is administered daily for 12 weeks or more, 24 weeks or more, 48 weeks or more, 1 year or more, 2 years or more, or 5 years or more.

10. 10. The pharmaceutical composition of claim 1, wherein the peptidomimetic is administered immediately after diagnosis for the remainder of the subject's life, or until administration of the peptidomimetic is no longer effective.

11. The pharmaceutical composition of claim 1 , wherein the subject is a mammal.

12. 12. The pharmaceutical composition of claim 11, wherein the mammalian subject is a human.

13. The pharmaceutical composition of claim 1 , wherein the peptidomimetic is administered orally.

14. The pharmaceutical composition of claim 1 , wherein the peptidomimetic is administered subcutaneously.

15. 10. The pharmaceutical composition of claim 1, wherein the peptidomimetic is administered topically, intranasally, systemically, intravenously, intraperitoneally, intradermally, intraocularly, ophthalmologically, intrathecally, intracerebroventricularly, iontophoretically, transmucosally, intravitreally, or intramuscularly.

16. The pharmaceutical composition of claim 1, wherein the method further comprises administering an additional treatment to the subject separately, sequentially, or simultaneously.

17. 17. The pharmaceutical composition of claim 16, wherein the additional therapy comprises administration of a therapeutic agent or multiple therapeutic agents.

18. 18. The pharmaceutical composition of claim 17, wherein the therapeutic agent is a small molecule selected from the group consisting of a modulator of tau phosphorylation, a modulator of tau acylation, a histone deacetylase (HDAC) inhibitor, a modulator / inhibitor of tau glycosylation (e.g., an O-GlcNAcase inhibitor), a modulator of tau cleavage (e.g., a capsase inhibitor), a tau aggregation inhibitor, a proteasome stimulator, a USP14 inhibitor, a phosphodiesterase inhibitor, an autophagy activator, a chaperone modulator, a co-chaperone modulator, and a tau-directed multi-target specific ligand.

19. 19. The pharmaceutical composition of claim 18, wherein the combination of the peptidomimetic and the additional therapeutic agent has a synergistic effect in the treatment of the tauopathy.

20. 2. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable salt comprises a tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, trifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate salt.

21. 10. The pharmaceutical composition of claim 1, wherein the peptidomimetic is formulated as a Tris-HCl salt, a Bis-HCl salt, or a Mono-HCl salt.

22. Use of a composition in the preparation of a medicament for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof, said composition comprising a therapeutically effective amount of a small molecule peptidomimetic, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

23. 23. The use of claim 22, wherein the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

24. 24. The use of claim 22 or 23, wherein the use of the composition reduces tau species levels and / or reduces toxicity associated with cellular tau accumulation.

25. 24. The use of claim 22 or 23, wherein the use of the composition reduces cellular oxidative stress caused by cellular accumulation of tau protein.

26. 23. The use of claim 22, wherein the subject has been diagnosed with Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, global gliotauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia.

27. 23. The use of claim 22, wherein the subject has been diagnosed with a primary age-related tauopathy.

28. 28. The use of claim 27, wherein the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tauastrogliopathy.

29. 23. The use of claim 22, wherein the composition / medicament is administered daily for two weeks or more.

30. 23. The use of claim 22, wherein the composition / medicament is administered daily for 12 weeks or more, 24 weeks or more, 48 weeks or more, 1 year or more, 2 years or more, or 5 years or more.

31. 23. The use of claim 22, wherein the composition / medicament is administered immediately after diagnosis for the remainder of the subject's life, or until administration of the composition is no longer effective.

32. 23. The use of claim 22, wherein the subject is a mammal.

33. 33. The use of claim 32, wherein the mammalian subject is a human.

34. 23. The use of claim 22, wherein the composition / medicament is formulated for oral administration.

35. 23. The use of claim 22, wherein the composition / medicament is formulated for subcutaneous administration.

36. 23. The use of claim 22, wherein the composition / medicament is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intracerebroventricular, iontophoretic, transmucosal, intravitreal, or intramuscular administration.

37. 23. The use according to claim 22, wherein the composition / medicament is intended to be used separately, sequentially or simultaneously with an additional treatment.

38. 38. The use of claim 37, wherein the additional treatment further comprises the use of a therapeutic agent or agents.

39. 39. The use of claim 38, wherein the therapeutic agent is selected from the group consisting of modulators of tau phosphorylation, modulators of tau acylation, histone deacetylase (HDAC) inhibitors, modulators / inhibitors of tau glycosylation (e.g., O-GlcNAcase inhibitors), modulators of tau cleavage (e.g., capsase inhibitors), tau aggregation inhibitors, proteasome stimulators, USP14 inhibitors, phosphodiesterase inhibitors, autophagy activators, chaperone modulators, co-chaperone modulators, and tau-directed multi-target specific ligands.

40. 40. The use of claim 39, wherein the combination of the composition / medication and the additional treatment / therapeutic agent has a synergistic effect in the treatment of the tauopathy.

41. 23. The use of claim 22, wherein the small molecule peptidomimetic used in formulating the composition / medicament is a pharmaceutically acceptable salt selected from the group consisting of tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, trifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, and tritosylate.

42. 23. The use of claim 22, wherein the peptidomimetic used in formulating the composition / medicament is a Tris-HCl salt, a Bis-HCl salt, or a Mono-HCl salt.

43. Use of a small molecule peptidomimetic, or a composition comprising a small molecule peptidomimetic, in the preparation of a medicament for treating, preventing, ameliorating, inhibiting, and / or delaying the onset of a tauopathy in a subject in need thereof.

44. 44. The use of claim 43, wherein the peptidomimetic is (R)-2-amino-N-((S)-1-(((S)-5-amino-1-(3-benzyl-1,2,4-oxadiazol-5-yl)pentyl)amino)-3-(4-hydroxy-2,6-dimethylphenyl)-1-oxopropan-2-yl)-5-guanidinopentanamide, or a pharmaceutically acceptable salt, stereoisomer, tautomer, hydrate, and / or solvate thereof.

45. 45. The use of claim 43 or 44, wherein the use of the agent reduces tau species levels and / or reduces toxicity associated with cellular tau accumulation.

46. 45. The use of claim 43 or 44, wherein the use of the medicament reduces cellular oxidative stress caused by cellular accumulation of tau protein.

47. 44. The use of claim 43, wherein the subject has been diagnosed with Alzheimer's disease, Pick's disease, corticobasal degeneration, progressive supranuclear palsy, global glial tauopathy, argyrophilic grain disease, familial British dementia, or familial Danish dementia.

48. 44. The use of claim 43, wherein the subject has been diagnosed with a primary age-related tauopathy.

49. 49. The use of claim 48, wherein the primary age-related tauopathy is selected from the group consisting of neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), and age-related tauastrogliopathy.

50. 44. The use of claim 43, wherein the agent is administered daily for two weeks or more.

51. 44. The use of claim 43, wherein the agent is administered daily for 12 weeks or more, 24 weeks or more, 48 weeks or more, 1 year or more, 2 years or more, or 5 years or more.

52. 44. The use of claim 43, wherein the agent is administered immediately after diagnosis for the remainder of the subject's life, or until administration of the peptidomimetic is no longer effective.

53. 44. The use of claim 43, wherein the subject is a mammal.

54. 54. The use of claim 53, wherein the mammalian subject is a human.

55. 44. The use of claim 43, wherein the medicament is formulated for oral administration.

56. 44. The use of claim 43, wherein the medicament is formulated for subcutaneous administration.

57. 44. The use of claim 43, wherein the medicament is formulated for topical, intranasal, systemic, intravenous, intraperitoneal, intradermal, intraocular, ophthalmic, intrathecal, intracerebroventricular, iontophoretic, transmucosal, intravitreal, or intramuscular administration.

58. 44. The use of claim 43, wherein the pharmaceutically acceptable salt comprises a tartrate, fumarate, monoacetate, bisacetate, triacetate, monotrifluoroacetate, bistrifluoroacetate, trifluoroacetate, monohydrochloride, bishydrochloride, trihydrochloride, monotosylate, bistosylate, or tritosylate salt.

59. 44. The use of claim 43, wherein the peptidomimetic is formulated as a Tris-HCl salt, a Bis-HCl salt, or a Mono-HCl salt.

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