WO2019074898A1

WO2019074898A1 - Disaggregation of alpha-synuclein with small molecules

Info

Publication number: WO2019074898A1
Application number: PCT/US2018/054961
Authority: WO
Inventors: Claude Nicolau; Jean-Marie Lehn; Youssef ATOINI; Renald THINARD
Original assignee: Alsatech Inc
Current assignee: Alsatech Inc
Priority date: 2017-10-09
Filing date: 2018-10-09
Publication date: 2019-04-18
Anticipated expiration: 2020-04-09

Abstract

Uses of pyridoxal phosphate, emoxypine, or methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound in the treatment or prevention of, inter alia, Parkinson Disease are described.

Description

DISAGGREGATION OF ALPHA-SYNUCLEIN WITH SMALL MOLECULES

FIELD

The present invention relates, in part, to treatments of synucleinopathies.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. Provisional Patent Application No. 62/569,830, filed on October 9, 2017, the entire contents of which are herein incorporated by reference.

DESCRIPTION OF THE TEXT FILE SUBMITTED ELECTRONICALLY

The contents of the text file submitted electronically herewith are incorporated herein by reference in their entirety: A computer readable format copy of the Sequence Listing (filename: ALS-005PC_106985-5005_Sequence Listing_ST25; date recorded: Oct 3, 2018; file size: 1.70 KB).

BACKGROUND

Parkinsonism or Parkinsonian syndromes are a group of progressive, neurodegenerative disorders that can significantly impair one's quality of life. Notable features of these diseases are tremor at rest, rigidity, bradykinesia and postural instability. Parkinson's disease afflicts 4% of the population over 80 years old.

The pathophysiology of Parkinson's disease is characterized, in part, by a synucleinopathy characterized by the abnormal accumulation of alpha-synuclein protein into inclusions called Lewy bodies in the brain. The distribution of the Lewy bodies throughout the brain varies from one individual to another but is often directly associated with the expression and degree of the clinical symptoms.

As no biological test is available, diagnosis of Parkinson's disease is mainly based on observation of clinical symptoms. Postmortem confirmation is required for a definitive diagnosis. The most widely used treatment, especially at earlier stages, is the dopamine precursor, levodopa (L-DOPA). However, most of the drug is metabolized before to reach the blood brain barrier (BBB), causing a variety of side effects, including gastrointestinal effects (such as anorexia, nausea or vomiting), dyskinesia and psychiatric symptoms.

Parkinson's disease remains an incurable disease and no effective disease-modifying treatment has been discovered yet. Therefore, there remains a need for more effective therapies for diseases such as Parkinson's disease.

SUMMARY

The present invention provides, in one aspect, a method for treating or preventing a synucleinopathy, comprising administering an effective amount of a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound) to a subject in need thereof, wherein the method comprises disaggregation of a-synuclein. In various embodiments, the synucleinopathy is a condition characterized by Lewy bodies, e.g., Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.

In various embodiments, the compound of formula (I) is

wherein:

R⁸ is null, H, (C1-C6)alkyl, (C1-C6) alkoxy, (C3-C7)cycloalkyl, -C(=0)OR¹⁴, -C(0)N(R¹⁴)₂, -S(=0)₂OR¹⁴, (C6-C10)aryl, or (C3-C10)heteroaryl, each alkyl, alkoxy, cycloalkyi, aryl and heteroaryl optionally substituted with one or more groups selected from hydroxyl, halo, and (C1-C6)alkyl;

R⁹ is null, H, -OR¹⁴, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, -C(=0)OR¹⁴, -C(0)N(R¹ )₂, -S(=0)₂OR¹⁴, - (CH₂)_mP(=0)(OR¹⁴)₂, (C6-C10)aryl, or (C3-C10)heteroaryl, each alkyl, alkoxy, cycloalkyi, aryl and heteroaryl optionally substituted with one or more groups selected from hydroxyl, halo, and (C1-C6)alkyl;

R¹⁰ is H, -OR¹⁴, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, -C(=0)OR¹⁴, -C(=0)R¹⁴, or -C(0)N(R¹⁴)₂;

R¹¹ is H, -OR¹⁴, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, -C(=0)OR¹⁴, -C(=0)R¹⁴, or -C(0)N(R¹⁴)₂;

R¹² is null, H, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, -C(=0)OR¹⁴, -C(0)N(R¹ )₂, -S(=0)₂OR¹⁴, (C6-C10)aryl, or (C3-C10)heteroaryl, each alkyl, alkoxy, cycloalkyi, aryl and heteroaryl optionally substituted with one or more groups selected from hydroxyl, halo, and (C1-C6)alkyl;

R¹³ is null, H, (C1-C6)alkyl, (C1-C6)alkoxy, (C3-C7)cycloalkyl, -C(=0)OR¹⁴, -C(0)N(R¹ )₂, -S(=0)₂OR¹⁴, (C6-C10)aryl, or (C3-C10)heteroaryl, each alkyl, alkoxy, cycloalkyi, aryl and heteroaryl optionally substituted with one or more groups selected from hydroxyl, halo, and (C1-C6)alkyl;

each R¹⁴ is independently H or (C1-C6)alkyl;

m is 1 , 2, 3, 4, or 5; Xi, X2, X¾ X4, each independently is C or N;

or a salt, hydrate, or solvate thereof.

In various embodiments, R⁸ is H, (C1-C6)alkyl, or -C(=0)OR¹⁴; R⁹ is H, -OR¹⁴, or

R¹⁰ is H, - C(=0)R¹⁴, or (C1-C6)alkyl; R¹¹ is H, -OR¹⁴, or

R¹² is H, (C1-C6)alkyl, or -C(=0)OR¹⁴; R¹³ is null; each R¹⁴ is independently H or (C1-C6)alkyl; m is 1 or 2; Xi is C; X₂ is N; X₃ is C; and X₄ is C.

In various embodiments, R⁸ is (C1-C6)alkyl or -C(=0)OR¹⁴; R⁹ is H, -OR¹⁴, or -(CH₂)_mP(=0)(OR¹⁴)₂; R¹⁰ is H, - C(=0)R¹⁴, -C(=0)OR¹⁴, or (C1-C6)alkyl; R¹¹ is H, -OR¹⁴, or -(CH₂)_mP(=0)(OR¹ )₂; R¹² is H, (C1-C6)alkyl, or - C(=0)OR¹⁴; R¹³ is null; each R¹⁴ is independently H or (C1-C6)alkyl; m is 1 or 2; Xi is C; X₂ is N; X₃ is C; and X₄ is C.

In various embodiments, R⁸ is -S(=0)₂OR¹⁴; R⁹ is H, -OR¹⁴, or -(CH₂)_mP(=0)(OR¹ )₂; R¹⁰ is H, -C(=0)R¹⁴, - C(=0)OR¹⁴, or (C1-C6)alkyl; R¹¹ is H, -OR¹⁴, or -(CH₂)_mP(=0)(OR¹ )₂; R¹² is H, (C1-C6)alkyl, or -C(=0)OR¹⁴; R¹³ is H; each R¹⁴ is independently H or (C1-C6)alkyl; m is 1 or 2; Xi is C; X₂ is C; X3 is C; and X4 is C.

In various embodiments, the compound is

In various embodiments, the compound is

In various embodiments, the compound is

In various embodiments, the compound is

In various embodiments, the compound of formula (la) is:

wherein: R¹ is H or substituted or unsubstituted (C1-C6)alkyl or substituted or unsubstituted (C1-C8)heteroalkyl; R² is H or OR⁵ or substituted or unsubstituted (C1-C6)alkyl, wherein R⁵ is H or substituted or unsubstituted (C1-C6)alkyl; A is CH or N or CR³ or CR⁴; B is CH or N or CR³ or CR⁴;

C is CH or N or CR³ or CR⁴; D is CH or N or CR³ or CR⁴; R³ is substituted or unsubstituted (C1-C6)alkyl or substituted or unsubstituted (C1-C8)heteroalkyl or -S0₂(OR⁶) or -OP(0)(OR⁶)(OR⁷) wherein R⁶ is H or substituted or unsubstituted (C1-C6)alkyl and R⁷ is H or substituted or unsubstituted (C1-C6)alkyl; R⁴ is substituted or unsubstituted (C1-C6)alkyl; with the proviso that no more than one member selected from the group consisting of A, B, C, and D is CR³; with the proviso that no more than one member selected from the group consisting of A, B, C, and D is CR⁴; with the proviso that no more than two members selected from the group consisting of A, B, C, and D are N or a salt, hydrate, or solvate thereof. In various embodiments, R¹ is H. In various embodiments, R² is H or OH. In various embodiments, Formula (I) is with the proviso that A, B, C, and D are not N; or with the proviso that one member selected from the group consisting of A, B, C, and D is N.

In various embodiments, A is CH; B is CR³; C is CH; and D is CH; or A is CR³; B is CH; C is N; and D is CR⁴.

In various embodiments, R³ is -S0₂(OR⁶) or alkyl substituted with -OP(0)(OR⁶)(OR⁷).

In various embodiments, R³ is -SO2OH.

In various embodiments, R³ is alkyl substituted with -OP(0)(OH)(OH).

In various embodiments, R³ is -CH₂OP(0)(OR⁶)(OR⁷).

In various embodiments, R³ is -CH₂OP(0)(OH)(OH).

In various embodiments, R⁴ is methyl or ethyl or propyl or isopropyl.

In various embodiments, R⁴ is methyl.

In various embodiments, the compound is

In various embodiments, the compound is

In various embodiments, the compound of formula (lb) is

(lb) wherein:

R¹⁵ is H, (C1-C6)alkyl, -C(=0)OR¹⁴, or -C(0)N(R¹⁴)₂;

R¹⁷ is H, -OR¹⁴, -C(=0)OR¹⁴, -C(=0)R¹⁴, or -C(0)N(R¹⁴)₂;

R¹⁸ is H, -OR¹⁴, -C(=0)OR¹⁴, -C(=0)R¹⁴, or -C(0)N(R¹⁴)₂;

R¹⁹ is H or (C1-C6)alkyl;

each R¹⁴ is independently H or (C1-C6)alkyl;

m is 1 , 2, 3, 4, or 5;

or a salt, hydrate, or solvate thereof.

In various embodiments, R¹⁵ is H, (C1-C6)alkyl, or -C(=0)OR¹⁴; R¹⁶ is H, -OR¹⁴, or -(CH₂)_mP(=0)(OR¹⁴)₂; R¹⁷ is H, - C(=0)R¹⁴, or -C(=0)OR¹⁴; R¹⁸ is H or -OR¹⁴; R¹⁹ is H or (C1-C6)alkyl; each R¹⁴ is independently H or (C1-C6)alkyl; and m is 1 or 2.

In various embodiments, R¹⁵ is (C1-C6)alkyl or -C(=0)OR¹⁴; R¹⁶ is H, -OR¹⁴, or -(CH₂)_mP(=0)(OR¹⁴)₂; R¹⁷ is H, - C(=0)R¹⁴, or -C(=0)OR¹⁴; R¹⁸ is H or -OR¹⁴; R¹⁹ is H or (C1-C6)alkyl; each R¹⁴ is independently H or (C1-C6)alkyl; and m is 1.

In various embodiments, the compound is

In various embodiments, the compound is

In various embodiments, the method treats or prevents Parkinson's disease, selected from Idiopathic Parkinson's disease, Vascular parkinsonism, drug-induced parkinsonism, dementia with Lewy bodies, Inherited Parkinson's, Juvenile Parkinson's disease.

In various embodiments, the method provides about a 20%, or about a 30%, or about a 40%, or about a 50%, or about a 60%, or about a 70%, or about a 80%, or about a 90%, or about a 95%, or about a 100% reduction in a- synuclein aggregation relative to an untreated subject.

In various embodiments, the method provides does not substantially dissolve aggregates of beta-amyloid.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 A-K shows spectrofluorometry results. FIG 1 A shows a first assay results for emission intensity 1 min. FIG. 1 B shows a first assay results for emission intensity 30min. FIG. 1C shows a first assay results for emission intensity 1 h. FIG 1 D shows a first assay results for emission intensity 24h. FIG. 1 E shows a first assay shows results for emission intensity 72 hr. FIG. 1 F is a second assay showing results for emission intensity 1 min. FIG. 1G shows a second assay results for emission intensity 30min. FIG. 1 H shows a second assay results for emission intensity 1 h. FIG 11 shows a second assay results for emission intensity 24hr. FIG. 1 J is a second assay showing results for emission intensity 48h. FIG. 1 K is a second assay showing results for emission intensity 72h.

FIG. 2A-C shows a tabulation of the spectrofluorometry data of FIG. 1. FIG. 2A is a bar graph showing a first pyridoxal phosphate (PLP) disaggregation assay. FIG. 2B is a bar graph showing a second pyridoxal phosphate disaggregation assay and FIG. 2C is a bar graph showing the percentage of a-synuclein aggregates. FIG. 3A-H shows scanning electron microscopy results. FIGs. 3A, 3C, 3E, and 3G show a-synuclein aggregates and FIGs. 3B, 3D, 3F, and 3H show a-synuclein aggregates with PLP.

FIG. 4 is an image of a schematic representation showing the process for the "preventive measure" (top) and for the curative measure (bottom).

FIG. 5 is a bar graph showing the emission intensity of ThT at 482 nm (Aexc= 450 nm), in the presence of a- synuclein amyloids fibrils, with and without emoxypine (r 200), (dark-shaded trace and light-shaded trace, respectively) from 1 minute to 6 days (144 hours).

FIG. 6 is a bar graph showing the percentage of α-synuclein amyloid fibrils left after addition of emoxypine with r 200, from 1 minute to 6 days (144 hours). The light-shaded bar represents a sample without emoxypine, i.e. with 100% of aggregates left.

FIG. 7A-D are scanning electron microscope (SEM) images of: aggregates without emoxypine, scale bar= 100μιη (FIG. 7A); aggregates without emoxypine, scale bar= 500μιη (FIG. 7B); aggregates with emoxypine (r 200), scale bar= 100μιη (FIG. 7C); aggregates with emoxypine (r 200), scale bar= 500μιη (FIG. 7D).

FIG. 8 is a bar graph showing the emission intensity of ThT at 482 nm (Aexc= 450 nm), in the presence of a- synuclein amyloids fibrils, with and without emoxypine (r 100), from 1 minute to 6 days (144 hours). For each time point (x-axis), the far left bar is "Control ThT" sample, the next bar is the "Control Tht + Emo" sample, the next bar is the "Aggregates + ThT" sample (without emoxypine), and the far right bar is the "Aggregates + ThT+Emo" sample (with emoxypine).

FIG. 9 is a bar graph showing the percentage of α-synuclein amyloid fibrils left after addition of emoxypine (r 100). The light-shaded bar (far left) represents a sample without emoxypine, i.e. with 100% of aggregates left.

FIG. 10A-B are SEM images of: aggregates with emoxypine (r 100), scale bar= 100 μιη (FIG. 10A); aggregates with emoxypine (r 100), scale bar= 400 μπη (FIG. 10B).

FIG. 11 is a bar graph showing the emission intensity of ThT, in the presence of α-synuclein amyloids fibrils, with and without emoxypine (r 50), from 1 minute to 6 days (144 hours). For each time point (x-axis), the far left bar is "Control ThT" sample, the next bar is the "Control ThT + Emo" sample, the next bar is the "Aggregates + ThT" sample (without emoxypine), and the far right bar is the "Aggregates + ThT+Emo" sample (with emoxypine).

FIG. 12 is a bar graph showing the percentage of α-synuclein amyloid fibrils left after addition of emoxypine (r 50). The light-shaded bar (far left) represents a sample without emoxypine, i.e. with 100% of aggregates left.

FIG. 13A-B are SEM images of: aggregates with emoxypine (r 50), scale bar= 100 μιη (FIG. 13A); aggregates with emoxypine (r 50), scale bar= 500 μπη (FIG. 13B). FIG. 14 is a bar graph showing the emission intensity of ThT, in the presence of a-synuclein amyloids fibrils, with and without emoxypine (r 20), from 1 minute to 6 days (144 hours). For each time point (x-axis), the far left bar is "Control ThT" sample, the next bar is the "Control ThT + Emo" sample, the next bar is the "Aggregates + ThT" sample (without emoxypine), and the far right bar is the "Aggregates + ThT+Emo" sample (with emoxypine).

FIG. 15 is a bar graph showing the percentage of a-synuclein amyloid fibrils left after addition of emoxypine (r 20). The light-shaded bar (far left) represents a sample without emoxypine, i.e. with 100% of aggregates left.

FIG. 16 is a bar graph showing the emission intensity of ThT, in the presence of α-synuclein amyloids fibrils, with and without emoxypine using the preventive method and at different concentrations of emoxypine. The light-shaded bar (far left) represents a sample without emoxypine.

FIG. 17 is a bar graph showing the percentage of α-synuclein amyloid fibrils formed for the curative method using different emoxypine concentration. The light-shaded bar (far left) represents a sample without emoxypine, i.e. with 100% of aggregates left.

FIG. 18A-F are images showing a schematic representation of peptide bond and multivalent derivatives of MHP- ester: FIG. 18A and FIG. 18B show single peptide bond linkage; FIG. 18C and FIG. 18D show divalent peptide bond derivatives; FIG. 18E and FIG. 18F show multivalent peptide bond derivatives. FIG. 18A, FIG. 18C, and FIG. 18E are schematic representations of the systems.

FIG. 19 is a bar graph showing the emission intensity of ThT at 482 nm (Aexc= 450 nm), in the presence of a- synuclein amyloids fibrils, with and without MHP-ester (r 200), from 1 minute to 6 days (144 hours). For each time point (x-axis), the far left bar is "Control ThT" sample, the next bar is the "Control ThT + MHP ester" sample, the next bar is the "Aggregates + MHP ester" sample, and the far right bar is the "Aggregates + ThT+ MHP ester" sample.

FIG. 20 is a bar graph showing the percentage of α-synuclein amyloid fibrils left after addition of MHP-ester with r200, from 1 minute to 6 days (144 hours). The dark-shaded bar (far left) represents a sample without MHP-ester, i.e. with 100% of aggregates left.

FIG. 21A-E are SEM images of samples containing α-synuclein amyloid fibrils and MHP-ester. FIG. 21A, scale-bar= 100 μιτι; FIG. 21 B, scale-bar= 50 μιτι; FIG. 21C, scale-bar= 20 μιτι; FIG. 21 D, scale-bar= 10 μιτι; FIG. 21 E, scale- bar= 100 μιπ

FIG. 22 is a bar graph showing the emission intensity ThT at 482 nm (Aexc= 450 nm), in the presence of TDP-43 amyloids fibrils alone and with lgG37, Fab37 and Irrelevant IgG.

FIG. 23 is a bar graph showing the emission intensity of ThT at 482 nm (Aexc= 450 nm), in the presence of a- synuclein amyloids fibrils alone and with different antibodies, including Fab37 (second from the right bar), the sample of interest. FIG. 24A-C are SEM images of: FIG. 24A, TDP-43 aggregates; FIG. 24B, TDP-43 aggregates with lgG37; FIG. 24C TDP-43 with Irr IgG. Images involving TDP-43 and Fab37 could not be recorded for sample instability reasons.

FIG. 25 are SEM images of a-synuclein aggregates (left image), and a-synuclein aggregates with Fab37 (right image).

DETAILED DESCRIPTION

The present invention is based, in part, on the surprising discovery of a novel activity of pyridoxal phosphate, emoxypine, or methyl 3-hydroxy-6-methyl picolinate (MHP ester), specifically, in dissolving aggregates of alpha- synuclein but not aggregates of beta-amyloid.

In some aspects, the present invention provides a method for treating or preventing a synucleinopathy, comprising administering an effective amount of compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) to a subject in need thereof, wherein the method comprises disaggregation of α-synuclein. In various embodiments, the synucleinopathy is a condition characterized by Lewy bodies, e.g., Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.

Neurodegenerative disorders, such as Parkinson, Huntington and Alzheimer diseases, fronto-temporal lobar degeneration (FTLD) and Amyotrophic Lateral Sclerosis (ALS) are associated with the accumulation of misfolded proteins both inside and outside of neuronal and glial cells in the central nervous system. These misfolded protein aggregates are pathological hallmarks of these diseases. The major component of these aggregates is characteristic for each neurodegenerative disease, e.g., alpha-synuclein for Parkinson.

Accordingly, in various embodiments, the present methods treat or prevent a synucleinopathy, e.g., Parkinson's disease by promoting the dissolution of aggregates of alpha-synuclein or preventing the accumulation of aggregates of alpha-synuclein, e.g., in the brain.

Lewy bodies are the hallmark of Parkinson's disease which is mainly composed of alpha-synuclein. Alpha-synuclein plays a role in the development of rare familial and more common sporadic cases of Parkinson's disease. In familial Parkinson's disease, the expression levels of alpha-synuclein gene is increased or an abnormal form of the protein is found which are toxic to brain cells and result in neuron dysfunction. Alpha-synuclein is the primary structural component of Lewy bodies, suggesting that protein aggregation plays a role in sporadic Parkinson's disease. Alpha-synuclein is abundant in the human brain at the neurons tips in specialized structures called presynaptic terminals. Presynaptic terminals release chemical messengers, neurotransmitters, from synaptic vesicles. The release of neurotransmitters relays signals between neurons and is critical for normal brain function. So, alpha- synuclein is a presynaptic neuronal protein that is thought that its abnormal soluble oligomeric conformations, i.e. protofibrils, are the toxic species that mediate disruption of cellular homeostasis and neuronal death, through effects on various intracellular targets, including synaptic function. Furthermore, secreted alpha-synuclein may exert deleterious effects on neighboring cells, including seeding of aggregation, thus possibly contributing to disease propagation. In various embodiments, the present methods prevent or reduce the seeding of aggregation in a subject.

The human alpha-synuclein protein is made of 140 amino acids and is encoded by the SNCA gene. In some embodiments, the amino acid sequence of human alpha-synuclein is shown by SEQ ID NO.: 1 :

SNCAMDVFMKGLSKAKEGWAAAEKTKQGVAEAAGKTKEGVLYVGSKTKEG WHGVATVAEKTKEQVTNVGGAVVTGVTAVAQKTVEGAGSIAAATGFVKKDQ LGKEGYQDYEPEA.

In various embodiments, the present methods prevent or reduce the formation of Lewy bodies, e.g., in the brain.

Examples of Parkinsonism conditions that are treated or prevented by the present methods include Parkinson's disease, progressive supranuclear palsy, multiple system atrophy, cortical-basal ganglionic degeneration, diffuse Lewy body disease, Parkinson-dementia, X-linked dystonia-parkinsonism, and secondary Parkinsonism (resulting from environmental etiology, e.g., toxins, drugs, post encephalitic, brain tumors, head trauma, normal pressure hydrocephalus).

In various embodiments, the present methods prevent or reduce degeneration of dopaminergic neurons within the substantia nigra. In various embodiments, the present methods prevent or reduce tremor, hypokinesia (e.g., bradykinesia, akinesia, rigidity), postural instability, abnormal gait and swallowing disturbances. Non-motor symptoms include autonomic and neuropsychiatric disturbances such as anosmia, or sleep abnormalities.

As used herein, "treatment" includes the therapy, prevention, prophylaxis, retardation or reduction of symptoms provoked by or of the causes of Parkinsonism, e.g., Parkinson's disease. The term treatment also designates a retardation or delayed onset of tremor, a reduction of pain, a decrease or reduction of bradykinesia, akinesia, rigidity, postural instability, abnormal gait, anosmia, and/or sleep abnormalities, and/or an increase of survival. The term treatment includes in particular the control of disease progression and associated motor and non-motor symptoms. The term treatment, in various embodiments, particularly includes a protection against the toxicity caused by alpha- synuclein, or a reduction or retardation of this toxicity. Unless otherwise stated, the chemical structures depicted herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds where one or more hydrogen atoms is replaced by deuterium or tritium, or wherein one or more carbon atoms is replaced by 13C- or 14C-enriched carbons, are within the scope of this invention. "Alkyl" refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to ten carbon atoms (e.g., (C1 -10)alkyl or C1 -10 alkyl). Whenever it appears herein, a numerical range such as "1 to 10" refers to each integer in the given range - e.g., "1 to 10 carbon atoms" means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the definition is also intended to cover the occurrence of the term "alkyl" where no numerical range is specifically designated. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl isobutyl, tertiary butyl, pentyl, isopentyl, neopentyl, hexyl, septyl, octyl, nonyl and decyl. The alkyl moiety may be attached to the rest of the molecule by a single bond, such as for example, methyl (Me), ethyl (Et), n-propyl (Pr), 1 -methy lethy I (iso-propyl), n-butyl, n-pentyl, 1 , 1 -dimethylethyl (t-butyl) and 3- methylhexyl. Unless stated otherwise specifically in the specification, an alkyl group is optionally substituted by one or more of substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, - ORa, -SRa, -OC(0)-Ra, -N(Ra)2, -C(0)Ra, C(0)ORa, -OC(0)N(Ra)2, -C(0)N(Ra)2, -N(Ra)C(0)ORa, - N(Ra)C(0)Ra, N(Ra)C(0)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2), S(0)tN(Ra)2 (where t is 1 or 2), or P03(Ra)2 where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

The term "alkoxy" or "alkoxyl" refers to the group -O-alkyI or -alkylene-O-alkyl, including from 1 to 8 carbon atoms of a straight, branched, cyclic configuration and combinations thereof attached to the parent structure. Examples include, but are not limited to, methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and -CH2CH2- 0-CH3. "Lower alkoxy" refers to alkoxy groups containing one to six carbons.

The term "aryl" or "Ar" refers to an aromatic radical with six to ten ring atoms (e.g., C₆-C₁₀ aromatic or C₆-C₁₀ aryl) which has at least one ring having a conjugated pi electron system which is carbocyclic (e.g., phenyl, fluorenyl, and naphthyl). Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals. Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in "-yl" by removal of one hydrogen atom from the carbon atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical, e.g., a naphthyl group with two points of attachment is termed naphthylidene. Whenever it appears herein, a numerical range such as "6 to 10" refers to each integer in the given range; e.g., "6 to 10 ring atoms" means that the aryl group may consist of 6 ring atoms, 7 ring atoms, efc., up to and including 10 ring atoms. The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of ring atoms) groups. Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, trifluoromethyl, trifluoromethoxy, nitro, trimethylsilanyl, -OR^a, -SR^a, -OC(0)-R^a, -N(R^a)₂, -C(0)R^a, -C(0)OR^a, - OC(0)N(R^a)₂, -C(0)N(R^a)₂, -N(R^a)C(0)OR^a, -N(R^a)C(0)R^a, -N(R^a)C(0)N(R^a)₂, N(R^a)C(NR^a)N(R^a)₂, -N(R^a)S(0)_tR^a (where t is 1 or 2), -S(0)_tOR^a (where t is 1 or 2), -S(0)_tN(R^a)₂ (where t is 1 or 2), or P0₃(R^a)₂, where each R^a is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Heteroalkyl" includes optionally substituted alkyl radicals and which have one or more skeletal chain atoms selected from an atom other than carbon, e.g., oxygen, nitrogen, sulfur, phosphorus or combinations thereof. A numerical range may be given - e.g., C1-C4 heteroalkyl which refers to the chain length in total, which in this example is 4 atoms long. A heteroalkyl group may be substituted with one or more substituents which independently are: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, -OC(0)-Ra, -N(Ra)2, C(0)Ra, C(0)ORa, -OC(0)N(Ra)2, - C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, N(Ra)C(0)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2), S(0)tN(Ra)2 (where t is 1 or 2), or P03(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

"Halo", "halide", or, "halogen" is intended to mean fluoro, chloro, bromo or iodo.

"Heteroaryl" or "heteroaromatic" or "HetAr" refers to a 5- to 18-membered aromatic radical (e.g., C5-C13 heteroaryl) that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic ring system. Whenever it appears herein, a numerical range such as "5 to 18" refers to each integer in the given range - e.g., "5 to 18 ring atoms" means that the heteroaryl group may consist of 5 ring atoms, 6 ring atoms, efc., up to and including 18 ring atoms. Bivalent radicals derived from univalent heteroaryl radicals whose names end in "-yl" by removal of one hydrogen atom from the atom with the free valence are named by adding "-idene" to the name of the corresponding univalent radical - e.g., a pyridyl group with two points of attachment is a pyridylidene. A N-containing "heteroaromatic" or "heteroaryl" moiety refers to an aromatic group in which at least one of the skeletal atoms of the ring is a nitrogen atom. The polycyclic heteroaryl group may be fused or non-fused. The heteroatom(s) in the heteroaryl radical are optionally oxidized. One or more nitrogen atoms, if present, are optionally quaternized. The heteroaryl may be attached to the rest of the molecule through any atom of the ring(s). Examples of heteroaryls include, but are not limited to, azepinyl, acridinyl, benzimidazolyl, benzindolyl, 1,3-benzodioxolyl, benzofuranyl, benzooxazolyl, benzo[d]thiazolyl, benzothiadiazolyl, benzo[b][1 ,4]dioxepinyl, benzo[b][1 ,4]oxazinyl, 1 ,4-benzodioxanyl, benzonaphthofuranyl, benzoxazolyl, benzodioxolyl, benzodioxinyl, benzoxazolyl, benzopyranyl, benzopyranonyl, benzofuranyl, benzofuranonyl, benzofurazanyl, benzothiazolyl, benzothienyl(benzothiophenyl), benzothieno[3,2-d]pyrimidinyl, benzotriazolyl, benzo[4,6]imidazo[1 ,2-a]pyridinyl, carbazolyl, cinnolinyl, cyclopenta[d]pyrimidinyl, 6,7-dihydro-5H- cyclopenta[4,5]thieno[2,3-d]pyrimidinyl, 5,6-dihydrobenzo[h]quinazolinyl, 5,6-dihydrobenzo[h]cinnolinyl, 6,7-dihydro- 5H-benzo[6J]cyclohepta[1 ,2-c]pyridazinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, furazanyl, furanonyl, furo[3,2- c]pyridinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyrimidinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridazinyl, 5,6,7,8,9, 10-hexahydrocycloocta[d]pyridinyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, indolinyl, isoindolinyl, isoquinolyl, indolizinyl, isoxazolyl, 5,8-methano-5,6J,8-tetrahydroquinazolinyl, naphthyridinyl, 1 ,6- naphthyridinonyl, oxadiazolyl, 2-oxoazepinyl, oxazolyl, oxiranyl, 5,6,6aJ,8,9,10,10a-octahydrobenzo[h]quinazolinyl, 1-phenyl-1 H-pyrrolyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrrolyl, pyrazolyl, pyrazolo[3,4-d]pyrimidinyl, pyridinyl, pyrido[3,2-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, 5,6,7,8- tetrahydroquinazolinyl, 5,6J,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidinyl, 6,7,8,9-tetrahydro-5H- cyclohepta[4,5]thieno[2,3-d]pyrimidinyl, 5,6,7,8-tetrahydropyrido[4,5-c]pyridazinyl, thiazolyl, thiadiazolyl, thiapyranyl, triazolyl, tetrazolyl, triazinyl, thieno[2,3-d]pyrimidinyl, thieno[3,2-d]pyrimidinyl, thieno[2,3-c]pyridinyl, and thiophenyl (i.e. thienyl). Unless stated otherwise specifically in the specification, a heteroaryl moiety is optionally substituted by one or more substituents which are independently: alkyl, heteroalkyl, alkenyl, alkynyl, cycloalkyi, heterocycloalkyl, aryl, arylalkyl, heteroaryl, heteroaryl alkyl, hydroxy, halo, cyano, nitro, oxo, thioxo, trimethylsilanyl, -ORa, -SRa, - OC(0)-Ra, -N(Ra)2, C(0)Ra, C(0)ORa, -OC(0)N(Ra)2, -C(0)N(Ra)2, -N(Ra)C(0)ORa, -N(Ra)C(0)Ra, N(Ra)C(0)N(Ra)2, N(Ra)C(NRa)N(Ra)2, -N(Ra)S(0)tRa (where t is 1 or 2), -S(0)tORa (where t is 1 or 2), S(0)tN(Ra)2 (where t is 1 or 2), or P03(Ra)2, where each Ra is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocycloalkyl, heterocycloalkylalkyl, heteroaryl or heteroarylalkyl.

As used herein, "substituted" means that the referenced group may have attached one or more additional groups, radicals or moieties individually and independently selected from, for example, acyl, alkyl, alkylaryl, cycloalkyi, aralkyl, aryl, carbohydrate, carbonate, heteroaryl, heterocycloalkyl, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, oxo, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, urea, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. The substituents themselves may be substituted, for example, a cycloalkyi substituent may itself have a halide substituent at one or more of its ring carbons. The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.

The efficacy of treating Parkinson's disease using methods and compositions of the present invention may be assessed by various methods. For example, efficacy may be assessed by monitoring and assessing the motor symptoms of the disease, including tremor, bradykinesia, rigidity of limb and muscle tone, postural instability. Additionally, efficacy may be assessed by monitoring for improvements in neuropsychiatric symptoms which include, for example, speech, cognition, mood, behavior, and thought.

In various embodiments, the present methods show an improvement in disease symptoms as measured by the Unified Parkinson's Disease Rating Scale as described in Movement Disorders Vol. 23, No. 15, 2008, pp. 2129— 2170, which is incorporated herein by reference in its entirety.

In various embodiments, the present methods show an improvement in disease symptoms as measured by the MDS- UPDRS Movement Disorders. 22 (1): 41-47, which is incorporated herein by reference in its entirety. In various embodiments, the present methods show improvement in the following scales and subscales: (1) nonmotor experiences of daily living, (2) motor experiences of daily living, (3) motor examination, and (4) motor complications (e.g., each subscale rating is reduced towards normal (e.g., 4 to 0, or 4 to 1 , or 4 to 2, or 4 to 3, or 3 to 0, or 3 to 1 , or 3 to 2, or 2 to 1 , or 2 to 0, or 1 to 0, where 0 = normal, 1 = slight, 2 = mild, 3 = moderate, and 4 = severe).

In various embodiments, the present methods pertain to the use of pyridoxal phosphate or a related compound as shown by Formula I:

Xi, X₂, X¾ X4, R⁸, R⁹, R¹⁰, R¹¹ and R¹² are as defined above.

In various embodiments, the present methods pertain to the use of pyridoxal phosphate or a related compound shown by Formula la:

(la), as defined above. In various embodiments, the present methods pertain to the use of pyridoxal phosphate (PLP, pyridoxal 5'- phosphate, P5P) (CsHioNOsP) or a related compound for the present treatments or preventions.

Pyridoxal phosphate is a coenzyme in a variety of enzymatic reactions. It is the active form of vitamin Ε¾.

In various embodiments, related compounds of the present invention include several forms (vitamers) of vitamin B6. For instance: pyridoxine (PN), pyridoxal (PL), pyridoxal 5'-phosphate (PLP), pyridoxamine (PM), pyridoxamine 5'- phosphate (PMP), 4-pyridoxic acid (PA), and pyritinol.

In various embodiments, related compounds of the present invention include pyridoxal.

In various embodiments, related compounds of the present invention include sulfosalicylic acid.

In various embodiments, the present methods pertain to the use of pyridoxal phosphate or a related compound as shown by Formula lb:

(lb)

R¹⁵, R¹⁶, R¹⁷, R¹⁸, R¹⁹ are as defined above

In various embodiments, the present methods pertain to the use of emoxypine or a related compound for the present treatments or preventions.

In various embodiments, the present methods pertain to the use of methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound for the present treatments or preventions.

In various embodiments, acids and salts of the compounds described herein are provided. In some embodiments, a compound described herein (a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3- hydroxy-6-methyl picolinate (MHP ester) or a related compound)) is an anion. The counterpart species may be a counterion and the combination of a compound described herein with a counterion is an acid or salt. Counter ions of a compound described herein may include, but are not limited to, cationic hydrogen species including protons; monovalent inorganic cations including lithium, sodium, and potassium; divalent inorganic cations including magnesium, calcium, manganese, zinc, copper and iron; polyvalent inorganic cations including iron; quaternary nitrogen species including ammonium, cycloheptyl ammonium, cyclooctyl ammonium, N, N-dimethylcyclohexyl ammonium, and other organic ammonium cations; sulfonium species including triethylsulfonium and other organic sulfonium compounds; organic cations including pyridinium, piperidinium, piperazinium, quinuclidinium, pyrrolium, tripiperazinium, and other organic cations; polymeric cations including oligomers, polymers, peptides, proteins, positively charged ionomers, and other macromolecular species that possess sulfonium, quaternary nitrogen and/or charged organometallic species in pendant groups, chain ends, and/or the backbone of the polymer.

The invention is not limited to pairings that are purely ionic; indeed, it is known in the art that paired ions may evidence some degree of covalent or coordinate bond characteristic between the two components of the pair. The compounds of the invention may comprise a single type of counterion or may contain mixed counterions, and may optionally contain a mixture of anions of which a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound) is one. The compositions may optionally include crown ethers, cryptands, and other species capable of chelating or otherwise complexing the counterions. The compounds of the invention may likewise optionally include acidic macrocycles or other species that are capable of complexing the compounds of the invention through hydrogen bonds or other molecular attractions. In some embodiments, the compounds described herein include derivatives that are modified, i.e., by the covalent attachment of any type of molecule to the compound such that covalent attachment does not prevent the activity of the compound. For example, but not by way of limitation, derivatives include compounds that have been modified by, inter alia, glycosylation, lipidation, acetylation, pegylation, phosphorylation, amidation, derivatization by known protecting/blocking groups, proteolytic cleavage, linkage to a cellular ligand or other protein, efc. Any of numerous chemical modifications can be carried out by known techniques, including, but not limited to specific chemical cleavage, acetylation, or formylation. Additionally, the derivatives can contain one or more non-classical amino acids.

In still other embodiments, the compounds described herein may be modified to add effector moieties such as chemical linkers, detectable moieties such as for example fluorescent dyes, enzymes, substrates, bioluminescent materials, radioactive materials, and chemiluminescent moieties, or functional moieties such as for example streptavidin, avidin, biotin, a cytotoxin, a cytotoxic agent, and a targeting agent.

In yet other embodiments, the present invention provides for the compounds described herein and pharmaceutically acceptable esters, prodrugs, salts, solvates, enantiomers, stereoisomers, active metabolites, co-crystals, and other physiologically functional derivatives thereof.

In an embodiment, the compound described herein is in the form of a pharmaceutically acceptable salt, namely those salts which are suitable for use in contact with the tissues of humans and other animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. The salts can be prepared in situ during the final isolation and purification of the compound, or separately by reacting the free base function with a suitable acid or a free acid functionality with an appropriate alkaline moiety. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphersulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptonate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like, as well as nontoxic ammonium, quaternary ammonium, and amine cations, including, but not limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, ethylamine, and the like.

The compounds described herein, or their pharmaceutically acceptable salts which are used in accordance with the present invention, may exhibit stereoisomerism by virtue of the presence of one or more asymmetric or chiral centers in the compounds. The present invention contemplates the various stereoisomers and mixtures thereof. Desired enantiomers can be obtained by chiral synthesis from commercially available chiral starting materials by methods well known in the art, or may be obtained from mixtures of the enantiomers by resolution using known techniques.

Solvate as used herein refers to a pharmaceutically acceptable solvate form of an agent that retains the biological effectiveness of such agent. Examples of solvates include a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound) of the invention in combination with, for example, water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid, or ethanolamine.

Prodrug, as used herein refers to an agent that is converted under physiological conditions or by solvolysis or metabolically (e.g., in vivo) to a specified agent that is pharmaceutically active.

Active metabolite, as used herein refers to a pharmacologically active product produced through metabolism in the body of a specified agent.

Co-crystal as used herein refers to a physical association of two or more molecules which owe their stability through non-covalent interaction. One or more components of this molecular complex provide a stable framework in the crystalline lattice. In certain instances, the guest molecules are incorporated in the crystalline lattice as anhydrates or solvates.

In one aspect, the present invention provides a compounds described herein, and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition can be in any suitable form appropriate for the desired use and route of administration. Pharmaceutical excipients can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like. The pharmaceutical excipients can be, for example, saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like. In one embodiment, the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when any agent described herein is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions. Suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like. Other examples of suitable pharmaceutical excipients are described in Remington's Pharmaceutical Sciences 1447-1676 (Alfonso R. Gennaro eds., 19th ed. 1995), incorporated herein by reference.

Additionally, the pharmaceutical compositions of the present invention may contain adjuvants such as preservatives, wetting agents, emulsifying agents, pH buffering agents, and dispersing agents. Further, auxiliary, stabilizing, thickening, lubricating, and coloring agents can be included. Prevention of the action of microorganisms may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. The pharmaceutical compositions may also include isotonic agents such as sugars, sodium chloride, and the like.

Where necessary, the pharmaceutical compositions can also include a solubilizing agent. Also, the agents can be delivered with a suitable vehicle or delivery device as known in the art. Compositions for administration can optionally include a local anesthetic such as, for example, lidocaine to lessen pain at the site of the injection.

The pharmaceutical compositions of the present invention can take the form of solutions, suspensions, emulsion, drops, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. In one embodiment, the pharmaceutical composition is in the form of a capsule. In another embodiment, the pharmaceutical composition is in the form of a tablet.

In some embodiments, the administration of any of the described compounds is any one of oral, intravenous, and parenteral. In various embodiments, routes of administration include, for example: oral, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, intranasal, epidural, sublingual, intranasal, intracerebral, intravaginal, transdermal, rectally, by inhalation, or topically, for example, to the ears, nose, eyes, or skin. In some embodiments, the administering is effected orally or by parenteral injection. The mode of administration can be left to the discretion of the practitioner, and depends in-part upon the site of the medical condition. In various embodiments, administration results in the release of any agent described herein into the bloodstream. Any compound and/or pharmaceutical composition described herein can be administered orally. Such compounds and/or pharmaceutical compositions can also be administered by any other convenient route, for example, by intravenous infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, efc.) and can be administered together with an additional therapeutic agent. Administration can be systemic or local. In some embodiments, administration is not at the site of infection to avoid, for example, hydrolysis of the compound at the site of infection. Various delivery systems are known, e.g., encapsulation in liposomes, microparticles, microcapsules, capsules, efc., and can be used. In specific embodiments, it may be desirable to administer locally to the area in need of treatment.

In various embodiments, a compound of F Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3- hydroxy-6-methyl picolinate (MHP ester) or a related compound) is formulated as described in WO 2006/102748, which is incorporated herein by reference in its entirety.

In one embodiment, a compound described herein and/or pharmaceutical composition described herein is formulated in accordance with routine procedures as a composition adapted for oral administration to humans. Solid dosage forms for oral administration include, for example, capsules, tablets, pills, powders, and granules. In such dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate, dicalcium phosphate, efc., and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, silicic acid, microcrystalline cellulose, and Bakers Special Sugar, efc., b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, acacia, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxypropyl cellulose (HPC), and hydroxymethyl cellulose efc., c) humectants such as glycerol, efc., d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, sodium carbonate, cross-linked polymers such as crospovidone (cross-linked polyvinylpyrrolidone), croscarmellose sodium (cross-linked sodium carboxymethylcellulose), sodium starch glycolate, efc., e) solution retarding agents such as paraffin, efc., f) absorption accelerators such as quaternary ammonium compounds, efc., g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, efc., h) absorbents such as kaolin and bentonite clay, efc., and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, glyceryl behenate, efc., and mixtures of such excipients. One of skill in the art will recognize that particular excipients may have two or more functions in the oral dosage form. In the case of an oral dosage form, for example, a capsule or a tablet, the dosage form may also comprise buffering agents.

The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Non-limiting examples of embedding compositions which can be used include polymeric substances and waxes.

The active compounds can also be in micro-encapsulated form, if appropriate, with one or more of the above- mentioned excipients.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3- butylene glycol, dimethyl formamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. Suspensions, in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Dosage forms suitable for parenteral administration (e.g., intravenous, intramuscular, intraperitoneal, subcutaneous and intra-articular injection and infusion) include, for example, solutions, suspensions, dispersions, emulsions, and the like. They may also be manufactured in the form of sterile solid compositions (e.g., lyophilized composition), which can be dissolved or suspended in sterile injectable medium immediately before use. They may contain, for example, suspending or dispersing agents known in the art. Pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or nonaqueous solutions, dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just prior to use. Examples of suitable aqueous and nonaqueous carriers, diluents, solvents or vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils (such as olive oil) and injectable organic esters such as ethyl oleate. Proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.

Any compound described herein and/or pharmaceutical composition described herein can be administered by controlled-release or sustained-release means or by delivery devices that are known to those of ordinary skill in the art. Examples include, but are not limited to, those described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 4,008,719; 5,674,533; 5,059,595; 5,591,767; 5, 120,548; 5,073,543; 5,639,476; 5,354,556; and 5,733,556, each of which is incorporated herein by reference in its entirety. Such dosage forms can be useful for providing controlled- or sustained-release of one or more active ingredients using, for example, hydropropyl cellulose, hydropropylmethyl cellulose, polyvinylpyrrolidone, Eudragit, other polymer matrices, gels, permeable membranes, osmotic systems, multilayer coatings, microparticles, liposomes, microspheres, or a combination thereof to provide the desired release profile in varying proportions. Suitable controlled- or sustained-release formulations can be readily selected for use with the active ingredients of the agents described herein. The invention thus provides single unit dosage forms suitable for oral administration such as, but not limited to, tablets, capsules, gelcaps, and caplets that are adapted for controlled- or sustained-release.

Formulations comprising the compounds described herein and/or pharmaceutical compositions of the present invention may conveniently be presented in unit dosage forms and may be prepared by any of the methods known in the art of pharmacy. Such methods generally include the step of bringing the therapeutic agents into association with a carrier, which constitutes one or more accessory ingredients. Typically, the formulations are prepared by uniformly and intimately bringing the therapeutic agent into association with a liquid carrier, a finely divided solid carrier, or both, and then, if necessary, shaping the product into dosage forms of the desired formulation (e.g., wet or dry granulation, powder blends, etc., followed by tableting using conventional methods known in the art).

It will be appreciated that the actual dose of the compounds described herein and/or pharmaceutical compositions of the present invention to be administered according to the present invention may vary according to the particular compound, the particular dosage form, and the mode of administration. Many factors that may modify the action of the inositpresent agents (e.g., body weight, gender, diet, time of administration, route of administration, rate of excretion, condition of the subject, drug combinations, genetic disposition and reaction sensitivities) can be taken into account by those skilled in the art. Administration can be carried out continuously or in one or more discrete doses within the maximum tolerated dose. Optimal administration rates for a given set of conditions can be ascertained by those skilled in the art using conventional dosage administration tests.

Individual doses of the compounds described herein and/or pharmaceutical compositions of the present invention can be administered in unit dosage forms (e.g., tablets or capsules) containing, for example, from about 0.01 mg to about 1 ,000 mg, from about 0.01 mg to about 950 mg, from about 0.01 mg to about 900 mg, from about 0.01 mg to about 850 mg, from about 0.01 mg to about 800 mg, from about 0.01 mg to about 750 mg, from about 0.01 mg to about 700 mg, from about 0.01 mg to about 650 mg, from about 0.01 mg to about 600 mg, from about 0.01 mg to about 550 mg, from about 0.01 mg to about 500 mg, from about 0.01 mg to about 450 mg, from about 0.01 mg to about 400 mg, from about 0.01 mg to about 350 mg, from about 0.01 mg to about 300 mg, from about 0.01 mg to about 250 mg, from about 0.01 mg to about 200 mg, from about 0.01 mg to about 150 mg, from about 0.01 mg to about 100 mg, from about 0.1 mg to about 90 mg, from about 0.1 mg to about 80 mg, from about 0.1 mg to about 70 mg, from about 0.1 mg to about 60 mg, from about 0.1 mg to about 50 mg, from about 0.1 mg to about 40 mg, from about 0.1 mg to about 30 mg, from about 0.1 mg to about 20 mg, from about 0.1 mg to about 10 mg, from about 0.1 mg to about 5 mg, from about 0.1 mg to about 3 mg, or from about 0.1 mg to about 1 mg per unit dosage form. For example, a unit dosage form can be about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1 ,000 mg, inclusive of all values and ranges therebetween.

In some embodiments, the compounds described herein and/or pharmaceutical compositions of the present invention are administered at an amount of from about 0.01 mg to about 1 ,000 mg daily, from about 0.01 mg to about 950 mg daily, from about 0.01 mg to about 900 mg daily, from about 0.01 mg to about 850 mg daily, from about 0.01 mg to about 800 mg daily, from about 0.01 mg to about 750 mg daily, from about 0.01 mg to about 700 mg daily, from about 0.01 mg to about 650 mg daily, from about 0.01 mg to about 600 mg daily, from about 0.01 mg to about 550 mg daily, from about 0.01 mg to about 500 mg daily, from about 0.01 mg to about 450 mg daily, from about 0.01 mg to about 400 mg daily, from about 0.01 mg to about 350 mg daily, from about 0.01 mg to about 300 mg daily, from about 0.01 mg to about 250 mg daily, from about 0.01 mg to about 200 mg daily, from about 0.01 mg to about 150 mg daily, from about 0.1 mg to about 100 mg daily, from about 0.1 mg to about 95 mg daily, from about 0.1 mg to about 90 mg daily, from about 0.1 mg to about 85 mg daily, from about 0.1 mg to about 80 mg daily, from about 0.1 mg to about 75 mg daily, from about 0.1 mg to about 70 mg daily, from about 0.1 mg to about 65 mg daily, from about 0.1 mg to about 60 mg daily, from about 0.1 mg to about 55 mg daily, from about 0.1 mg to about 50 mg daily, from about 0.1 mg to about 45 mg daily, from about 0.1 mg to about 40 mg daily, from about 0.1 mg to about 35 mg daily, from about 0.1 mg to about 30 mg daily, from about 0.1 mg to about 25 mg daily, from about 0.1 mg to about 20 mg daily, from about 0.1 mg to about 15 mg daily, from about 0.1 mg to about 10 mg daily, from about 0.1 mg to about 5 mg daily, from about 0.1 mg to about 3 mg daily, or from about 0.1 mg to about 1 mg daily.

In various embodiments, the compounds described herein and/or pharmaceutical compositions of the present invention are administered at a daily dose of about 0.01 mg, about 0.02 mg, about 0.03 mg, about 0.04 mg, about 0.05 mg, about 0.06 mg, about 0.07 mg, about 0.08 mg, about 0.09 mg, about 0.1 mg, about 0.2 mg, about 0.3 mg, about 0.4 mg, about 0.5 mg, about 0.6 mg, about 0.7 mg, about 0.8 mg, about 0.9 mg, about 1 mg, about 2 mg, about 3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about 9 mg about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 350 mg, about 400 mg, about 450 mg, about 500 mg, about 550 mg, about 600 mg, about 650 mg, about 700 mg, about 750 mg, about 800 mg, about 850 mg, about 900 mg, about 950 mg, or about 1,000 mg, inclusive of all values and ranges therebetween.

In some embodiments, a suitable dosage of the compounds described herein and/or pharmaceutical compositions of the present invention is in a range of about 0.01 mg/kg to about 10 mg/kg of body weight of the subject, for example, about 0.01 mg/kg, about 0.02 mg/kg, about 0.03 mg/kg, about 0.04 mg/kg, about 0.05 mg/kg, about 0.06 mg/kg, about 0.07 mg/kg, about 0.08 mg/kg, about 0.09 mg/kg, about 0.1 mg/kg, about 0.2 mg/kg, about 0.3 mg/kg, about 0.4 mg/kg, about 0.5 mg/kg, about 0.6 mg/kg, about 0.7 mg/kg, about 0.8 mg/kg, about 0.9 mg/kg, about 1 mg/kg, about 1.1 mg/kg, about 1.2 mg/kg, about 1.3 mg/kg, about 1.4 mg/kg, about 1.5 mg/kg, about 1.6 mg/kg, about 1.7 mg/kg, about 1.8 mg/kg, 1.9 mg/kg, about 2 mg/kg, about 3 mg/kg, about 4 mg/kg, about 5 mg/kg, about 6 mg/kg, about 7 mg/kg, about 8 mg/kg, about 9 mg/kg, about 10 mg/kg body weight, inclusive of all values and ranges therebetween. In other embodiments, a suitable dosage of a compound of Formula I, la, or lb (e.g. pyridoxal phosphate, emoxypine, methyl 3-hydroxy-6-methyl picolinate (MHP ester) or a related compound) is in a range of about 0.01 mg/kg to about 10 mg/kg of body weight, in a range of about 0.01 mg/kg to about 9 mg/kg of body weight, in a range of about 0.01 mg/kg to about 8 mg/kg of body weight, in a range of about 0.01 mg/kg to about 7 mg/kg of body weight, in a range of 0.01 mg/kg to about 6 mg/kg of body weight, in a range of about 0.05 mg/kg to about 5 mg/kg of body weight, in a range of about 0.05 mg/kg to about 4 mg/kg of body weight, in a range of about 0.05 mg/kg to about 3 mg/kg of body weight, in a range of about 0.05 mg/kg to about 2 mg/kg of body weight, in a range of about 0.05 mg/kg to about 1.5 mg/kg of body weight, or in a range of about 0.05 mg/kg to about 1 mg/kg of body weight.

In accordance with certain embodiments of the invention, the compounds and/or pharmaceutical compositions described herein may be administered, for example, more than once daily, about once per day, about every other day, about every third day, about once a week, about once every two weeks, about once every month, about once every two months, about once every three months, about once every six months, or about once every year.

Administration of the present compounds may be combined with one or more additional therapeutic agents (e.g., 1 , or 2, or 3, or 4, or 5 additional therapeutic agents). Such combinations may lead to synergism and/or additive and/or potent effects at a lower dose of the present compounds and/or the one or more additional therapeutic agents. Coadministration of the present compounds and the additional therapeutic agent may be simultaneous or sequential. Further the pharmaceutical compositions including the present compounds may comprise the additional therapeutic agent (e.g., via co-formulation). Further, in some embodiments, the present compounds may be administered to a patient that is undergoing treatment with one or more additional therapeutic agent. Further, in some embodiments, the present compounds may supplant a patient's current treatment with one or more additional therapeutic agent.

In one embodiment, the additional therapeutic agent and the present compounds are administered to a subject simultaneously. The term "simultaneously" as used herein, means that the additional therapeutic agent and the present compounds are administered with a time separation of no more than about 60 minutes, such as no more than about 30 minutes, no more than about 20 minutes, no more than about 10 minutes, no more than about 5 minutes, or no more than about 1 minute. Administration of the additional therapeutic agent and present compounds can be by simultaneous administration of a single formulation (e.g., a formulation comprising the additional therapeutic agent and the present compounds) or of separate formulations (e.g., a first formulation including the additional therapeutic agent and a second formulation including the present compounds).

Co-administration does not require the additional therapeutic agent to be administered simultaneously, if the timing of their administration is such that the pharmacological activities of the additional therapeutic agent and the present compounds overlap in time, thereby exerting a combined therapeutic effect. For example, the additional therapeutic agent and the present compounds can be administered sequentially. The term "sequentially" as used herein means that the additional therapeutic agent and the present compounds are administered with a time separation of more than about 60 minutes. For example, the time between the sequential administration of the additional therapeutic agent and the present compounds can be more than about 60 minutes, more than about 2 hours, more than about 5 hours, more than about 10 hours, more than about 1 day, more than about 2 days, more than about 3 days, or more than about 1 week apart. The optimal administration times may depend on the rates of metabolism, excretion, and/or the pharmacodynamic activity of the additional therapeutic agent and the present compounds being administered. Either the additional therapeutic agent or the present compound may be administered first.

Co-administration also does not require the additional therapeutic agents to be administered to the subject by the same route of administration. Rather, each therapeutic agent can be administered by any appropriate route, for example, parenterally or non-parenterally.

In various embodiments, the additional therapeutic agent is a Parkinson's disease treatment agent. For example, in various embodiments, the Parkinson's disease treatment agent is optionally selected from one or more of levodopa (for example, in combination with tolcapone, entacapone, carbidopa, or benserazide), dopamine agonists as described herein (for example, apomorphine, bromocriptine, pergolide, pramipexole, ropinirole, piribedil, cabergoline, apomorphine and lisuride), MAO-B inhibitors as described herein (for example, deprenyls such as selegiline and rasagiline), Piribedil, pramipexole (e.g., MIRAPEX, MIRAPEXIN, SIFROL), bromocriptine (e.g., PARLODEL, CYCLOSET, BROTIN), Ropinirole (e.g., REQUIP, REPREVE, RONIROL, ADARTREL), sumanirole (e.g. PNU- 95,666), aplindore (e.g., DAB-452), amantadine, anticholinergics (for example, artane, Cogentin), quetiapine, cholinesterase inhibitors, modafinil, tyrosine hydroxylase, N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1 a- carboxamide (PHCCC), and non-steroidal anti-inflammatory drugs.

In various embodiments, the terms "patient" and "subject" are used interchangeably. In some embodiments, the subject and/or animal is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, rabbit, sheep, or non-human primate, such as a monkey, chimpanzee, or baboon. In various embodiments, methods of the invention are useful in treatment a human subject. In some embodiments, the human is a pediatric human. In other embodiments, the human is an adult human. In other embodiments, the human is a geriatric human. In other embodiments, the human may be referred to as a patient or a subject. In some embodiments, the human is a female. In some embodiments, the human is a male.

The invention provides kits that can simplify the administration of the compounds and/or pharmaceutical compositions described herein. The kit is an assemblage of materials or components, including at least one of the formulations described herein. The exact nature of the components configured in the kit depends on its intended purpose. In one embodiment, the kit is configured for the purpose of treating human subjects.

Instructions for use may be included in the kit. Instructions for use typically include a tangible expression describing the technique to be employed in using the components of the kit to affect a desired outcome, such as to treat, for example, Parkinson's disease. Optionally, the kit also contains other useful components, such as, diluents, buffers, pharmaceutically acceptable carriers, syringes, catheters, applicators, pipetting or measuring tools, bandaging materials or other useful paraphernalia as may be readily recognized by those of skill in the art.

The materials and components assembled in the kit can be provided to the practitioner store in any convenience and suitable ways that preserve their operability and utility. For example, the components can be provided at room, refrigerated or frozen temperatures. The components are typically contained in suitable packaging materials. In various embodiments, the packaging material is constructed by well-known methods, preferably to provide a sterile, contaminant-free environment. The packaging material may have an external label which indicates the contents and/or purpose of the kit and/or its components.

This invention is further illustrated by the following non-limiting examples.

EXAMPLES

Example 1: Experiments Related to the α-synuclein Disaggregation with Pyridoxal Phosphate

Disaggregation of a-synuclein with Pyridoxal Phosphate.

Pyridoxal phosphate (PLP) powder was rehydrated at 5mg/mL in Sodium phosphate buffer (SPB) 0.2M pH 6. SPB is prepared with a mix of two powder: disodium phosphate (Na₂HP0₄) and monosodium phosphate (NaH₂P0₄) diluted in distilled water and adjusted at a pH of 6 with addition of sodium hydroxide (NaOH 5M). PLP solution at 5mg/mL is store at room temperature.

Spectrofluorometry of a-synuclein disaggregation with PLP

10 mg of a-synuclein (60-95) human trifluoroacetate salt (Bachem, art n°4105037, lot n°3016948, purity 86.6%, molecular weight 3388.82 g/mol) were rehydrated with 5mL of Phosphate-Buffered Saline (PBS). Then, 5 mg of a- synuclein (60-95) at 3mg/mL in PBS pH 7.3 was used to produce aggregates incubating the solution for one week at 37°C.

After one week of incubation, two parallel measures were done:

1) 10μΙ_ of α-synuclein aggregates with 90 μΙ_ of PBS and 1 μΙ_ of Thioflavin T (Sigma, ref T3516-5G, lot#MKBZ3619V, molecular weight: 318.86 g/mol, rehydrated at 3 mM in SPB 50 mM pH6) completed at 1 mL with

SPB 50 mM pH6.

2) 10 μΙ_ of α-synuclein aggregates with 90 μΙ_ of PBS, 400 μΙ_ of PLP at 1.25 mg/mL in SPB 50 mM pH 6 and 1 μί of Thioflavin T 3 mM in SPB 50 mM pH 6 completed at 1 mL with SPB 50 mM pH 6.

Several measures were done at different times:

1 min after addition of Thioflavin T alone or Thioflavin T with PLP, 30min, 1 h, 24h, 48h, 72h. A different sample of a- synuclein aggregates with PLP and Thioflavin T was used for each point while the same sample of a-synuclein aggregates with Thioflavin T was used for each point as control.

Tubes were analyzed at room temperature with spectrofluorometer Fluorolog (Horiba) with 2mm plastic cuvettes, run at 1s and slit at 5. Excitation is done with wavelength of 450nm and measures are registered between 470nm and 600nm.

The same experiment was done twice in the same conditions with the same α-synuclein aggregates.

The first assay is shown in FIG. 1, panels A-E. The second assay is shown in FIG. 1, panels F-K.

The results of FIG. 1 are summarized in FIG. 2, panels A-C.

Scanning Electron Microscopy of a-synuclein Disaggregation with PLP

Sample analyzed in spectrofluorometry: 30μg of α-synuclein aggregates with 1 μί of Thioflavin T 3mM in SPB 50mM pH6 completed at 1mL with SPB 50mM pH6 is dried at 37°C to be more concentrated. Then, 5μί of aggregates concentrate was combined with 5μί of PBS or 5μί of PLP 5mg/mL and 2 samples of 10 L placed of Scanning Electron Microscopy (SEM) support (one sample on each side). Samples were then dried at room temperature under hood and coated with gold during 1 min and finally analyzed with Quanta FEG 250.

FIG. 3 shows scanning electron microscopy results. FIGs. 3A, 3C, 3E, and 3G shows α-synuclein aggregates and FIGs. 3B, 3D, 3F, and 3H show α-synuclein aggregates with PLP.

Example 2: Methods Related to the Use of Emoxypine to Solubilize α-Synuclein Amyloids Fibrils

α-synuclein amyloids fibrils are responsible for neurodegenerative disease such as Parkinson's disease. These fibrils are formed by the aggregation of α-synuclein. The aim of the experiments of this example is, therefore, the breaking, i.e. the solubilization of α-synuclein aggregates. In this respect, disclosed herein is a method of incorporating chemical species in a-synuclein amyloids fibrils. Chemical species can intercalate between the of a-synuclein proteins and hence break the aggregates (this can be called the "curative measure", as the proteins are already aggregated). Another method of the present disclosure is the incorporation of the chemical species before aggregation, in order to prevent the amassment (this can be called the "preventive measure", as the proteins are not aggregated yet). A schematic representation of both measures is displayed in FIG. 4.

It was shown above that pyridoxal phosphate response towards α-synuclein amyloids fibrils is highly efficient, featuring a solubilization up to 48%. This result was unexpected for such a small molecule. In the experiments of the present example, several different water soluble, biocompatible small molecules were tested for solubilization. In this regard, solubilization tests using 2-ethyl-6-methyl-3-hydroxypyrdine, most commonly called emoxypine (MEXIDOL), were performed since the molecule itself presents two characteristics mentioned herein (i.e., water solubility and a certain biocompatibility).

Disclosed herein are methods related to the use of emoxypine in the solubilization of α-synuclein amyloids fibrils. For this purpose, a specific α-synuclein fragment responsible for the peptide aggregation, called the non-Abeta component (NAC) domain (i.e., from residues 61 to 95), was utilized in the experiments of this example. The sequence, referred to herein as SEQ ID N0.2, is the following: EQVTNVGGAWTGVTAVAQKTVEGAGSIAAATGFV. The structure of emoxypine is shown below:

These studies were performed using thioflavin T (ThT) as a fluorescent label, having the advantage of emitting at 482 nm only when linked to amyloid fibrils, but not to the single peptide. The curative and preventive methods were studied, at different molar ratio emoxypine/ a-synuclein (200, 100, 50, 20).

In order to follow the kinetics of disaggregation, fluorescence measurements were performed by comparing the emission of ThT in the presence of aggregates, without and with emoxypine at different times after emoxypine addition, from one minute to several days.

Results and Discussion

1. Curative Measure

1.1 Molar ratio Emoxypine/ a-synuclein= 200 (r 200) The results presenting a ratio emoxypine/ a-synuclein= 200 (r 200) are shown in FIG. 5, while Table 1 (below) and FIG. 6 depict the percentage of disaggregation for each measurement point.

In the experiments of this example, it was clear that numerous aggregates were broken in the presence of emoxypine already after one minute. For instance, after 24h, 60.2% of the aggregates were broken, and hence, 39.8% of the aggregates remained in respect to the samples without Emoxypine. This trend is confirmed along a length of time, until reaching a solubilization of almost 80% after 6 days (again, in respect to the samples without emoxypine). The results of these experiments are reproducible, since several identical samples gave the same result.

In order to confirm these interesting results, scanning electron microscopy studies were performed on the same samples, and images are displayed in FIG.7A, FIG. 7B, FIG. 7C, and FIG. 7D.

As demonstrated in the experiments, for the samples without emoxypine, large fibers of around 100 μιη were present, with an important monodispersity index. Regarding the sample in the presence of emoxypine, the big fibers were much less numerous, and instead, several smaller were observed due to the breaking of aggregates and thus, formation of monomers.

Table 1. Percentage of solubilization along the time with r 200, from 1 minute to 6 days (144 hours)

This result is in line with the fluorescence data, since in both cases the yield of disaggregation is high but not quantitative. In the scope of a-synuclein amyloids fibrils solubilization, emoxypine gives a very interesting and undeniable capability of action, demonstrated using both fluorescence, by the help of ThT, and scanning electron microscopy.

1.2 Molar ratio Emoxypine/ a-synuclein= 100 (r 100) Solubility tests featuring a ratio emoxypine/ a-synuclein= 100 (r 100) were performed. Fluorescence measurement using the process disclosed herein, with ThT as a fluorescent label, were performed, and the results are depicted in FIG. 8. After 1 minute, 50% of the aggregates were broken and about the same value was found until 2 days of emoxypine addition. After 3 days, only 38% of aggregates were left (i.e. 62% of disaggregation). Similar solubility efficiency was found after 5 days, and, very interestingly, only 24% of the aggregates were remaining after 6 days. Even though the solubilization process was slightly slower than with r 200, the similarities between the two experiments after 6 days were striking (78% of disaggregation for r 200 and 76% of disaggregation for r 100). A clear recap chart of the solubility using r 100 is shown in Table 2 below and in FIG. 9.

Table 2. Percentage of solubilization with r 100 along the time, from 1 minute to 6 days (144 hours)

From SEM pictures (FIG. 10A and FIG. 10B), fibers were again observed around 60 μιη, together with monomers (around 3 μιη big). However, the clarity of the picture was not as pronounced as for FIG.7A, FIG. 7B, FIG. 7C, and FIG. 7D. Moreover, no SEM picture of the aggregates without emoxypine could be recorded, and this was due experimental processes. Given the experiments of this example, it can be concluded that only the sample containing emoxypine yielded an important disaggregation index, and this was because of the low quantity of fibers and the high number of monomers.

1.3 Molar ratio Emoxypine/ a-synuclein= 50 (r 50)

The same experiments were achieved using a lower emoxypine concentration, all the other components remaining identical in terms of concentration. FIG. 11 displays the emission intensities recorded versus the time. Interestingly, a certain percentage of disaggregation was observed, which was in this case less important than what was previously mentioned, meaning r 200 and r 100. Indeed, after 1 minute, 40% of the initial aggregates were destroyed, and this value slightly increased to reach, after 6 days, about 60% of solubilization.

This result was very interesting, since showed the effect of emoxypine itself, and also the effect on its concentration. Therefore, it is certain that the species responsible for the aggregates breaking is emoxypine, since its amount was the only parameter that changed for this experiment. The data has been summed up in Table 3 below and in FIG. 12.

Table 3. Percentage of solubilization with r 50 along the time, from 1 minute to 6 days (144 hours)

Regarding SEM images, the same problem as for r 100 was noticed. Indeed, no SEM micrograph of the aggregates without emoxypine were recorded. Pictures of the aggregates with emoxypine (r 50) are shown in FIG. 13A and FIG. 13B. As disclosed herein, the presence of a few number of fibers, together with a large amount of monomers resulting of fibrils disaggregation, were observed.

1.4. Molar ratio Emoxypine/ a-synuclein= 20 (r 20)

Identical solubilization experiments were performed, using this time a lower ratio emoxypine/ a-synuclein (r 20) (FIG. 14). As expected, the solubilization was less efficient with such a low amount of emoxypine. Indeed, after 1 minute, only 30% of the aggregates were broken, and this value remained relatively the same after 4 days. The data confirmed the tendency previously explained, as the disaggregation efficiency was already weaker with r 50. The data also confirmed once again, that as the amount of emoxypine was the only variable, the fact is that emoxypine is indeed the factor responsible for the solubilization of a-synuclein amyloids fibrils. Table 4 and FIG. 15 sum up the results using r 20.

Table 4. Percentage of solubilization with r 20 along the time, from 1 minute to 6 days (144 hours) Time Percentage of

solubilization

1 min 36.6

30 min 33.9

1 h 31.6

24 h 25.8

48 h 23.8

72 h 30.9

2. Preventive measure

Similar experiments were performed with one important change: the aggregation process (incubation of the peptides in phosphate buffer saline at 37°C for one week) was performed in the presence of emoxypine, again with different concentrations of emoxypine ( r 200, r 100, r 50, r 20). This would prevent aggregation instead of breaking the aggregate (cf. FIG. 4). The samples were taken out from the incubator after one week and fluorescence measurements in the presence of ThT were carried out, with the same concentration of every component, except emoxypine that was the variable parameter.

The results (FIG. 16 and FIG. 17) show that for r 200, the solubility was quite efficient (72%), a value comparable with the "curative method" after 6 days, which was 78%. Nevertheless, with r 100 and r 50, the disaggregation was much less efficient, reaching a value of 24% and 28%, respectively. As a reminder, the "curative method" for r 100 and r 50 after 6 days gave solubility efficiencies of 76% and 63%, respectively. Using less amount of emoxypine is therefore up to 4 times less efficient by this method.

Regarding r 20, no change was observed in respect to the sample without emoxypine. Indeed, the emission intensity of ThT was the same, even slightly higher.

Conclusion

It was shown in the experiments of this example that emoxypine response towards a-synuclein amyloids fibrils was highly efficient, featuring a solubilization up to 78% after a few days, which was much more powerful than with pyridoxal phosphate. The results were still promising with a relatively low ratio emoxypine/ a-synuclein, and the importance of the role played by emoxypine for the aggregates solubilization has been demonstrated, since its amount is the only variable all along this work. Moreover, the "curative method" appears to be more promising than the "preventive method", featuring a higher solubility performance. More SEM pictures can be acquired, as well as additional tests using another type of aggregates can be performed, for instance amyloid-β amyloids, in order to study the possible specificity of such a response. In light of these very interesting and undeniable results, the same experiments using other water soluble and biocompatible molecules would be worthwhile in order to understand the mechanism of the disaggregation process.

Experimental Section

a-synuclein₆i-95 and emoxypine, commercially available, were used as bought without any further purification. All the tubes, tips and buffers were sterilized prior to use.

The aggregation was performed as following:

a-synuclein6i-95 was dissolved in water (0.5mg/mL), 60 μΙ_ of the resulting solution (i.e. 30 μg, 9.2 nmol) were taken and allowed to dry. The given powder was then suspended in PBS, pH=7.4, (10 μΙ_). The resulting suspension was then incubated at 37°C for 1 week to yield the final aggregates.

The disaggregation (i.e. solubilization) was performed as following:

Two types of control samples were used: The first one containing 1 μΙ_ of a solution of ThT 3mM (3nmol) and 999μΙ_ of SPB 50mM, pH=6; while the second one containing 1 μΙ_ of a solution of ThT 3mM (3nmol), 899μΙ_ of SPB 50mM and 100 μΙ_ of a solution of emoxypine 20.2mM (2.02μιτιοΙ).

Two types of samples of interest were made, without emoxypine, 1) and the other one containing the latter at different concentrations, 2).

Preparation of 1).

In 10 μΙ_ of aggregates (cf. procedure for the aggregation) was added 889 μΙ_ of SPB and 1 μΙ_ of a SPB solution of ThT 3mM. The mixture was immediately poured into a polystyrene semi-micro cuvette and shaken for a few second and left to stand for 1 minute before the first fluorescence measurement.

Preparation of 2).

In 10 μΙ_ of aggregates (cf. procedure for the aggregation) was added 100 μΙ_ of a solution of emoxypine, 889 μΙ_ of SPB and 1 μΙ_ of a SPB solution of ThT 3mM. The mixture was immediately poured into a polystyrene semi-micro cuvette and shaken for a few second and left to stand for 1 minute before the first fluorescence measurement.

Preparation of the mother solutions of emoxypine:

r 200: 27.75 mg of emoxypine in 10 mL of SPB pH 6, 20.2 mM, 2.02μιτιοΙ;

r 100: 13.875 mg of emoxypine in 10 mL of SPB pH 6, 10.1 mM, 1.01 μιτιοΙ r 50: 6.94 mg of emoxypine in 10 mL of SPB pH 6, 5.05 mM, 505 nmol

r 20: 2.77 mg of emoxypine in 10 mL of SPB pH 6, 2.02 mM, 202 nmol

Emission spectra were recorded on a Horiba Jobin-Yvon IBH FL-322 Fluorolog 3 spectrometer equipped with a 450 W xenon arc lamp, double-grating excitation, and emission monochromators (2.1 nm mm-1of dispersion; 1200 grooves mm-1) and a TBX-04 single photon-counting detector. Emission spectra were corrected for source intensity (lamp and grating) and emission spectral response (detector and grating) by standard corrections. The cuvettes used for the fluorescence measurements are transparent polystyrene semi-micro cuvettes, with a maximum volume of 1.6 ml and 2 optical sides, suitable for use beginning at 330 nm. All the sample were excited at 450 nm and the emission spectra were recorded between 470 nm and 600 nm.

Scanning Electron Microscopy (SEM) images were recorded with a FEI Quanta FEG 250 instrument (FEI corporate, Hillsboro, Oregon, USA) with an acceleration voltage of 20 kV. The sample is prepared by deposition of 5μΙ_ of the sample solution (200 μΙ_) onto a glass cover slip, subsequently sputter coated with gold (Emitech K575X peltier cooled) for 60 s at 60 mA prior to fixation on an aluminum support.

Example 3: Methods Related to the Use of Methyl 3-hydroxy-6-methylpicolinate (MHP-Ester) to Solubilize a- Synuclein Amyloids Fibrils

As disclosed herein, the response of emoxypine towards a-synuclein fibrils solubilization was very interesting, showing up to 75% of disaggregation.

Specificity tests were performed, employing amyloid-β instead of a-synuclein. In the experiments of this example, the focus is no longer dedicated to the specificity of emoxypine, but to the understanding of the mechanism of emoxypine. In this regard, a similar molecule, an emoxypine counterpart containing an methylester group instead of the ethyl group, i.e. at position 2 of the pyridine ring, was investigated (see structure below). This molecule was also chosen due to the possibility of a peptidic bond formation by reaction with an amino group. For instance, using, a branched poly-amine, it would be possible to anchor several emoxypine derivatives on the same molecule (See FIG. 18A, FIG. 18B, FIG. 18C, FIG. 18D, FIG. 18E, and FIG. 18F). The amount of molecules needed to perform an efficient solubilization can therefore be dramatically decreased. This emoxypine derivative was called Methyl 3- hydroxy-6-methylpicolinate, but for clarity reasons, it will be called herein as "MHP-ester".

Structure of methyl 3-hydroxy-6-methylpicolinate, or MHP-ester

In order to follow the kinetics of disaggregation, fluorescence measurements were performed by comparing the emission of thiovlavin T (ThT) in the presence of aggregates, without and with MHP-ester at different times after emoxypine addition, from one minute to several days. The molar ratio of MHP: a-synuclein was 200 (r 200). As usual, the emission wavelength of interest was 482 nm, and the excitation wavelength is 450 nm. The results of the disaggregation process using r 200 are shown in FIG. 19, while Table 4 and FIG. 20 display respectively the percentage of disaggregation and the percentage of aggregates left at each measurement time (1 min, 30 min, 1 hour, 24 hours, 72 hours, 96 hours, 144 hours).

During the first 30 minutes, almost no disaggregation was observed (around 10%). In fact, one hour was needed to see a relevant disaggregation (around 40 %). The solubilization process was more and more obvious during the next days, until reaching a value close to 60% (57.3% of solubilization). This was a relatively good solubilization efficiency, similar to the solubilization results using pyridoxal phosphate at the same ratio, r200. However, it was quite intriguing not to have a higher disaggregation percentage, since this molecule has to be compared with emoxypine rather than pyridoxal phosphate.

As a reminder, the solubilization of a-synuclein amyloid fibrils with emoxypine reaches 75% after 6 days at r200, and the only difference between both molecules was the replacement of the ethyl group, which was supposed to not have any effect, by an ester moiety. It was nevertheless worthy to point the interesting result out. Indeed, the potential of this molecule, able to be linked several times on the same molecule, together with the relatively high degree of solubilization, was promising in the view of the use of poly MHP-esters to disaggregate α-synuclein amyloid fibrils. SEM experiments were achieved in order to find a correlation with the fluorescence tests. FIG. 21 A, FIG. 21 B, FIG. 21C, FIG. 21 D, and FIG. 21 E display some of the images recorded from samples involving α-synuclein amyloid fibrils and MHP-ester. Small particles of around 500 nm were observed, assembling together to form geometric patterns of around 4 μιπ Those particles might refer to α-synuclein monomers. Only a very few fibers were seen (FIG. 21 E. surrounded by circles). It was surprising not to observe more fibers, since according to the fluorescence experiments, 40% of fibers were left. Unfortunately, due to the instability of some samples destroyed by the electron beam, no picture could be recorded for samples without MHP-ester. This problem was quite recurrent; that is why other samples were needed to be prepared until obtain decent images were obtained. However, the fact that that so many monomers can be seen in a homogenous way and in different batches is very promising for the future. Furthermore, the SEM experiments were only performed to support the fluorescence experiments. The fact that fluorescence measurements were performed in solution, at room temperature and room pressure; whereas SEM samples were analyzed in solid state (thin film) at low pressure, make the fluorescence data more reliable. More samples were then observed under the electronic microscope. These samples involved the use of antibodies (lgG37, Fab37, Irrelevant antibodies) to dissolve a-synuclein and TDP-43 amyloid fibrils. The fluorescence measurements (FIG. 22 and FIG. 23) and the samples preparation were performed prior to SEM analyses. SEM images of the samples containing TDP-43 and α-synuclein are shown in FIG. 24A, FIG. 24B, FIG. 24C, and FIG. 25, respectively.

Again, those experiments were performed in order to correlate with the fluorescence data. The latter show for TDP- 43 a decrease of the emission, meaning a decrease of the number of aggregates, with lgG37. The Irrelevant IgG, as expected, does not feature any solubilization effect. More surprisingly, the sample containing Fab37 gives an increase of the emission intensity, which would mean that Fab 37 has an aggregation effect. It is predicted that Fab37 contains impurities that could emit at 482 nm as well. Moreover, it was impossible to record pictures with Fab37, most likely due to this impurity. Regarding α-synuclein, Fab37 does not have any effect on the aggregates solubilization. The reason for that could also be the presence of an impurity, preventing the reliability of the data.

Conclusion:

The experiments of this example demonstrate that MHP-ester response towards α-synuclein amyloids fibrils was relatively high, featuring a solubilization up to almost 60% after a few days, which was approximately as powerful as pyridoxal phosphate. This molecule is very interesting for two reasons: (1) it shows a rather good efficiency, and (2) this efficiency is potentially improvable, since it is possible to connect this molecule on polyamines via peptidic coupling {c.f. FIG. 18A-F). This coupling could allow for decreasing the ratio molecule/peptide and increasing the degree of solubilization. Moreover, peptidic bonds are known to be bio-compatible, hence this would help to solve possible toxicity issues.

Thus, analogues of MHP-ester can be examined, where the MHP group is linked to molecular scaffolds of different structures (e.g. linear, branched, cyclic)

EQUIVALENTS

While the invention has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the invention following, in general, the principles of the invention and including such departures from the present disclosure as come within known or customary practice within the art to which the invention pertains and as may be applied to the essential features hereinbefore set forth and as follows in the scope of the appended claims.

Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.

INCORPORATION BY REFERENCE All patents and publications referenced herein are hereby incorporated by reference in their entireties.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. As used herein, all headings are simply for organization and are not intended to limit the disclosure in any manner. The content of any individual section may be equally applicable to all sections.

Claims

CLAIMS What is claimed is:

1. A method for treating or preventing a synucleinopathy, comprising administering an effective amount of a compound having a structure according to formula (la) to a subject in need thereof:

wherein

R¹ is H or substituted or unsubstituted (C1-C6)alkyl or substituted or unsubstituted (C 1 -C8) heteroal kyl ;

R² is H or OR⁵ or substituted or unsubstituted (C1-C6)alkyl

wherein

R⁵ is H or substituted or unsubstituted (C1-C6)alkyl;

A is CH or N or CR³ or CR⁴;

B is CH or N or CR³ or CR⁴;

C is CH or N or CR³ or CR⁴;

D is CH or N or CR³ or CR⁴;

R³ is substituted or unsubstituted (C1-C6)alkyl or substituted or unsubstituted (C 1 -C8) heteroal kyl or

-S0₂(OR⁶) or -OP(0)(OR⁶)(OR⁷)

wherein

R⁶ is H or substituted or unsubstituted (C1-C6)alkyl and

R⁷ is H or substituted or unsubstituted (C1-C6)alkyl;

R⁴ is substituted or unsubstituted (C1-C6)alkyl;

with the proviso that no more than one member selected from the group consisting of A, B, C, and D is CR³ with the proviso that no more than one member selected from the group consisting of A, B, C, and D is CR⁴ with the proviso that no more than two members selected from the group consisting of A, B, C, and D are N or a salt, hydrate, or solvate thereof,

wherein the method comprises disaggregation of a-synuclein.

2. The method of claim 1 , wherein R¹ is H.

3. The method of claim 1 or claim 2, wherein R² is H or OH.

4. The method of claim 1 or claim 2,

with the proviso that A, B, C, and D are not N; or

with the proviso that one member selected from the group consisting of A, B, C, and D is N.

5. The method of a preceding claim, wherein

A is CH; B is CR³; C is CH; and D is CH; or

A is CR³; B is CH; C is N; and D is CR⁴.

6. The method of a preceding claim, wherein R³ is -S02(OR⁶) or alkyl substituted with -OP(0)(OR⁶)(OR⁷^

7. The method of a preceding claim, wherein R³ is -SO2OH.

8. The method of claims 1-6, wherein R³ is alkyl substituted with -OP(0)(OH)(OH).

9. The method of claims 1-6, wherein R³ is -CH₂OP(0)(OR⁶)(OR⁷).

10. The method of claims 1-6, wherein R³ is -CH₂OP(0)(OH)(OH).

11. The method of a preceding claim, wherein R⁴ is methyl or ethyl or propyl or isopropyl.

12. The method of a preceding claim, wherein R⁴ is methyl.

13. The method of claim 1 , wherein the compound is

14. A method for treating or preventing a synucleinopathy, comprising administering an effective amount of a compound having a structure according to formula (lb) to a subject in need:

(lb) wherein:

R¹⁵ is H, (C1-C6)alkyl, -C(=0)OR¹⁴, or -C(0)N(R¹⁴)₂;

R¹⁷ is H, -OR¹⁴, -C(=0)OR¹⁴, -C(=0)R¹⁴, or -C(0)N(R¹⁴)₂;

R¹⁸ is H, -OR¹⁴, -C(=0)OR¹⁴, -C(=0)R¹⁴, or -C(0)N(R¹⁴)₂;

R¹⁹ is H or (C1-C6)alkyl;

each R¹⁴ is independently H or (C1-C6)alkyl;

m is 1 , 2, 3, 4, or 5;

or a salt, hydrate, or solvate thereof.

15. The method of claim 14, wherein R¹⁵ is H, (C1-C6)alkyl, or -C(=0)OR¹⁴; R¹⁶ is H, -OR¹⁴, or - (CH₂)_mP(=0)(OR¹⁴)₂; R¹⁷ is H, -C(=0)R¹⁴, or -C(=0)OR¹⁴; R¹⁸ is H or -OR¹⁴; R¹⁹ is H or (C1-C6)alkyl; each R¹⁴ is independently H or (C1-C6)alkyl; and m is 1 or 2.

16. The method of claim 14, wherein R¹⁵ is (C1-C6)alkyl or -C(=0)OR¹⁴; R¹⁶ is H, -OR¹⁴, or - (CH₂)_mP(=0)(OR¹⁴)₂; R¹⁷ is H, -C(=0)R¹⁴, or -C(=0)OR¹⁴; R¹⁸ is H or -OR¹⁴; R¹⁹ is H or (C1-C6)alkyl; each R¹⁴ is independently H or (C1-C6)alkyl; and m is 1.

17. The method of claim 14, wherein the compound is

The method of claim 14, wherein the compound

19. The method of any of the preceding claims, wherein the synucleinopathy is a condition characterized by Lewy bodies.

20. The method of any of the preceding claims, wherein the synucleinopathy is selected from Parkinson's disease, dementia with Lewy bodies, and multiple system atrophy.

21. The method of claim 20, wherein the Parkinson's disease is selected from Idiopathic Parkinson's disease, Vascular parkinsonism, drug-induced parkinsonism, dementia with Lewy bodies, Inherited Parkinson's, Juvenile Parkinson's disease.

22. The method of any of the preceding claims, wherein the disaggregation of a-synuclein comprises about a 20%, or about a 30%, or about a 40%, or about a 50%, or about a 60%, or about a 70%, or about a 80%, or about a 90%, or about a 95%, or about a 100% reduction in α-synuclein aggregation relative to an untreated subject.

23. The method of any of the preceding claims, wherein the method does not substantially dissolve aggregates of beta-amyloid.

24. Use of a compound of Formula la in the treatment of a synucleinopathy, wherein the use comprises disaggregation of a-synuclein.

25. Use of a compound of Formula la for the preparation of a medicament for the treatment of a synucleinopathy, wherein the treatment comprises disaggregation of a-synuclein.

26. Use of a compound of Formula lb in the treatment of a synucleinopathy, wherein the use comprises disaggregation of a-synuclein.

27. Use of a compound of Formula lb for the preparation of a medicament for the treatment of a synucleinopathy, wherein the treatment comprises disaggregation of a-synuclein.

28. A method for treating or preventing a synucleinopathy, comprising administering an effective amount of a compound to a subject in need thereof, wherein the compound is selected from

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