OA20556A - Treatment for synucleinopathies - Google Patents
Treatment for synucleinopathies Download PDFInfo
- Publication number
- OA20556A OA20556A OA1202100562 OA20556A OA 20556 A OA20556 A OA 20556A OA 1202100562 OA1202100562 OA 1202100562 OA 20556 A OA20556 A OA 20556A
- Authority
- OA
- OAPI
- Prior art keywords
- compound
- formula
- synucleinopathies
- treating
- dose
- Prior art date
Links
- 201000003356 synucleinopathy Diseases 0.000 title claims abstract description 37
- 150000001875 compounds Chemical class 0.000 claims abstract description 61
- 201000002832 Lewy body dementia Diseases 0.000 claims description 14
- 206010067889 Dementia with Lewy body Diseases 0.000 claims description 9
- 208000001089 Multiple System Atrophy Diseases 0.000 claims description 9
- 201000000410 REM sleep behavior disease Diseases 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 abstract description 3
- 239000011780 sodium chloride Substances 0.000 abstract description 3
- 102000003802 alpha-Synuclein Human genes 0.000 description 23
- 108090000185 alpha-Synuclein Proteins 0.000 description 23
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 20
- 210000004556 Brain Anatomy 0.000 description 16
- 102000031061 Tyrosine 3-monooxygenases Human genes 0.000 description 16
- 108091000118 Tyrosine 3-monooxygenases Proteins 0.000 description 16
- 206010061536 Parkinson's disease Diseases 0.000 description 15
- 210000002569 neurons Anatomy 0.000 description 13
- 229960003638 dopamine Drugs 0.000 description 10
- 201000010099 disease Diseases 0.000 description 6
- 208000009829 Lewy Body Disease Diseases 0.000 description 5
- 241000700159 Rattus Species 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000000324 neuroprotective Effects 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 230000004770 neurodegeneration Effects 0.000 description 4
- 230000003287 optical Effects 0.000 description 4
- 235000018102 proteins Nutrition 0.000 description 4
- 102000004169 proteins and genes Human genes 0.000 description 4
- 108090000623 proteins and genes Proteins 0.000 description 4
- 206010053643 Neurodegenerative disease Diseases 0.000 description 3
- 238000009825 accumulation Methods 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 210000004027 cells Anatomy 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000003291 dopaminomimetic Effects 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000000626 neurodegenerative Effects 0.000 description 3
- WNLRTRBMVRJNCN-UHFFFAOYSA-N Adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N Benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N HCl Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 208000008456 Leukemia, Myelogenous, Chronic, BCR-ABL Positive Diseases 0.000 description 2
- 210000004558 Lewy Bodies Anatomy 0.000 description 2
- 210000001259 Mesencephalon Anatomy 0.000 description 2
- 208000003715 Parkinsonian Disorders Diseases 0.000 description 2
- 206010034010 Parkinsonism Diseases 0.000 description 2
- WLJVNTCWHIRURA-UHFFFAOYSA-N Pimelic acid Chemical compound OC(=O)CCCCCC(O)=O WLJVNTCWHIRURA-UHFFFAOYSA-N 0.000 description 2
- 102200036626 SNCA A53T Human genes 0.000 description 2
- TYFQFVWCELRYAO-UHFFFAOYSA-N Suberic acid Chemical compound OC(=O)CCCCCCC(O)=O TYFQFVWCELRYAO-UHFFFAOYSA-N 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 201000006934 chronic myeloid leukemia Diseases 0.000 description 2
- AEMRFAOFKBGASW-UHFFFAOYSA-N glycolic acid Chemical compound OCC(O)=O AEMRFAOFKBGASW-UHFFFAOYSA-N 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- AFVFQIVMOAPDHO-UHFFFAOYSA-N methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 239000008188 pellet Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 206010000117 Abnormal behaviour Diseases 0.000 description 1
- 241000432074 Adeno-associated virus Species 0.000 description 1
- 229960005261 Aspartic Acid Drugs 0.000 description 1
- 210000001130 Astrocytes Anatomy 0.000 description 1
- BDJRBEYXGGNYIS-UHFFFAOYSA-N Azelaic acid Chemical compound OC(=O)CCCCCCCC(O)=O BDJRBEYXGGNYIS-UHFFFAOYSA-N 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- 210000004369 Blood Anatomy 0.000 description 1
- 210000003169 Central Nervous System Anatomy 0.000 description 1
- 208000000264 Deglutition Disorders Diseases 0.000 description 1
- 206010013950 Dysphagia Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 229960002989 Glutamic Acid Drugs 0.000 description 1
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 description 1
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 description 1
- OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N Malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 210000004126 Nerve Fibers Anatomy 0.000 description 1
- 208000001094 Neuroaxonal Dystrophy Diseases 0.000 description 1
- 102000004022 Protein-Tyrosine Kinases Human genes 0.000 description 1
- 108090000412 Protein-Tyrosine Kinases Proteins 0.000 description 1
- 102000004278 Receptor protein-tyrosine kinases Human genes 0.000 description 1
- 108090000873 Receptor protein-tyrosine kinases Proteins 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 235000003704 aspartic acid Nutrition 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 230000037348 biosynthesis Effects 0.000 description 1
- 230000001851 biosynthetic Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 229910052805 deuterium Inorganic materials 0.000 description 1
- 125000004431 deuterium atoms Chemical group 0.000 description 1
- 230000018109 developmental process Effects 0.000 description 1
- 231100000676 disease causative agent Toxicity 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- -1 for example Chemical class 0.000 description 1
- 238000005755 formation reaction Methods 0.000 description 1
- 230000014509 gene expression Effects 0.000 description 1
- 230000002068 genetic Effects 0.000 description 1
- 235000013922 glutamic acid Nutrition 0.000 description 1
- 239000004220 glutamic acid Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000977 initiatory Effects 0.000 description 1
- 230000004576 lipid-binding Effects 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 229940099690 malic acid Drugs 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000003550 marker Substances 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 229940098779 methanesulfonic acid Drugs 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 230000001537 neural Effects 0.000 description 1
- 210000004255 neuroglia Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 239000000546 pharmaceutic aid Substances 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 239000003757 phosphotransferase inhibitor Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000000902 placebo Substances 0.000 description 1
- 229940068196 placebo Drugs 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000005483 tyrosine kinase inhibitor Substances 0.000 description 1
- 229940121358 tyrosine kinase inhibitors Drugs 0.000 description 1
- 230000003612 virological Effects 0.000 description 1
Abstract
A method of treating or preventing synucleinopathies in a human subject comprising administering a therapeutically effective amount of a compound of Formula I, or its pharmaceutically acceptable salt.
Description
TREATMENT FOR SYNUCLEINOPATHIES
FIELD OF THE INVENTION
The invention relates to a method of treating or preventing synucleinopathies in a human subject comprising administering a compound of Formula 1
Formula or a pharmaceutically acceptable sait thereof.
BACKGROUND OF THE INVENTION
A number of neurodegenerative diseases are characterized by the accumulation of distinct misfolded protein inclusions. Development of such inclusions often initiâtes a sériés of biochemical events that eventually culminate into the programmed death of the affected neurons. One such protein is alpha synuclein (aSYN). Alpha synuclein (aSYN) is a member of a family of soluble proteins that includes alpha, beta and gamma synuclerns. Al! synucteins hâve a common highly conserved lipid binding domain using which they associate with various phospholipid vesicles. Significant emphasis has been placed on mutations in alpha synuclein because these mutant alpha synucteins can cause autosomal, dominant, early onset, familial Parkinson’s Disease (PD).
In addition to PD, there are at least two otherdistinct neurodegenerative conditions in which alpha synuclein has been implicated as a causative agent, and these are collectively referred to as synucleinopathies. Synucleinopathies are neurodegenerative diseases characterized by the abnormal accumulation of aggregates of alpha synuclein protein in neurons, nerve fibers, astrocytes or glial cells. There are three main types of central nervous System synucleinopathies: Parkinson’s Disease (PD), Dementia with Lewy Bodies (DLB), also known as Lewy Body Dementia (LBD), and Multiple System Atrophy (MSA). In addition to these three major synucleinopathies, there is evidence that many patients with REM-sieep behavior disorder will go on to develop a synucteinopathy (McCann H et al., Parkinson ism & Related Disorders. 20 Suppl 1: S62-7, 2014). There are also rare disorders, such as various neuroaxonal dystrophies and primary autonomie faitere, characterized by central or peripheral α-synuciein-based pathologies. (Kahle P J et al., Acta Neuropathol. 115(1):87-95, 2008; Goedert M étal., J Parkinsons Dis. 7 (s1): S53-S71, 2017; Lindholm D et al„ Front. Aging Neurosci. 26; 8:254. 2016.).
One of the key events associated with varions neurodegenerative conditions including synucleinopathies is the increased expression and activation of a non-receptor protein tyrosine kinase, c-Abl, Once activated, c-Abl phosphorylâtes a diverse group of proteins (substrates of c-Abl) often altering their normal physiological functions. Alpha synucleîn is one such substrate which is phosphorylated by c-Abl on Tyrosine 39. Once phosphorylated, alpha synuctein tends to form aggregates resulting in the formation of tendrils and fibrils that eventually go on to form Lewy Bodies that are often observed in the autopsied brains of patients with synucleinopathies such as PD and LBD. Evidence from genetic models of synucleinopathies in the CNS suggests that pre-formed fibrils of alpha synucleîn are unable to cause neurodegeneration in the absence of functional c-Abl (Ko HS, et al., Proc Natl Acad Sci U S A. 21 ; 107(38):16691-6, 2010). Given the dependence of alpha synuclein-initiated neurodegenerative processes on functional c-Abl, phamnacologicai inhibition using a small molécule inhibitor of c-Abl may provide therapeutically meaningful and advantageous neuroprotective effects.
PCT publication No. WO2012098416A1 discloses many spécifie compounds which hâve tyrosine kinase inhibitory properties. One of the compounds disclosed in the ‘416’ application is
Pcmïmta t
WÎPO publication No. WO2017208267A1 discloses the use ofthe compound of Formula i for the treatment of Parkinson’s Disease (PD).
Following references describe methods for treating neurodegenerative diseases using tyrosine kinase inhibitors:
US patent application No. US20150087653A1, US20170216287, US20140045826, US20060128720, US20050043264; US patent No. US9474753, US7910586, US861806382 and WIPO application No. WO2012139027A1.
Although efforts to develop an effective treatment for PD and synucleinopathies has increased in past few years but effective disease-modifying alternatives and better symptomatic relief treatments are still necessary. Treatments or thérapies developed for PD may or may not be effective fortreating synucleinopathies like DLB and MSA. A person having ordinary skili in the art will hâve to carry out spécifie tests and trials to demonstrate the effectiveness of the therapy on these diseases.
SUMMARY OF THE INVENTION
The présent invention provides method of treating or preventing synucleinopathies in a human subject comprising administering a therapeutically effective amount of a compound of Formula 1,
or its pharmaceutically acceptable sait thereof.
In another aspect, the présent invention provides a method of treating or preventing synucleinopathies in a human subject comprising administering compound of Formula 1, or its pharmaceutically acceptable sait at a dose ranging from 0.1 mg to 1000 mg per day. In another aspect, the présent invention provîdes a method of treating or preventing synucleinopathies of the CNS, other than Parkinson’s disease, in a human subject comprising administering compound of Formula 1,
or its pharmaceutically acceptable sait at a dose ranging from 0.1 mg to 1000 mg per day.
DESCRIPTION OF THE FIGURES
Figure 1 : Nigral TH+ve cell counts (operated side).
Figure 2: Striata! TH OD (operated vs non-operated sides).
Figure 3: Striata! dopamine levels: Absolute values, operated vs non-operated sides.
DETAILED DESCRIPTION OF THE INVENTION in one aspect, the présent invention provides a method of treating or preventing synucleinopathies in a human subject comprising administering a therapeutically effective amount of the compound of Formula 1,
or its pharmaceuticaliy acceptable sait thereof.
In another aspect the présent invention provides a method of treating or preventing synucieinopathies in a human subject comprising administering compound of Formula 1,
Formula 1 or its pharmaceuticaliy acceptable sait thereof at a dose ranging from 0.1 mg to 1000 mg per day.
In an embodiment, the présent invention provides a method of treating synucieinopathies in a human subject comprising administering the compound of Formula l or pharmaceuticaliy acceptable sait thereof at a dose ranging from 10 to 500 mg per day. In an embodiment, the présent invention provides a method of treating synucieinopathies in a human subject comprising administering the compound of Formula I or pharmaceuticaliy acceptable sait thereof at a dose ranging from 100 to 600 mg per day, preferably the dose is 200 mg to 500 mg per day and more preferably, the dose is in the range of 300 mg to 400 mg. In an embodiment, the présent invention provides a method of treating synucieinopathies in a human subject comprising administering the compound of Formula I or pharmaceuticaliy acceptable sait thereof at a dose selected from 10 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, 600 mg, 650 mg, 700 mg, 750 mg or 800 mg per day.
In another aspect the présent invention provides a method of treating or preventing synucieinopathies other than Parkinson’s disease in a human subject comprising administering compound of Formula 1,
Formula I or its pharmaceutically acceptable sait thereof at a dose ranging from 5 mg to 500 mg per day.
In another embodiment, the present invention provides a method of treating or preventing synucleinopathies in a human subject comprising administering a compound of Formula I or its pharmaceutically acceptable sait, wherein synucleinopathy is Dementia with Lewy Bodies.
In another embodiment, the present invention provides a method of treating or preventing synucleinopathies in a human subject comprising administering a compound of Formula I or its pharmaceutically acceptable sait, wherein synucleinopathy is multiple system atrophy.
In another embodiment, the présent invention provides a method of treating or preventing synucleinopathies in a human subject comprising administering a compound of Formula 1 or its pharmaceutically acceptable sait, wherein synucleinopathy is associated with REM sleep behavior disorder
In another embodiment, the present invention provides a method of treating or preventing synucleinopathies in a human subject comprising administering a compound of Formula I or its pharmaceutically acceptable sait, wherein synucleinopathy is associated with neuroautonomic dystrophies and primary autonomie failure.
Suitable pharmaceutically acceptable salts of the compound of the invention may be salts of inorganîc acids such as hydrochloric acid, hydrobromîc acid, phosphoric acid, and the like or of organic acids such as, for example, acetic acid, benzenesuffonîc acid, methanesulfonic acid, benzoic acid, citric acid, glycolic acid, îactic acid, fumarie acid, succinic acid, adipic acid, pimelic acid, suberic acid, azelaic acid, malic acid, tartartic acid, or amino acids, such as glutamic acid or aspartic acid, and the like. One or more hydrogen atoms of the compound of Formula l may be deuteriated i.e. substituted with a deuterium atom.
WIPO publication WO2012098416 (the ‘416 publication) discloses a markush group of compounds active as c-Abl kinase inhibitors and their usefulness for the treatment of cancers like chronicmyelogenous leukemia (CML). Compounds of Formula l ofthe present invention may be prepared by the processes described in WO2012098416.
The compound of Formula I can be administered orally in the form of a suitable dosage form. A suitable dosage form may include tablet, pellets, capsule, sachet, peliets in sachet, pellets in capsule, powder, granules and the like. The compound of Formula I may be formulated in oral dosage form which may include pharmaceutically acceptable excipients which are in common knowledge of a person skilled in the art. Remington’s Pharmaceutical Sciences, Sixteenth Edition, E. W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses pharmaceutically acceptable carriers which can be used for préparation of a suitable dosage form.
WIPO Publication WO2017208267A1 discloses method of use of compound of Formula I for the treatment of Parkinson’s disease. The présent invention relates to the use of the compound of Formula I for diseases, other than PD, that are caused by accumulation of alpha-synuclein (aSYN) like Dementia with Lewy Bodies, Pure autonomie failure, REM sleep behavior disorder, Incidental Lewy body disease, Inherited Lewy body diseases, Lewy body dysphagia, and multiple system atrophy.
The phrase “compound of Formula Γ is used interchangeabiy with the phrase “compound F in the présent spécification and both the phrases refer to a compound having a following structure:
The following examples serve to illustrate the invention without lîmiting the invention in its scope.
Biologîcal studies
Neuroprotective potentiel of Compound I in a rat model of synucleinopathy
Compound l was evaluated in a adeno-associated virus (AAV) AAV1/2 alpha synuclein rat model based upon AAV1/2-medtated delivery and over-expression of human A53T alphasynuclein (hA53T-aSYN) in the strlatonigral région of the midbrain of femaie Sprague Dawley (SD) rats (Koprich et al, PLoS One. 7;6(3):e17698,2011). The study was designed to assess the ability of Compound I to protect dopaminergic neurons from virai vector mediated over-expression of aSYN leading to neurodegeneration in rat model. This model is typically used as a model for aSYN-induced Parkinsonism, but may serve as a model for aSYN-induced neuronal loss in general. AAV1/2 hA53T-aSYN (a viral vector delivering the capability to express human A53T mutant aSYN), or the control AAV1/2 empty vector, was 5 injected stereotactically and unilaterally, into the striatal région of the midbrain. Rats were treated orally with Compound i (melt extrusion suspension), once daily, to provide équivalent doses of Compound I at 15, 30 and 45 mg/kg.
AAV1/2 hA53T-aSYN or empty AAV1/2 vector was administered sterotactically and 10 unilaterally into the right striatal région on Day 1. Starting on Day 2 and continuing daily until Day 42, animais were fasted for 6 hr prior to oral administration of Compound I or vehicle (placebo). Food was reintroduced 60 minutes iater. A total of 5 groups of animais, each group N=12, were employed.
| Group | Initiation | Treatment | N |
| A | Empty Vector AAV1/2 | Vehicle | 12 |
| B | AAV1/2-hA53T-aSYN | Vehicle | 12 |
| C | Compound I (15 mg/kg) | 12 | |
| D | Compound 1 (30 mg/kg) | 12 | |
| E | Compound 1 (45 mg/kg) | 12 |
Animais were killed for post-mortem assessments on Day 43, at least 18 h after last administration of Compound I or vehicle. Brains were removed along with the terminal blood collection.
As a conséquence of localized synucleinopathy caused by the AAV1/2-encoded hA53T aSYN at or near the site of injection, tyrosine hydroxylase (TH)-expressing dopaminergic neurons in the affected striatonigrai area degenerate (Koprich et al., PLoS One., 7;6(3):e17698, 2011). Number of tyrosine hydroxylase positive (TH+ve) cells within the striatonigrai région of the right side of the brain (injected side), were assessed using rmmunohistochemistry and stereological cell counting. Tyrosine hydroxylase is a critical enzyme involved in dopamine biosynthesis and thus, its presence can be used as a marker of live neurons capable of producing dopamine.
As shown in Figure 1, animais injected with AAV1/2 encoding hA53T aSYN on the right side of the brain exhibited signrficant loss (p < 0.05) of TH*” neurons in the striatonigrai région compared to the animais that were injected, also on the nght side of the brain, with the empty vector AAV1/2 incapable of expressing aSYN and also received vehicle for the treatment period. In contrast, the loss of TH+ve neurons due to synucleinopathy in animais that were injected on the right side of the brain with AAV1/2 encoding hA53T aSYN and treated with different daily oral doses of Compound I was proportional to the dose of Compound I. Treatment with lower doses of Compound I (15 and 30 mg/kg) showed significant réduction (p < 0.05) in TH+we neurons in the striatonigral région compared to the control animais that received empty AAV1/2 incapable of causing synucleinopathy. In contrast, animais injected with AAV1/2 encoding hA53T aSYN and dosed with 45 mg/kg of Compound I did not show significant réduction (p > 0.05) in TH+ve neurons in the striatonigral région indicative of the neuroprotective effect of Compound i at this dose.
Optical densities of striatonigral TH-expressing neurons from the operated side of the brain of animais, that received the injection of AAV1/2 encoding hA53T aSYN, was compared with that from the non-operated side of the same animais that did not show synucleinopathy. Hence for any treatment, a comparison between the operated side and non-operated side provides a clear reflection of effects on the disease State. As shown in Figure 2, in animais that received AAV1/2 (empty vector), there was no significant différence in TH*’'® optical densities from the left (non-operated) and right (operated) side ofthe brain. In contrast, animais that received AAV1/2 hA53T aSYN vectoron the ride side of the brain (operated side) showed significantly lower (p <0.01) TH+ue optical densities compared to that from the non-operated parts of their brain. Compound l at doses of 30 and 45 mg/kg, but not at 15 mg/kg, showed significant neuroprotective effect refiected in the statistically insignificant différence (p > 0.05) between the optical densities from left (non-operated) and right (operated) sides of the brain.
In the example of AAV1/2 hA53T aSYN-induced synucleinopathy studied here, striatonigral TH+ve neurons capable ofsynthesizing dopamine were shown to be degenerated. Whether or not the neuroprotection of TH+7e dopaminergic neurons conferred by Compound I resulted in the increased production of dopamine was further examined. Hence the total dopamine levels of both the operated right side and non-operated left side of the brain of the animais under study were quantified. As shown in Figure 3, dopamine levels from the operated diseased right side of the brain were always lower, as a conséquence of synucleinopathy-associated neuro- degeneration, than their respective non-operated counterparts on the left side. Compound I at doses 15 and 30 mg/kg failed to restore the dopamine biosynthetic capability in the operated diseased right side of the brain. In contrast, in animais dosed at45 mg/kg of Compound I, while the dopamine levels produced from the right diseased side of the brain were still lower than that from its left counterpart, there appeared to be a graduai increase in the dopamine producing capabiiity of the diseased part of the brain proportional to the dose of Compound i reflecting its abîlity to not only protect neurons from degeneration but also help restore their functionaiity. Administration of Compound l at doses higher than 45 mg/kg may reduce this différence even further.
In conclusion, these studies collectively suggest that Compound I confers significant 10 protection against neurodegene ration caused by synucfeinopathy and help restore their functionaiity. This neuroprotective activity of Compound i supports therapeutic applications of compound 1 in various disease indications attributed to synucleinopathy.
Claims (6)
1. A compound of Formula 1,
or a pharmaceutically acceptable sait thereof, for use in treating or preventing synucleinopathies in a human subject, wherein synucleinopathy is Dementia with Lewy Bodies (DLB) or Multiple System Atrophy (MSA) or associated with REM sleep behavior disorder.
2. The compound for use as in claim 1, wherein the compound of Formula I is administered at a dose in the range of 100 mg to 600 mg per day.
3. The compound for use as in claim 1, wherein the compound of Formula I is administered at a dose in the range of 300 mg to 500 mg per day.
4. The use of a compound of Formula 1,
or a pharmaceutically acceptable sait thereof, in the manufacture of a médicament for treating or preventing synucleinopathies in a human subject, wherein synucleinopathy is Dementia with Lewy Bodies (DLB) or Multiple System Atrophy (MSA) or associated with REM sleep behavior disorder.
5. The use as in claim 4, wherein the compound of Formula I is administered ai a dose in the range of 100 mg to 600 mg per day.
6. The use as in claim 4, wherein the compound of Formula l is administered at a dose in the range of 300 mg to 500 mg per day.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN201921023164 | 2019-06-11 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| OA20556A true OA20556A (en) | 2022-10-27 |
Family
ID=
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Weinbroum et al. | Dextromethorphan and dexmedetomidine: new agents for the control of perioperative pain | |
| EP1708790B1 (en) | Use of pipamperone and a d2-receptor antagonist or a serotonin/dopamin antagonist for the treatment of psychotic disorders | |
| JP2014517050A5 (en) | ||
| JP2000514420A (en) | Use of K-252A Derivatives for the Treatment of Peripheral or Central Nervous Disorders and Cytokine Overproduction | |
| AU2012281042B2 (en) | Combination ALS therapy | |
| KR20170104597A (en) | Induced expression of brain-derived neurotrophic factor (BDNF) for the treatment of neuromuscular, neurodegenerative, autoimmune, developmental and / or metabolic diseases | |
| US11547700B2 (en) | Compositions and methods for treating synucleinopathies | |
| HU222039B1 (en) | Use of 1-(2-naphth-2-ylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine for preparing drugs for treating amyotrophic lateral sclerosis | |
| US20220257582A1 (en) | Treatment for synucleinopathies | |
| JP2021167361A (en) | Method of treating neurodegenerative disorders | |
| JP2023504731A (en) | Peptide compositions and methods for treating tauopathies | |
| OA20556A (en) | Treatment for synucleinopathies | |
| US10300068B2 (en) | Method of treating insomnia | |
| WO2018217845A1 (en) | Pharmaceutical combinations of zonisamide and praxipexole, and related methods, for treating synucleinopathies | |
| Aminoff | Basic & Clinical Pharmacology | |
| Zhang et al. | Opposite in vivo effects of agents that stimulate or inhibit the glutamate/cysteine exchanger system on the inhibition of hippocampal LTP by Aß | |
| DE60125062T2 (en) | Quetiapine for the treatment of dyskinesia in non-psychotic patients | |
| CA3096453A1 (en) | Pharmaceutical combination comprising fluoxetine and pramipexole and its use for treating synucleinopathies | |
| BR112019021125A2 (en) | COMBINATION OF NK1 ANTAGONIST AND METHOD FOR TREATING SYNUCLEINOPATHIES | |
| KR20000029647A (en) | Method for treating bipolar disorder | |
| US20200281928A1 (en) | Vitamin b1 in high doses for use in the medical treatment of motor symptoms of some sporadic neurodegenerative diseases, of genetic origin, and of cluster headache and of migraine headache | |
| Mucke | Repurposing for Alzheimer’s and Parkinson’s Diseases: The Ideas, the Pipeline, the Successes, and the Disappointments | |
| Dutta et al. | A Clinical Study for Removal of Impacted Mandibular Third Molar under Local Anaesthesia, with and without Ketamine-A Split Mouth Comparative Study | |
| Pae et al. | Effect of aripiprazole for a patient with psychotic symptoms and parkinsonism associated with delayed-sequelae of carbon monoxide intoxication | |
| EP2991645B1 (en) | Biotin for use in treating x-linked adrenoleukodystrophy |