CN107823643A - Prevention or medicine, target spot and its application for the treatment of Alzheimer's disease - Google Patents
Prevention or medicine, target spot and its application for the treatment of Alzheimer's disease Download PDFInfo
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- CN107823643A CN107823643A CN201711070024.4A CN201711070024A CN107823643A CN 107823643 A CN107823643 A CN 107823643A CN 201711070024 A CN201711070024 A CN 201711070024A CN 107823643 A CN107823643 A CN 107823643A
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
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Abstract
The invention discloses guanosine monophosphate reductase 1 as preventing or the application of the drug targets for the treatment of Alzheimer's disease, the medicine are Lumacaftor or derivatives thereof or the pharmaceutical composition containing Lumacaftor.The level of guanosine monophosphate reductase 1 (GMPR1) is higher than healthy person in Alzheimer Disease patient, is the therapy target of Alzheimer's disease.The Lumacaftor can suppress GMPR1 activity, and then prevent neuronal death, cure Alzheimer's disease.The present invention filters out Lumacaftor by molecular docking technology in all known drugs, and its therapeutic effect is demonstrated in Alzheimer's disease model mice.
Description
Technical field
The invention belongs to drug field, and in particular to prevention or medicine, target spot and its application for the treatment of Alzheimer's disease.
Background technology
Alzheimer's disease is a kind of nerve degenerative diseases for seriously endangering human health, is mainly showed on molecular level
Amyloid-beta precipitations outside for nerve cell and the nerve formed into the cell due to the assembling of the Tau albumen of phosphorylation are fine
Dimension is tangled (NFT).Both factors ultimately result in neuronal death by complex process, thereby result in patient's memory and cognition work(
The degeneration of energy is lost.
At present, the medicine of the treatment Alzheimer's disease of U.S.'s food and medicine surveillance authority (FDA) approval has：donepezil、
galantamine、memantine、rivastigmine、donepezil+memantine.The main mechanism of action of these medicines
It is to improve neurotransmitter system or modification disease pathway, and then relief of symptoms, (Nature reviews can not be cured
Drug discovery,2010,9(5):387-398).Also there is vaccine (AADvac1) of the research for Tau albumen at present,
Preclinical stage, final effect are unknown.
It was found that the change of disease pathway most upstream, then finds that medicine is treated, this is can fundamentally to cure Ah
The thinking of Er Cihaimo diseases.Current drug targets are mostly disease pathway middle and lower reaches, tend not to all correct pathologic process.
Thus, it is found that the original change (cause of disease) that Alzheimer's disease is most basic, then target administration, it may be possible to be most hopeful to cure Ah
One kind strategy of Er Cihaimo diseases.
The content of the invention
Goal of the invention：In order to solve the above-mentioned technical problem, first purpose of the invention is the provision of guanosine
Monophosphate reductase 1 is as prevention or the application of the drug targets for the treatment of Alzheimer's disease.Guanosine monophosphate reduces
Enzyme 1 is the target spot for treating Alzheimer's disease.
Second object of the present invention is the provision of Lumacaftor or derivatives thereof or its composition and is preparing treatment
Or the application in prevention Alzheimer disease drug.
The Lumacaftor of present invention chemical formula：C24H18F2N2O5, molecular structural formula is as follows：
The cytotropic guanosine monophosphate reductase 1 (GMPR1) of Lumacaftor (VX-809) target of the present invention, and
GMPR1 is higher than healthy person in Alzheimer Disease patient brain level, and its horizontal progress with the silent disease in Wurz sea gradually increases.
GMPR1 is closed by Adenylate cyclase (AMPK) approach and adenosine acid acceptor (A1/A2) approach with Alzheimer's disease
Connection, the horizontal increases of GMPR1 cause the phosphorylation level of Tau albumen in nerve cell to increase, and increase nerve fibre tangles, and causes god
Through first dead.Lumacaftor can suppress GMPR1 activity, and then prevent neuronal death, cure Alzheimer's disease.
Technical scheme：The technical scheme is that：Guanosine monophosphate reductase 1 is as prevention or treatment A Er
The application of the drug targets of Ci Haimo diseases.
Wherein, the guanosine monophosphate reductase 1 is prevention or the target spot for treating Alzheimer's disease.
Wherein, said medicine is Lumacaftor or derivatives thereof or the pharmaceutical composition containing Lumacaftor.
Wherein, the medicine of above-mentioned treatment or prevention Alzheimer's disease includes but is not limited only to one-component or compound preparation.
The formulation of the medicine of above-mentioned treatment or prevention Alzheimer's disease be comprising but be not limited only to tablet, capsule, sustained release
Piece, controlled release tablet, oral liquid, syrup, dripping pill, parenteral solution formulation or freeze-dried powder formulation.
Present invention also includes above-mentioned Lumacaftor or derivatives thereof or its pharmaceutical composition in structure A Erci
Application in the silent disease animal model in sea.
Present invention also includes above-mentioned Lumacaftor or derivatives thereof or its pharmaceutical composition in structure A Erci
Application in the silent disease mouse model in sea.
Preferably, every 12 hours Lumacaftor of every kilogram of Alzheimer's disease mouse or derivatives thereof in the present invention
Dosage is 3.33mg (milligram)~6.66mg.
Calculated by the effective dose of heretofore described Alzheimer's disease mouse to clinic and be grown up (60 kilograms)
The every 12 hours dosages of Lumacaftor or derivatives thereof are 200mg~400mg.
In the present invention research of Alzheimer's disease (Alzheimer ' s disease) is treated on Lumacaftor such as
Under：
Firstth, inventor show that guanosine monophosphate reductase 1 (GMPR1) is Alzheimer first by research
The target of disease treatment.Guanosine monophosphate reductase 1 (GMPR1) level is significantly higher than in Alzheimer Disease patient brain
Normal person (Fig. 1, P=1 × 10-6,t-test)；And aggravated with the course of disease and increase (Fig. 2).GMPR1 passes through AMPK and A1/A2 acceptors
Approach associates with the key character Tau of Alzheimer's disease phosphorylation.GMPR1 increases, the increase of Tau phosphorylations, intracellular god
(NFT) increase, neuronal death are tangled through fiber.Therefore, GMPR1 is the good targets for treating Alzheimer's disease.
Second, inventor is by studying effective suppression that the medicine Lumacaftor drawn first in the present invention is GMPR1
Agent.
For GMPR1 crystal structure (PDB ID：2BLE), using molecular docking (docking) method, from by the end of
Screening has the medicine of high-affinity structure with GMPR1 in 1174 kinds of medicines of in March, 2017 FDA approvals, finds
Lumacaftor has high compatibility (Fig. 3, Δ G=-8.0Kcal/mol, P-value=0.022).
Therefore, Lumacaftor is GMPR1 effective inhibitor, is a kind of medicine for treating Alzheimer's disease.Ah
Its therapeutic effect is demonstrated in Er Cihaimo disease model mices.After administration 20 days, in the brain of Alzheimer's disease model mice
Area, Tau phosphorylations are almost eliminated (Fig. 4), moreover, accumulative not also being further added by of Amyloid-beta precipitations, integrally shows
Good curative effect.
Beneficial effect：Screened in 1174 kinds of medicines that the present invention is ratified by molecular docking technology from FDA
Lumacaftor, and its therapeutic effect is demonstrated in Alzheimer's disease model mice.After administration 20 days, in alzheimer '
The brain area of silent disease model mice, Tau phosphorylations are almost eliminated, moreover, accumulative not also being further added by of Amyloid-beta precipitations,
Entirety shows good curative effect.
Brief description of the drawings
Fig. 1 is the expression conditions analysis chart of Alzheimer Disease patient (AD) and normal healthy people (Non-AD)；Fig. 1
In, the gene GMPR of coding guanosine monophosphate reductase 1 (GMPR1) expression shows in Alzheimer Disease patient brain
Work is higher than normal person, and chip data comes from the gene expression collection (GEO) of American National Biotechnology Information center (NCBI), data
Accession number is：GSE36980, data include 32 Alzheimer Disease patients and 47 normal healthy people controls；It is each in Fig. 1
Point represents a kind of gene, and abscissa represents gene in Alzheimer Disease patient group and the ratio of the expression average value of health group
(log2), i.e. log2 [average valuesAD/ average valueNon_AD], the right of abscissa 0 represents the high expression in AD；Ordinate is that gene exists
Otherness conspicuousness P the values (- log of expression in AD and Non-AD10) ,-log (P) is bigger, and difference is more notable；From two
Sample t-test (two-sample t-test)；In figure, ■ represents the position in the coordinate where gene GMPR, from the gene
GMPR abscissa positions can show that gene GMPR expression quantity is in high expression level, from gene GMPR ordinate P
Value position can show that the otherness of the expression of the gene is notable；
Fig. 2 is the gene of coding guanosine monophosphate reductase 1 (GMPR1) in healthy person, initial Alzheimer
Gene expression dose analysis chart in disease patient, moderate Alzheimer Disease patient and severe Alzheimer Disease patient；From Fig. 2
In find out, coding guanosine monophosphate reductase 1 (GMPR1) gene GMPR expression with Alzheimer's disease
Aggravate and increase, chip data comes from the gene expression collection (GEO) of American National Biotechnology Information center (NCBI), and data are stepped on
Record number is：GSE28146, data include 8 healthy persons, and 7 initial, 8 moderates and 7 severe Alzheimer's diseases are suffered from
Person；
Fig. 3 Lumacaftor and the result figure of guanosine monophosphate reductase 1 (GMPR1) molecular docking；Left figure, entirely
Looks；Right figure, act on details；Δ G is affine energy；Docking is completed with Autodock 4.0；GMPR1 crystal structures：PDB ID：
2BLE, resolution ratio
Fig. 4 Lumacaftor treat the assessment experimental result picture of Alzheimer's disease mouse.The A Er for compareing not to be administered
Ci Haimo diseases mouse 6, each sampling 2 at the 0th, 10,20 day.Treatment group for administration Alzheimer's disease mouse 8, to
Each grab sample 4 in 10th, 20 day of medicine.Left figure, average Amyloid-beta (β-Amyloid) area, from the top of mouse
Leaf, temporal lobe and hippocampus randomly choose 3 regions respectively, calculate Amyloid-beta areas, and average.Right figure, Tau phosphorylations
Positive neuron number, 3 regions are randomly choosed respectively from the top, temporal lobe and hippocampus of mouse, calculate Tau phosphorylations sun
Property (PHF-1+) neuron number, it is and average；The antibody PHF-1 of Tau phosphorylations.
Embodiment：
Embodiment 1：The screening of molecular docking method obtains Lumacator medicines
1174 kinds of drug molecules that FDA ratifies by the end of in March, 2017 are docked respectively at GMPR1.Docking uses
AutoDockVina instruments complete (J Computational Chemistry, 2010,31 (2):455-461).Drug molecule three
Tie up structure completed by Babel 2.4.0 (J Cheminformatics, 2011,3:33).In docking, GMPR1 is acceptor, thirdly
Dimension structure comes from protein data bank (PDB ID：2BLE)；Drug molecule is part.Docking lattice point includes whole GMPR1, searches for
Space isCompound compatibility is the compatibility (Δ G) that AutoDockVina is calculated.Experience P values are from 1174
Estimated in individual docking result.As a result show that Lumacaftor and GMPR1 has high compatibility (Fig. 3), be GMPR1 inhibitor.
Embodiment 2：Lumacator therapeutic process and recruitment evaluation in Alzheimer's disease mouse
1st, experimental design
Alzheimer's disease mouse B6C3-Tg (APPswePSEN1dE9Nju)/Nju is ground from Nanjing University's model animal
Study carefully institute.Control group is the Alzheimer's disease mouse 6 not being administered, each sampling 2 at the 0th, 10,20 day.Treatment group is administration
Alzheimer's disease mouse 8, each grab sample 4 in the 10th, 20 day in administration.49.5 ± 4.5 grams of body weight (g).Age：
11 months.
2nd, it is administered
Dosage：0.3332mg Lumacaftor (propane diols of+0.5% TWEEN80 80 (Tween80) of 30% polyethylene glycol+5%+
64.5% redistilled water)；Usage：Every 12 hours once；Add oiliness food (melon seeds).
3rd, SABC detects
Antibody-β-Amyloid (D12B2), Rabbit mAb#9888 (CST biological reagents, Shanghai).Anti- Tau phosphorylations
The antibody of site 404/396 (anti-PHF-1antibody), ab184951 (Abcam, Shanghai).Lumacaftor (VX-809),
Selleck Chemicals(Texas USA)。
3 regions are randomly choosed respectively from the top of control group mice and treatment group mouse, temporal lobe and hippocampus respectively, are counted
Amyloid-beta (β-Amyloid) area is calculated, and is averaged.Respectively from the top of control group mice and treatment group mouse,
Temporal lobe and hippocampus randomly choose 3 regions respectively, calculate the number of positive (PHF-1+) neuron of Tau phosphorylations, and make even
Average.Treatment results are shown in Fig. 4, after administration 20 days, in the brain area for the treatment of group's Alzheimer's disease model mice, Tau phosphorylations
Almost it is eliminated, moreover, accumulative not also being further added by of Amyloid-beta (β-Amyloid) precipitations, integrally shows good
Curative effect.
Claims (9)
1. guanosine monophosphate reductase 1 is as prevention or the application of the drug targets for the treatment of Alzheimer's disease.
2. application according to claim 1, it is characterised in that the guanosine monophosphate reductase 1 be treatment Ah
The target spot of Er Cihaimo diseases.
3. application according to claim 1, it is characterised in that the medicine is Lumacaftor or derivatives thereof or contained
Lumacaftor pharmaceutical composition.
4. application according to claim 1, it is characterised in that it is described treatment or prevention Alzheimer disease drug include but
It is not limited only to one-component or compound preparation.
5. application according to claim 1, it is characterised in that the formulation for treating or preventing Alzheimer disease drug
For comprising but be not limited only to tablet, capsule, sustained release tablets, controlled release tablet, oral liquid, syrup, dripping pill, parenteral solution formulation or freeze-dried powder
Formulation.
6. application according to claim 4, described Lumacaftor or derivatives thereof or its composition are in structure A Er
Application in Ci Haimo disease animal models.
7. application according to claim 4, described Lumacaftor or derivatives thereof or its composition are in structure A Er
Application in Ci Haimo disease mouse models.
8. application according to claim 7, it is characterised in that every 12 hours of every kilogram of Alzheimer's disease mouse
Lumacaftor or derivatives thereof dosage is 3.33 mg ~ 6.66mg.
9. according to the application described in any one of claim 1~8, it is characterised in that per 60kg Alzheimer Disease patients every 12
Hour Lumacaftor or derivatives thereof dosage is the mg of 200mg ~ 400.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201711070024.4A CN107823643B (en) | 2017-11-03 | 2017-11-03 | Prevention or drug, target spot and its application for the treatment of Alzheimer's disease |
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| CN201711070024.4A CN107823643B (en) | 2017-11-03 | 2017-11-03 | Prevention or drug, target spot and its application for the treatment of Alzheimer's disease |
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| CN107823643B CN107823643B (en) | 2019-09-10 |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102174099A (en) * | 2011-01-28 | 2011-09-07 | 河北农业大学 | Target protein for Alzheimer's disease and coding gene and application thereof |
| WO2011127290A2 (en) * | 2010-04-07 | 2011-10-13 | Vertex Pharmaceuticals Incorporated | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
| US20170304287A1 (en) * | 2016-04-25 | 2017-10-26 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
-
2017
- 2017-11-03 CN CN201711070024.4A patent/CN107823643B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011127290A2 (en) * | 2010-04-07 | 2011-10-13 | Vertex Pharmaceuticals Incorporated | Solid forms of 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl) cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoic acid |
| CN102174099A (en) * | 2011-01-28 | 2011-09-07 | 河北农业大学 | Target protein for Alzheimer's disease and coding gene and application thereof |
| US20170304287A1 (en) * | 2016-04-25 | 2017-10-26 | Druggability Technologies Ip Holdco Limited | Pharmaceutical combination composition comprising complex formulations of ivacaftor and lumacaftor and their salts and derivatives, process for their preparation thereof and pharmaceutical compositions containing them |
Non-Patent Citations (2)
| Title |
|---|
| LUN YANG ET AL: "Identifying Unexpected Therapeutic Targets via Chemical-Protein Interactome", 《PLOS ONE》 * |
| SHOBANA SEKAR ET AL: "Alzheimer’s disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes", 《NEUROBIOLOGY OF AGING》 * |
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