CN107823643B - Prevention or drug, target spot and its application for the treatment of Alzheimer's disease - Google Patents
Prevention or drug, target spot and its application for the treatment of Alzheimer's disease Download PDFInfo
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- CN107823643B CN107823643B CN201711070024.4A CN201711070024A CN107823643B CN 107823643 B CN107823643 B CN 107823643B CN 201711070024 A CN201711070024 A CN 201711070024A CN 107823643 B CN107823643 B CN 107823643B
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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 reductases 1 as prevention or the application of the drug targets for the treatment of Alzheimer's disease, and the drug is 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 inhibit the activity of GMPR1, 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 fields, and in particular to prevention or drug, target spot and its application for the treatment of Alzheimer's disease.
Background technique
Alzheimer's disease is a kind of neurodegenerative disease for seriously endangering human health, is mainly showed on molecular level
The nerve that Amyloid-beta outside for nerve cell is precipitated and formed into the cell due to the assembly of the Tau albumen of phosphorylation is fine
Dimension tangles (NFT).Both factors eventually lead to neuronal death by complex process, thereby result in patient's memory and cognition function
The degeneration of energy is lost.
Currently, the drug of the treatment Alzheimer's disease of food and medicine surveillance authority, the U.S. (FDA) approval has: donepezil,
galantamine,memantine,rivastigmine,donepezil+memantine.The main mechanism of action of these drugs
It is to improve neurotransmitter system or modification disease pathway, and then alleviate symptom, (Nature reviews can not be cured
Drug discovery,2010,9(5):387-398).Also there is research to be directed to the vaccine (AADvac1) of Tau albumen at present,
Preclinical stage, final effect are unknown.
It was found that the change of disease pathway most upstream, then finds that drug is treated, this is can fundamentally to cure Ah
The thinking of Er Cihaimo disease.Current drug targets are mostly disease pathway middle and lower reaches, tend not to all correct pathologic process.
Thus, it is found that the most fundamental original change (cause of disease) of Alzheimer's disease, then target administration, it may be possible to be most hopeful to cure Ah
A kind of strategy of Er Cihaimo disease.
Summary of the invention
Goal of the invention: in order to solve the above-mentioned technical problem, the first purpose of this 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 reduction
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 combinations thereof object and treats in preparation
Or the application in prevention Alzheimer disease drug.
The chemical formula of Lumacaftor of the invention: C24H18F2N2O5, molecular structural formula is as follows:
The cytotropic guanosine monophosphate reductase 1 (GMPR1) of Lumacaftor (VX-809) target of the 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 and Alzheimer's disease
Connection, GMPR1 level increase cause the phosphorylation level of Tau albumen in nerve cell to increase, and increase nerve fibre and tangle, lead to mind
Through first dead.Lumacaftor can inhibit the activity of GMPR1, and then prevent neuronal death, cure Alzheimer's disease.
Technical solution: the technical solution of the present invention is as follows: guanosine monophosphate reductase 1 is as prevention or treatment A Er
The application of the drug targets of Ci Haimo disease.
Wherein, the guanosine monophosphate reductase 1 is the target spot of prevention or treatment Alzheimer's disease.
Wherein, said medicine is Lumacaftor or derivatives thereof or the pharmaceutical composition containing Lumacaftor.
Wherein, the drug of above-mentioned treatment or prevention Alzheimer's disease includes but is not limited only to one-component or compound preparation.
The dosage form of the drug 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 solution, syrup, dripping pill, parenteral solution formulation or freeze-dried powder dosage form.
The content of present invention further includes above-mentioned Lumacaftor or derivatives thereof or its pharmaceutical composition in building A Erci
Application in the silent disease animal model in sea.
The content of present invention further includes above-mentioned Lumacaftor or derivatives thereof or its pharmaceutical composition in building 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.
It is calculated by the effective dose of heretofore described Alzheimer's disease mouse to clinical adult (60 kilograms)
The every 12 hours dosages of Lumacaftor or derivatives thereof are 200mg~400mg.
In the present invention such as about the research of Lumacaftor treatment Alzheimer's disease (Alzheimer ' s disease)
Under:
The first, inventor show that guanosine monophosphate reductase 1 (GMPR1) is Alzheimer by research for the first time
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 it is aggravated with the course of disease and increases (Fig. 2).GMPR1 passes through AMPK and A1/A2 receptor
Approach is associated with the phosphorylation of the important feature Tau of Alzheimer's disease.GMPR1 increases, and Tau phosphorylation increases, intracellular mind
It tangles (NFT) through fiber to increase, neuronal death.Therefore, GMPR1 is the good targets for treating Alzheimer's disease.
Second, inventor show that the drug Lumacaftor in the present invention is effective inhibition of GMPR1 by research for the first time
Agent.
For the crystal structure (PDB ID:2BLE) of GMPR1, using molecular docking (docking) method, from by the end of
Screening has the drug of high-affinity structure, discovery with GMPR1 in 1174 kinds of drugs of FDA in March, 2017 approval
Lumacaftor has high compatibility (Fig. 3, Δ G=-8.0Kcal/mol, P-value=0.022).
Therefore, Lumacaftor is effective inhibitor of GMPR1, is a kind of drug for treating Alzheimer's disease.Ah
Its therapeutic effect is demonstrated in Er Cihaimo disease model mice.After administration 20 days, in the brain of Alzheimer's disease model mice
Area, Tau phosphorylation are almost removed (Fig. 4), moreover, accumulative not also being further added by of Amyloid-beta precipitating, integrally shows
Good curative effect.
The utility model has the advantages that the present invention is screened from 1174 kinds of drugs that FDA ratifies by molecular docking technology
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 phosphorylation are almost removed, moreover, accumulative not also being further added by of Amyloid-beta precipitating,
Entirety shows good curative effect.
Detailed description of the invention
Fig. 1 is the expression conditions analysis chart of Alzheimer Disease patient (AD) and normal healthy people (Non-AD)；Fig. 1
In, the expression for encoding the gene GMPR of guanosine monophosphate reductase 1 (GMPR1) is aobvious in Alzheimer Disease patient brain
It writes and is higher than normal person, chip data comes from the gene expression collection (GEO) of National Center for Biotechnology Information (NCBI), data
Accession number are as follows: 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 indicates gene in the ratio of the expression average value of Alzheimer Disease patient group and health group
(log2), i.e. log2 [average valueAD/ average valueNon_AD], the high expression in AD is indicated on the right of abscissa 0；Ordinate is that gene exists
Otherness conspicuousness P the value (- log of expression in AD and Non-AD10) ,-log (P) is bigger, and difference is more significant；From two
Sample t-test (two-sample t-test)；In figure, ■ represents the position in the coordinate where gene GMPR, from the gene
The abscissa positions of GMPR it can be concluded that, gene GMPR expression quantity is in high expression level, from the ordinate P of gene GMPR
Be worth position it can be concluded that, the otherness of the expression of the gene is significant；
Fig. 2 is to encode the gene of 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, encode guanosine monophosphate reductase 1 (GMPR1) gene GMPR expression with Alzheimer's disease
It aggravates and increases, chip data comes from the gene expression collection (GEO) of National Center for Biotechnology Information (NCBI), and data are stepped on
Record number are as follows: GSE28146, data include that 8 healthy persons and 7 initial, 8 moderates and 7 severe Alzheimer's diseases are suffered from
Person；
The result figure of Fig. 3 Lumacaftor and guanosine monophosphate reductase 1 (GMPR1) molecular docking；Left figure, entirely
Looks；Right figure acts on details；Δ G is affine energy；Docking is with the completion of Autodock 4.0；GMPR1 crystal structure: PDB ID:
2BLE, resolution ratio
The assessment experimental result picture of Fig. 4 Lumacaftor treatment Alzheimer's disease mouse.Control is the A Er not being administered
Ci Haimo disease mouse 6, each sampling 2 at the 0th, 10,20 day.Treatment group is Alzheimer's disease mouse 8 of administration, is being given
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 area, and average.Right figure, Tau phosphorylation
Positive neuron number randomly chooses 3 regions from the top, temporal lobe and hippocampus of mouse respectively, calculates Tau phosphorylation sun
Property (PHF-1+) neuron number, and it is average；The antibody PHF-1 of Tau phosphorylation.
Specific embodiment:
Embodiment 1: the screening of molecular docking method obtains Lumacator drug
The 1174 kinds of drug molecules ratified by the end of FDA in March, 2017 are docked respectively at GMPR1.Docking uses
AutoDockVina tool completes (J Computational Chemistry, 2010,31 (2): 455-461).Drug molecule three
It ties up structure and (J Cheminformatics, 2011,3:33) is completed by Babel 2.4.0.In docking, GMPR1 is receptor, thirdly
It ties up structure and comes from protein data bank (PDB ID:2BLE)；Drug molecule is ligand.Docking lattice point includes entire GMPR1, search
Space isCompound compatibility is the compatibility (Δ G) that AutoDockVina is calculated.Experience P value is from 1174
It is estimated in a docking result.The result shows that Lumacaftor and GMPR1 have high compatibility (Fig. 3), it is the inhibitor of GMPR1.
Embodiment 2:Lumacator therapeutic process and recruitment evaluation in Alzheimer's disease mouse
1, experimental design
Alzheimer's disease mouse B6C3-Tg (APPswePSEN1dE9Nju)/Nju is ground from Nanjing University's model animal
Study carefully institute.Control group is Alzheimer's disease mouse 6 not be administered, each sampling 2 at the 0th, 10,20 day.Treatment group is administration
Alzheimer's disease mouse 8, in each grab sample 4 in the 10th, 20 day of administration.49.5 ± 4.5 grams of weight (g).Age:
11 months.
2, it is administered
Dosage: 0.3332mg Lumacaftor (+5% propylene glycol of+0.5% thorn 80 (Tween80) of 30% polyethylene glycol+
64.5% secondary distilled water)；Usage: every 12 hours primary；It adds oiliness food (melon seeds).
3, immunohistochemistry detects
Antibody-β-Amyloid (D12B2), Rabbit mAb#9888 (CST biological reagent, Shanghai).Anti- Tau phosphorylation
404/396 antibody of site (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 phosphorylation, and make even
Mean value.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 phosphorylation
It is almost removed, moreover, accumulative not also being further added by of Amyloid-beta (β-Amyloid) precipitating, integrally shows good
Curative effect.
Claims (5)
1. using guanosine monophosphate reductase 1 as target in the drug of preparation prevention or treatment Alzheimer's disease
Using.
2. application according to claim 1, which is characterized in that the drug is Lumacaftor or derivatives thereof or contains
The pharmaceutical composition of Lumacaftor.
3. application according to claim 1, which is characterized in that the treatment or prevention Alzheimer disease drug includes single
Component or compound preparation.
4. application according to claim 1, which is characterized in that the dosage form for treating or preventing Alzheimer disease drug
To include tablet, capsule, oral solution, dripping pill, parenteral solution formulation or freeze-dried powder dosage form.
5. application according to claim 4, which is characterized in that the tablet is sustained release tablets or controlled release tablet, the oral solution
For syrup.
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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 of 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 of 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 |
|---|
| Alzheimer’s disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes;Shobana Sekar et al;《Neurobiology of Aging》;20141002;第36卷(第2期);第583-591页 |
| Identifying Unexpected Therapeutic Targets via Chemical-Protein Interactome;Lun Yang et al;《PLOS ONE》;PLOS ONE;20100308;第5卷(第3期);第A71-A81页 |
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