CN109303782A - Application of the JNK-IN-8 in the neuroprotective agent for preparing Local Electroretinogram - Google Patents
Application of the JNK-IN-8 in the neuroprotective agent for preparing Local Electroretinogram Download PDFInfo
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- CN109303782A CN109303782A CN201811242480.7A CN201811242480A CN109303782A CN 109303782 A CN109303782 A CN 109303782A CN 201811242480 A CN201811242480 A CN 201811242480A CN 109303782 A CN109303782 A CN 109303782A
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
Abstract
The application that the invention discloses JNK-IN-8 in the neuroprotective agent for preparing Local Electroretinogram; JNK-IN-8 passes through specific inhibition JNK signal path; inhibit photoreceptor cell death, maintain the integrality of retina, to play the role of protecting retina.Since JNK-IN-8 can effectively penetrate blood retina barrier in animal experiments, therapeutic effect curative effect is obvious, and convenient drug administration, no obvious toxic-side effects, therefore JNK-IN-8 has broad prospects in terms of the drug development for the treatment of stemness AMD disease.
Description
Technical field
The invention belongs to macular degeneration class disease neuroprotective agent technical field of pharmaceuticals, and in particular to jnk inhibitor JNK-
Application of the IN-8 in the neuroprotective agent for preparing Local Electroretinogram.
Background technique
The data of the World Health Organization (WHO) show, macular degeneration class disease especially age-related macular degeneration
(age-related macular degeneration, AMD) is whole world blinding eye the third-largest after cataract and glaucoma
Disease, and cause the first cause of China 50 years old or more crowd blindness.According to the difference of clinical manifestation, AMD point for moist AMD and
Two class of stemness AMD.Wherein, moist AMD is mainly shown as choroidal neovascularization, clinically can use anti-vegf at present
Drug such as Pei Jiatani (Pegaptanib), Lucentis (Ranibizumab), bevacizumab (Bevacizumab), A Baixi
General (Aflibercept), Compaq western general (Conbercept) etc. carry out palliative.However 90% AMD patient is stemness
AMD, early stage stemness AMD, it can be observed that retinal pigment epithelium (retinal pigment epithelium,
RPE there is the generation of drusen outside).With the continuous development of disease, the volume of drusen constantly increases, while occurring rouge in RPE
Brown element deposition.Advanced stage disease, the RPE cell degradation of macular area is dead, leads to the photosensory cell mortality of macular area, from
And cause the forfeiture of central vision and visual sensitivity, referred to as geographic atrophy (geographic atrophy, GA).Stemness
AMD causes the key reason of the irreversible damage of eyesight to be the death of macular area photosensory cell.Photosensory cell is a kind of special
Neuronal cell is the key that electric signal is converted optical signals in retina.As neuronal cell, after photoreceptor cell death
It can not regenerate, so that the treatment of stemness AMD is more difficult.Newest studies have shown that is in patients with wet AMD, when anti-vegf medicine
After object controls choroidal neovascularization, the pathological change of stemness AMD sample secondary can occur in retina.Different from moist AMD, do
Property AMD still there is no effective therapeutic agent and method.
The pathophysiological mechanism of stemness AMD is still unintelligible so far, and associated risk factors include the age, inhale
It cigarette, hypertension, hyperlipidemia, abdominal obesity, high fat diet and does not get enough athletic exercise.The remedy measures and medicine currently studied
Object includes: 1, dietary adjustments: AREDS (age-related eye disease study) research group is special using one
Diet compensation process (take daily 80 milligrams of zinc oxide, 2 milligrams of copper oxide, 15 milligrams of beta carotenes, 50 milligrams of Vitamin Cs and
400 unit vitamin es) treatment disease stage stemness AMD patient.This diet compensation process is only carried in a part of high risk
Have the function of inhibiting disease development in the stemness AMD patient of disease risk gene mutation, but in Most patients not
Show due treatment remission effect；2, neuroprotection class drug: mainly including two classes (1) Brimonidine
(brimonidine): Brimonidine is the agonist of alpha-2 receptor, is used for the neuron of glaucoma patient protection retina at first
Cell, existing phase II clinical trials are for verifying neuroprotection of the drug in GA patient；(2) ciliary ganglion nerve cell
Trophic factors (ciliary neurotrophic factor-501, CNTF): being a kind of IL-6 cell factor, in animal model
Middle display has protective effect to retina.Existing phase II clinical trials use slow-released system NT-501 and CNTF combination therapy GA
Patient, follow-up is found to have certain protecting effect after 1 year.3, for the therapeutic agent of inflammation: (1) Iluvien: being directed to GA
In chronic inflammation, Alimera Sciences company of the U.S. just carrying out phase II clinical trials research sustained release preparation Fluocinonide
Effect, result is still uncertain at present；(2) for complement activation phenomenon in stemness AMD, some monoclonals for inhibiting complement activation
Antibody drug such as lampalizumab is carrying out clinical test, and certain GA therapeutic effect is shown in the II phase tests, but
That the generally existing administration mode of antibody class drug is complicated, can not long-term repeat administration, may cause the severe complications such as entophthamia
The shortcomings that；(3) the DNA aptamer of ARC1905:C5 gene, proves its safety, but it has in Phase I clinical trial
There is still a need for further confirm that for effect property；(4) inhibitor of POT-4:C3 proves its safety by Phase I clinical trial.4, blood vessel
Expander: the phenomenon that declining is supplied in old AMD patient's median nexus film blood flow, using vasodilator come the confession that has additional nutrients
It gives, retinal degeneration, including (1) Alprostadil (Alprostadil) is delayed to pass through phase III clinical trial, it was demonstrated that pass through 6
The treatment of the moon has the function of that retinal function is delayed to degenerate compared with placebo；(2) silaenafil (Sildenafil) and not
Salverine (Moxaverine): the inhibitor of non-selective phosphodiesterase, but its clinical effectiveness is still not clear.5, it is directed to
The therapeutic agent of visual cycle: (1) it is visual cycle isomerase that Yi Shusita (Emixustat), which is a kind of non-retinoid,
The regulator of RPE65 has passed through II clinical trial phase；(2) the inhibitor retinamide (Fenretinide) of visual cycle
Also just under study for action, its validity is verified in patients not yet.But all visual cycle regulators all due to
Visual cycle is influenced, may cause the side effects such as yctalopia.6, stem cell therapy: existing research is divided into using stem cell at present
RPE and photosensory cell treat stemness AMD, but their validity and safety also need long-term verifying.
JNK-IN-8 (CAS No:1410880-22-6, molecular formula: C29H29N7O2, molecular weight: 507.59, molecular formula is such as
Shown in above formula) it is chemical synthesis compound, it is a species specificity, irreversible jnk inhibitor, by conservative with JNK
The site the ATP covalent bond of cysteine reduces the protein level of p-c-Jun to inhibit the activity of JNK kinases.It grinds
Study carefully and shows that JNK signal path is the potential treatment target spot that a variety of diseases include cancer, diabetes etc..Existing research shows JNK-
IN-8 has the function of inhibiting cell Proliferation and inducing cell death in human melanoma cells, in triple negative breast cancers
In cell, JNK-IN-8 can inhibit the phenotype of tumor stem cell effectively to limit the tumour growth in mouse model.Also have
Researches show that in mouse nigro-striatal pathway damage model, JNK-IN-8 can be by inhibiting the activity of JNK1/2/4 effectively
Protection neuronal cell and the release for reducing inflammatory factor.In the myocardial injury models of anoxic Reperfu- sion, JNK-IN-8 can be with
Inhibit the phosphorylation of NF- κ B, to inhibit its activation and the generation of downstream inflammatory factor.Also have that researches show that JNK-IN-8 simultaneously
As gene target drug, it can effectively improve the ability that body self immune system resists fungal infection, can be used for antimycotic
The research and development of drug.Furthermore cell dedifferente and break up as vascular endothelial cell, vascular smooth muscle cells, osteoblast,
In cartilage cell, have been reported that JNK-IN-8 can be used as the conversion that regulator promotes cell fate.But there is not JNK signal also at present
Access is related to Local Electroretinogram and JNK-IN-8 can be used as the mind of Local Electroretinogram
Through protectant report.
Summary of the invention
It is an object of the invention to provide jnk inhibitor JNK-IN-8 and preparing in place of overcome the deficiencies in the prior art
Application in the neuroprotective agent of Local Electroretinogram.
The technical solution adopted by the present invention to solve the technical problems is:
Application of the JNK-IN-8 in the neuroprotective agent for preparing Local Electroretinogram.The neuroprotection
Agent is the stress reaction referred to reduce under pathological condition, the regeneration and reparation etc. for reducing inflammation damnification, promotion nerve cell
A kind of drug.
In one embodiment: the application, which refers to, prevents geographic atrophy.
In one embodiment: the application refers to protection retina, improves retinal damage or maintains view film integrality.
In one embodiment: the application refers to protection retinal photoreceptor cells, prevents retinal photoreceptor cells degeneration or dead
It dies.
In one embodiment: the protection retinal photoreceptor cells refer to maintain retinal photoreceptor cells acromere normal morphology and
Length.
In one embodiment: the protection retinal photoreceptor cells, which refer to, maintains retinal photoreceptor cells outer nuclear layer normal morphology
And thickness.
In one embodiment: the application refers to the apoptosis for preventing retina.
In one embodiment: the application is by inhibiting JNK signal path to carry out.
In one embodiment: the administration mode of the JNK-IN-8 includes intracavitary administration, intravenously administrable, subcutaneous administration, takes orally
Administration.
The technical program compared with the background art, it has the following advantages:
In stemness AMD genius morbi, RPE cell degradation eventually leads to the death of photosensory cell.JNK-IN-8 passes through spy
The opposite sex blocks JNK signal path, inhibits photoreceptor cell death, the integrality of retina is maintained, to play protection retina
Effect.Since JNK-IN-8 can effectively penetrate blood retina barrier in animal experiments, therapeutic effect curative effect is obvious, and gives
Prescription just, no obvious toxic-side effects, thus JNK-IN-8 treatment stemness AMD disease drug development in terms of have it is wide before
Scape.
Detailed description of the invention
Present invention will be further explained below with reference to the attached drawings and examples.
Fig. 1 is JNK-IN-8 to Abca4 after illumination-/-Rdh8-/-Double HE dyeing pictures for striking Mouse Retina.
Fig. 2 is that JNK-IN-8 passes through Abca4 after inhibiting JNK signal path to mitigate illumination-/-Rdh8-/-It is double to strike Mouse Retina
The damage being subject to.
Specific embodiment
The contents of the present invention are illustrated below by embodiment:
Embodiment
Experimental design: JNK-IN-8, which is dissolved in DMSO, is made into 10mg/mL mother liquor.Successively pure solvent is added in mother liquor,
It is ready-to-use: 2%DMSO+30%PEG 300+5%Tween 80+ddH2O。
Animal model: all-trans-retinal excessive buildup will cause the lesion regression of RPE cell and photosensory cell.Vision is followed
The abnormal metabolism of all-trans-retinal (all-trans-retinaldehyde, atRAL) is the key that AMD occurs in ring
One of factor.The mutation of Abca4 gene is to cause blueness few in the most common hereditary class macular degeneration class disease Stargardt disease
The main reason of year macular degeneration.ABCA4, RDH8 are that atRAL is made to live again in visual cycle for two keys of 11-cis-RAL
Albumen, Abca4-/-Rdh8-/-It is double to strike mouse and show atRAL removing obstacles, and it is dead RPE cell degradation, photosensory cell occur
Die, lipofuscin accumulation, complement activation phenomena such as.Meanwhile studies have found that Abca4-/-Rdh8-/-It is double to strike mouse progress illumination
Afterwards, quick photosensory cell degeneration phenotype is shown, it is protectant excellent to can be used as screening exploitation AMD retinal photoreceptor cells
Good model.
The present embodiment selects the Abca4 of 4~5 week old-/-Rdh8-/-It is double to strike mouse as experimental subjects, JNK-IN-8 experiment
Group mouse is injected intraperitoneally according to 5mg/kg weight, and control group is injected intraperitoneally according to the solvent of equivalent.1 is small after injection
When, illumination is carried out 2 hours to mouse with the white light of 10K lux.Before illumination, with Tropicamide eye drops to mouse eye into
The processing of row mydriasis.1 day (D1) after illumination, 3 days (D3), 5 days (D5) execution mouse take eyeball to be analyzed.
As shown in Figure 1, in Abca4-/-Rdh8-/-In double illumination damage models for striking mouse, JNK-IN-8 processing is to view
Film has significant protective effect.Abca4-/-Rdh8-/-It is double that strike mouse solvent processing group D1, D3, D5 after 10K lux illumination equal
There is apparent damage phenomenon, the acromere and outer nuclear layer of photosensory cell are obviously thinning, the view such as photoreceptor cell nuclei core distribution at random
Nethike embrane degradation phenomena, however in JNK-IN-8 processing group, the retina of mouse have an apparent recovery, the acromere of photosensory cell and outer
Core presents normal form, shows JNK-IN-8 processing to Abca4-/-Rdh8-/-It is double to strike the illumination damage that mouse is subject to and have
Apparent improvement result.
As shown in Fig. 2, Abca4-/-Rdh8-/-It is double to strike mouse after 10K lux illumination, the discovery of TUNEL coloration result
Abca4-/-Rdh8-/-Double neural retinas for striking mouse have apparent apoptosis after 10K lux illumination.It detects in neural retina
The phenomenon that expression of apoptosis relevant albumen RIP1, Bax and p-JNK show obvious rising further illustrates Abca4-/-
Rdh8-/-Double mouse neural retinas after illumination that strike have apoptosis phenomenon, but RIP1, Bax, p-JNK after JNK-IN-8 processing
Protein level decline illustrates that JNK-IN-8 passes through Abca4 after inhibiting JNK signal path to protect illumination-/-Rdh8-/-It is double to strike mouse view
The damage apoptosis that nethike embrane is subject to.
The above is only the preferred embodiment of the present invention, the range implemented of the present invention that therefore, it cannot be limited according to, i.e., according to
Equivalent changes and modifications made by the invention patent range and description, should still be within the scope of the present invention.
Claims (9)
1.JNK-IN-8 the application in the neuroprotective agent for preparing Local Electroretinogram.
2. application according to claim 1, it is characterised in that: the application, which refers to, prevents geographic atrophy.
3. application according to claim 1, it is characterised in that: the application refers to protection retina, improves retina damage
Wound maintains view film integrality.
4. application according to claim 1, it is characterised in that: the application refers to protection retinal photoreceptor cells, prevents
Retinal photoreceptor cells are degenerated or death.
5. application according to claim 4, it is characterised in that: the protection retinal photoreceptor cells refer to maintenance retina
Photosensory cell acromere normal morphology and length.
6. application according to claim 4, it is characterised in that: the protection retinal photoreceptor cells refer to maintenance retina
Photosensory cell outer nuclear layer normal morphology and thickness.
7. application according to claim 1, it is characterised in that: the application refers to the apoptosis for preventing retina.
8. application according to claim 1, it is characterised in that: the application is by inhibiting JNK signal path to carry out.
9. application according to claim 1, it is characterised in that: the administration mode of the JNK-IN-8 include intracavitary administration,
Intravenously administrable, subcutaneous administration, oral administration.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201811242480.7A CN109303782A (en) | 2018-10-24 | 2018-10-24 | Application of the JNK-IN-8 in the neuroprotective agent for preparing Local Electroretinogram |
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| CN201811242480.7A CN109303782A (en) | 2018-10-24 | 2018-10-24 | Application of the JNK-IN-8 in the neuroprotective agent for preparing Local Electroretinogram |
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| CN1732003A (en) * | 2002-10-31 | 2006-02-08 | 细胞基因公司 | Methods for the treatment, prevention and management of macular degeneration |
| CN101048156A (en) * | 2004-10-29 | 2007-10-03 | 爱尔康公司 | Inhibitors of Jun N-terminal kinases for the treatment of glaucomatous retinopathy and ocular diseases |
| WO2008024776A1 (en) * | 2006-08-22 | 2008-02-28 | Children's Medical Center Corporation | Inhibiting jnk signaling promotes cns axon regeneration |
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