CN105816461A - Application of trametinib in preparation of drug for treating Parkinson's disease - Google Patents
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- 239000003814 drug Substances 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 8
- LIRYPHYGHXZJBZ-UHFFFAOYSA-N trametinib Chemical compound CC(=O)NC1=CC=CC(N2C(N(C3CC3)C(=O)C3=C(NC=4C(=CC(I)=CC=4)F)N(C)C(=O)C(C)=C32)=O)=C1 LIRYPHYGHXZJBZ-UHFFFAOYSA-N 0.000 title abstract description 23
- 229960004066 trametinib Drugs 0.000 title abstract description 23
- 208000018737 Parkinson disease Diseases 0.000 title abstract description 17
- 229940079593 drug Drugs 0.000 title abstract description 15
- 210000005064 dopaminergic neuron Anatomy 0.000 claims abstract description 17
- 239000002671 adjuvant Substances 0.000 claims description 2
- UWAOJIWUVCMBAZ-UHFFFAOYSA-N [1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutyl]-dimethylazanium;chloride Chemical compound Cl.C=1C=C(Cl)C=CC=1C1(C(N(C)C)CC(C)C)CCC1 UWAOJIWUVCMBAZ-UHFFFAOYSA-N 0.000 claims 4
- 229960003466 sibutramine hydrochloride Drugs 0.000 claims 4
- 230000007850 degeneration Effects 0.000 abstract description 7
- 230000000694 effects Effects 0.000 abstract description 5
- 230000003412 degenerative effect Effects 0.000 abstract description 2
- 238000002347 injection Methods 0.000 abstract 1
- 239000007924 injection Substances 0.000 abstract 1
- VYFYYTLLBUKUHU-UHFFFAOYSA-N dopamine Chemical compound NCCC1=CC=C(O)C(O)=C1 VYFYYTLLBUKUHU-UHFFFAOYSA-N 0.000 description 22
- 210000004556 brain Anatomy 0.000 description 11
- 229960003638 dopamine Drugs 0.000 description 11
- 241000255581 Drosophila <fruit fly, genus> Species 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 238000010586 diagram Methods 0.000 description 3
- 210000002569 neuron Anatomy 0.000 description 3
- 241000255925 Diptera Species 0.000 description 2
- 206010064571 Gene mutation Diseases 0.000 description 2
- 229940124647 MEK inhibitor Drugs 0.000 description 2
- 108700019146 Transgenes Proteins 0.000 description 2
- 239000004480 active ingredient Substances 0.000 description 2
- 238000010171 animal model Methods 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000002651 drug therapy Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002829 mitogen activated protein kinase inhibitor Substances 0.000 description 2
- 230000002018 overexpression Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- -1 2-fluoro-4-iodophenyl Chemical group 0.000 description 1
- 241000255579 Ceratitis capitata Species 0.000 description 1
- 101000619542 Homo sapiens E3 ubiquitin-protein ligase parkin Proteins 0.000 description 1
- 102000008109 Mixed Function Oxygenases Human genes 0.000 description 1
- 108010074633 Mixed Function Oxygenases Proteins 0.000 description 1
- 208000027089 Parkinsonian disease Diseases 0.000 description 1
- 206010034010 Parkinsonism Diseases 0.000 description 1
- 101150066884 Pink1 gene Proteins 0.000 description 1
- 206010044565 Tremor Diseases 0.000 description 1
- 239000000556 agonist Substances 0.000 description 1
- 230000002973 anti-dopamine Effects 0.000 description 1
- 210000005056 cell body Anatomy 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000012744 immunostaining Methods 0.000 description 1
- 210000001259 mesencephalon Anatomy 0.000 description 1
- 238000000034 method Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000001577 neostriatum Anatomy 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 102000045222 parkin Human genes 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000000392 somatic effect Effects 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 210000003523 substantia nigra Anatomy 0.000 description 1
- 239000013589 supplement Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
Classifications
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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
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
技术领域technical field
本发明属于医药技术领域，具体涉及曲美替尼（Trametinib）在制备治疗帕金森药物上的应用。The invention belongs to the technical field of medicine, and in particular relates to the application of Trametinib in the preparation of medicines for treating Parkinson's disease.
背景技术Background technique
帕金森病（Parkinson’sDisease，PD）又称“震颤麻痹”，是一种常见的中枢神经系统变性疾病，主要影响中老年人，患者多在50岁后发病，但近年来已呈现日渐年轻化的趋势。帕金森病患者的主要病症有动作缓慢，手脚或身体其它部分发生控制不了的震颤，身体变得僵硬，平衡障碍，以致生活不能自理。据统计显示，我国60岁以上的人群中帕金森的患病率约为1.7%，共约有100多万患者，而且每年至少增加10万新病例。中脑黑质多巴胺（dopamine，DA）能神经元的变性死亡，纹状体DA含量显著减少，不能满足人体的正常需要，是造成帕金森病的主要原因之一。Parkinson's disease (Parkinson's Disease, PD), also known as "parkinsonism", is a common degenerative disease of the central nervous system, mainly affecting middle-aged and elderly people. the trend of. The main symptoms of patients with Parkinson's disease are slow movement, uncontrollable tremors in hands, feet or other parts of the body, body stiffness, balance disturbance, so that they cannot take care of themselves. According to statistics, the prevalence of Parkinson's among people over 60 years old in my country is about 1.7%, with a total of more than 1 million patients, and at least 100,000 new cases are added every year. The degeneration and death of dopamine (DA) neurons in the substantia nigra of the midbrain, and the significant reduction of DA content in the striatum, which cannot meet the normal needs of the human body, are one of the main causes of Parkinson's disease.
目前对帕金森的治疗主要包括药物治疗及手术治疗辅助药物治疗。常用的药物主要有三种：一种是多巴胺制剂，其可直接补充脑内分泌不足的多巴胺；二是抑制多巴胺降解的药物，其可减少多巴胺的降解，使脑内多巴胺含量相对增多；三是多巴胺受体激动剂，其可增强大脑对多巴胺的吸收和利用。但其均不能延缓多巴胺能神经元的退化，因此不能从根本上起到治疗的作用。At present, the treatment of Parkinson's mainly includes drug therapy and surgical treatment adjuvant drug therapy. There are mainly three types of drugs commonly used: one is dopamine preparations, which can directly supplement dopamine in the brain endocrine deficiency; the other is drugs that inhibit the degradation of dopamine, which can reduce the degradation of dopamine and increase the content of dopamine in the brain; A somatic agonist that enhances the uptake and utilization of dopamine in the brain. But none of them can delay the degeneration of dopaminergic neurons, so they cannot fundamentally play a therapeutic role.
发明内容Contents of the invention
曲美替尼（Trametinib）是一种MEK抑制剂，本发明的目的在于提供一种曲美替尼的新用途。Trametinib is a MEK inhibitor, and the purpose of the present invention is to provide a new application of Trametinib.
为实现上述目的，本发明采用如下技术方案：To achieve the above object, the present invention adopts the following technical solutions:
一种曲美替尼在制备治疗帕金森药物上的应用，具体是将曲美替尼单独或与其他活性成分或辅料配合制备成延缓多巴胺能神经元退化的药物。The invention relates to an application of trametinib in the preparation of a drug for treating Parkinson's disease, specifically preparing trametinib alone or in combination with other active ingredients or auxiliary materials into a drug for delaying degeneration of dopaminergic neurons.
本发明的显著优点在于：本发明提供了一种曲美替尼（Trametinib）的新用途，是将曲美替尼用于制备延缓多巴胺能神经元退化的药物。所得产品可有效延缓多巴胺能神经元的退行性死亡，从根本上达到治疗帕金森病的作用；且其药物无须进行注射，只通过口服即可达到治疗效果，对多种原因引起的帕金森病有较好疗效，对帕金森病的治疗及治愈具有重要意义。The remarkable advantage of the present invention is that: the present invention provides a new application of trametinib, which is to use trametinib to prepare a drug for delaying degeneration of dopaminergic neurons. The obtained product can effectively delay the degenerative death of dopaminergic neurons, and fundamentally achieve the effect of treating Parkinson's disease; and the drug does not need to be injected, and the therapeutic effect can be achieved only by oral administration. It has a good curative effect and is of great significance to the treatment and cure of Parkinson's disease.
附图说明Description of drawings
图1为经曲美替尼处理后果蝇局部脑区多巴胺能神经元状态的示意图。Figure 1 is a schematic diagram of the state of dopaminergic neurons in the local brain area of flies treated with trametinib.
图2为经曲美替尼处理后果蝇局部脑区多巴胺能神经元数量的统计图。Fig. 2 is a statistical diagram of the number of dopaminergic neurons in the local brain area of flies treated with trametinib.
具体实施方式detailed description
为了使本发明所述的内容更加便于理解，下面结合具体实施方式对本发明所述的技术方案做进一步的说明，但是本发明不仅限于此。In order to make the content of the present invention easier to understand, the technical solutions of the present invention will be further described below in conjunction with specific embodiments, but the present invention is not limited thereto.
曲美替尼（N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6,7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide）的化学式为：C26H23FIN5O4，结构式为：，是一种MEK抑制剂。Trametinib (N-(3-{3-Cyclopropyl-5-[(2-fluoro-4-iodophenyl)amino]-6,8-dimethyl-2,4,7-trioxo-3,4,6, The chemical formula of 7-tetrahydropyrido[4,3-d]pyrimidin-1(2H)-yl}phenyl)acetamide is: C 26 H 23 FIN 5 O 4 , and the structural formula is: , is a MEK inhibitor.
本发明提供了一种曲美替尼（Trametinib）在制备治疗帕金森药物上的应用，具体是将曲美替尼单独或与其他活性成分或辅料配合制备成延缓多巴胺能神经元退化的药物。The invention provides an application of trametinib (Trametinib) in the preparation of drugs for treating Parkinson's disease, specifically preparing trametinib alone or in combination with other active ingredients or auxiliary materials to prepare drugs for delaying degeneration of dopaminergic neurons.
以300只地中海果蝇为实验对象，随机分为4个实验组和1个正常对照组（Ctrl），每组各60只，每组再平行分实验组和正常对照组进行试验。4个实验组分别建立由a-synuclein转基因过表达、Lrrk2转基因过表达、Parkin基因突变、Pink1基因突变造成的帕金森症动物模型，并从5天成虫龄起开始，实验组分别持续喂服16.24μM/mL曲美替尼30天，正常对照组喂服5%DMSO作为溶剂对照。喂药30天后解剖果蝇大脑，利用抗多巴胺羟化酶抗体对果蝇大脑进行全组织免疫染色标记多巴胺神经元，镜检观察果蝇大脑PPL区多巴胺神经元的形态以及数量，以判断曲美替尼(Trametinib)对果蝇局部脑区多巴胺能神经元的作用，其结果见图1、2。Taking 300 medflies as experimental objects, they were randomly divided into 4 experimental groups and 1 normal control group (Ctrl), 60 in each group, and each group was divided into experimental group and normal control group in parallel for the test. The four experimental groups respectively established animal models of Parkinson's disease caused by a-synuclein transgene overexpression, Lrrk2 transgene overexpression, Parkin gene mutation, and Pink1 gene mutation. The experimental groups continued to feed 16.24 μM/mL trametinib for 30 days, the normal control group was fed with 5% DMSO as solvent control. Drosophila brain was dissected after 30 days of drug feeding, and the whole tissue immunostaining of Drosophila brain was carried out with anti-dopamine hydroxylase antibody to mark dopamine neurons, and the morphology and number of dopamine neurons in the PPL area of Drosophila brain were observed under microscope to judge Qumei The effect of Trametinib on dopaminergic neurons in the local brain area of Drosophila, the results are shown in Figures 1 and 2.
图1为经曲美替尼处理后局部脑区多巴胺能神经元状态的示意图，其中，荧光部分为多巴胺能神经元的细胞体轮廓，可通过其观察多巴胺能神经元的状态及数量；图2为经曲美替尼处理后PPL脑区多巴胺能神经元数量的统计图。Figure 1 is a schematic diagram of the state of dopaminergic neurons in the local brain area after trametinib treatment, wherein the fluorescent part is the outline of the cell body of the dopaminergic neurons, through which the state and number of dopaminergic neurons can be observed; Figure 2 It is a statistical map of the number of dopaminergic neurons in the PPL brain area after trametinib treatment.
从图1、2可见，16.24μM/mL曲美替尼能有效逆转不同起因帕金森症病理模型动物中多巴胺能神经元的退化及死亡，甚至可使其完全恢复正常。因此，将曲美替尼（Trametinib）制备成治疗帕金森的药物，可维护多巴胺能神经元的健康，有望从根本上治疗帕金森症患者。It can be seen from Figures 1 and 2 that 16.24 μM/mL trametinib can effectively reverse the degeneration and death of dopaminergic neurons in animal models of Parkinson's disease with different causes, and even completely restore them to normal. Therefore, preparing trametinib (Trametinib) as a drug for treating Parkinson's can maintain the health of dopaminergic neurons, and is expected to fundamentally treat patients with Parkinson's disease.
以上所述仅为本发明的较佳实施例，凡依本发明申请专利范围所做的均等变化与修饰，皆应属本发明的涵盖范围。The above descriptions are only preferred embodiments of the present invention, and all equivalent changes and modifications made according to the scope of the patent application of the present invention shall fall within the scope of the present invention.
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Priority Applications (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610208591.0A CN105816461B (en) | 2016-04-06 | 2016-04-06 | Application of the Trimetinib on preparing treatment parkinsonism drug |
| PCT/CN2016/102154 WO2017173800A1 (en) | 2016-04-06 | 2016-10-14 | Application using mapk signal pathway inhibitor for preparing pharmaceutical product for delaying dopaminergic neuron degeneration |
| EP16897732.0A EP3441066B1 (en) | 2016-04-06 | 2016-10-14 | Mapk inhibitors for the treatment of parkinson's disease |
| US16/091,438 US20190151320A1 (en) | 2016-04-06 | 2016-10-14 | Application of mapk signaling pathway inhibitor in manufacture of drugs for delaying degeneration of dopaminergic neurons |
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| CN201610208591.0A CN105816461B (en) | 2016-04-06 | 2016-04-06 | Application of the Trimetinib on preparing treatment parkinsonism drug |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2017173800A1 (en) * | 2016-04-06 | 2017-10-12 | 福州大学 | Application using mapk signal pathway inhibitor for preparing pharmaceutical product for delaying dopaminergic neuron degeneration |
| KR101892457B1 (en) * | 2016-11-25 | 2018-08-31 | 주식회사 샤인바이오 | Composition for promoting and protecting the differentiation of neural stem cells and a method for inducing neural regeneration using the same |
| CN111374977A (en) * | 2018-12-27 | 2020-07-07 | 浙江大学 | Application of axitinib and its analogs in the preparation of blood-brain barrier permeability regulators |
| WO2021210897A1 (en) * | 2020-04-14 | 2021-10-21 | 주식회사 지뉴브 | Method and composition for evaluating response to neurodegenerative disease treatment agent |
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Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2017173800A1 (en) * | 2016-04-06 | 2017-10-12 | 福州大学 | Application using mapk signal pathway inhibitor for preparing pharmaceutical product for delaying dopaminergic neuron degeneration |
| KR20210095748A (en) * | 2016-11-25 | 2021-08-02 | 주식회사 지뉴브 | Composition for promoting differentiation of and protecting neural stem cells and method for inducing neural regeneration using same |
| CN109073634A (en) * | 2016-11-25 | 2018-12-21 | 山映生物制药公司 | Composition for inducing differentiation and protection of neural stem cells and method for inducing nerve regeneration using the composition |
| JP2019513806A (en) * | 2016-11-25 | 2019-05-30 | シャイン バイオファーマ インク． | Composition for promoting and protecting neural stem cell differentiation, and method of inducing nerve regeneration using the same |
| US10485802B2 (en) | 2016-11-25 | 2019-11-26 | Genuv Inc. | Composition for inducing differentiation and protection of neural stem cells and method for inducing neuro-regeneration using the same composition |
| KR101892457B1 (en) * | 2016-11-25 | 2018-08-31 | 주식회사 샤인바이오 | Composition for promoting and protecting the differentiation of neural stem cells and a method for inducing neural regeneration using the same |
| US11147816B2 (en) | 2016-11-25 | 2021-10-19 | Genuv Inc. | Composition for inducing differentiation and protection of neural stem cells and method for inducing neuro-regeneration using the same composition |
| CN109073634B (en) * | 2016-11-25 | 2022-07-08 | 基诺富公司 | Composition for inducing differentiation and protection of neural stem cells and method for inducing neural regeneration using the same |
| KR102519796B1 (en) | 2016-11-25 | 2023-04-11 | 주식회사 지뉴브 | Composition for promoting differentiation of and protecting neural stem cells and method for inducing neural regeneration using same |
| US11701360B2 (en) | 2016-11-25 | 2023-07-18 | Genuv Inc. | Composition for inducing differentiation and protection of neural stem cells and method for inducing neuro-regeneration using the same composition |
| CN111374977A (en) * | 2018-12-27 | 2020-07-07 | 浙江大学 | Application of axitinib and its analogs in the preparation of blood-brain barrier permeability regulators |
| CN111374977B (en) * | 2018-12-27 | 2022-03-18 | 浙江大学 | Application of axitinib and analogues thereof in preparation of blood brain barrier permeability regulator |
| US12419875B2 (en) | 2018-12-27 | 2025-09-23 | Zhejiang University | Use of Axitinib and analogs thereof in preparing blood-brain barrier permeability regulator |
| WO2021210897A1 (en) * | 2020-04-14 | 2021-10-21 | 주식회사 지뉴브 | Method and composition for evaluating response to neurodegenerative disease treatment agent |
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