CN102648906A - Application of sunitinib in preparation of acetylcholinesterase inhibitor - Google Patents
Application of sunitinib in preparation of acetylcholinesterase inhibitor Download PDFInfo
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- CN102648906A CN102648906A CN2012101537630A CN201210153763A CN102648906A CN 102648906 A CN102648906 A CN 102648906A CN 2012101537630 A CN2012101537630 A CN 2012101537630A CN 201210153763 A CN201210153763 A CN 201210153763A CN 102648906 A CN102648906 A CN 102648906A
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- acetylcholine
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- sunitinib
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Abstract
The invention discloses an application of sunitinib in preparation of an acetylcholinesterase inhibitor. Sunitinib used as an antineoplastic agent in the prior art is applied to the preparation of the acetylcholinesterase inhibitor in the technical solution provided by the invention and is used as a medicine for treating the Alzheimer's disease.
Description
Technical field
The present invention relates to a kind of antitumor drug, Sutent (Sunitinib, trade name: new purposes Suo Tan).
Background technology
Acetylcholine (Ach) is a kind of neurotransmitter, mainly is present in presynaptic cholinergic nerve tip position.In brain, acetylcholine is kept certain content and is played an important role for human body memory and recognition function; In the somatic motor nerve system, acetylcholine is present in neural flesh junction and controls the contraction of muscle; In sympathetic nerve, acetylcholine is the nerve conduction material that nerve disengages before the joint, and normal physiological function has important function in the body for keeping.Acetylcholinesterase (AchE) mainly is present in myoneural junction and the cholinergic nerve system, and its physiological action in vivo is to make acetylcholine hydrolyzation and inactivation.Acetylcholinesteraseinhibitors inhibitors can be blocked the activity of AchE, delays the hydrolysis rate of acetylcholine, improves the levels of acetylcholine of synaptic space, guarantees the normal conduction of nerve signal, therefore is usually used in neural impulse transmission imbalance type treatment of diseases.
(Alzheimer disease AD), claims senile dementia again to alzheimer's disease, is a kind of lethal neurodegenerative diseases that carries out sexual development.Increase year by year along with world population average life; The sickness rate of senile dementia also rises year by year; Estimate that whole world alzheimer's disease number of the infected is up to more than 1,200 ten thousand; The mortality rate of alzheimer's disease is only second to cardiovascular and cerebrovascular disease patient and tumor patient in the worldwide, is the major disease that threatens human health.Research thinks that alzheimer's disease is relevant with acetylcholine (Ach) the level decline of synaptic space in the cerebral cortex.Acetylcholinesteraseinhibitors inhibitors can help patients of senile dementia to improve levels of acetylcholine in the body, can be used to improve the memory and the cognitive level of patients of senile dementia.
(Myasthenia Gravis MG) is the relevant autoimmune disease of a kind of and neural flesh to myasthenia gravis.Usually acetylcholine esterase active raises unusually in patient's body; Proper interior effectively levels of acetylcholine is significantly reduced; The too minimizing that combines also with acetylcholinergic receptor (AChR); Can make myoneural junction transmission retardance, thereby cause clinical symptoms such as patient's muscle twitches, weakness and easy fatigue.Acetylcholinesteraseinhibitors inhibitors can make the Ach level in the blood samples of patients obviously raise through suppressing the activity of AchE, and MG patient is had significant therapeutic effect.Acetylcholinesteraseinhibitors inhibitors is a routine and a clinical line medicine that is used to treat MG at present.
At present; Gone on the market and more effective clinically acetylcholinesteraseinhibitors inhibitors as; Tacrine (Tarcine), aricept (Aricept), Exelon (Exelon) and neostigmine (as follows) such as (Neostigmine); Their levels of acetylcholine in patient's body that can effectively raise, and effectively improve patient's clinical symptoms.The exploitation acetylcholinesteraseinhibitors inhibitors has become the research direction like diseases such as senile dementia, myasthenia gravis, glaucomas, and its potential economic benefit is huge.
Sutent (Sunitinib; Trade name: being the substituted 2-indoline of a kind of pyrroles ketone compounds Suo Tan), is a kind of oral angiogenesis tyrosine kinase receptor (RTK) inhibitor of company of Pfizer (Pfizer) research and development, target spots such as vasoactive endothelial growth factor receptor VEGFR2, PDGFR; Existing pertinent literature report; This compounds can be applied to treatment of diseases such as cancer, diabetes and nephropathy, and these documents are: CN1439005, PT1255752E etc.At present, Sutent clinically principal indication be the treatment that is used for gastrointestinal stromal tumor (GIST) and late period or transitivity renal carcinoma.
We find effectively acetylcholine esterase inhibition of Sutent, delay the hydrolysis rate of acetylcholine, and intravital levels of acetylcholine is significantly raise, and are expected to open up a brand-new approach for senile dementia, Therapy for Myasthemia Gravis.Acetylcholinesterase plays an important role in the neural impulse transmittance process in vivo; It is a kind of cholinester hydrolytic enzyme; Belong to diverse target spot category with tyrosine kinase receptor, do not have Sutent to be used for the relevant report of acetylcholinesteraseinhibitors inhibitors in the prior art as yet.
Summary of the invention
Based on above-mentioned result of study, the present invention at first provides the application of Sutent (chemical compound 1) in the preparation acetylcholinesteraseinhibitors inhibitors.
The present invention's purpose on the other hand provides the unusual treatment of diseases method that mediates of a kind of acetylcholine function, and said method comprises the Sutent (chemical compound 1) of treating effective dose, or its salt and the pharmaceutically acceptable derivant of other form.
Wherein said and the unusual disease that mediates of acetylcholine function be meant by the acetylcholine level relevant disease that significantly descends and cause in vivo, more specifically, be like diseases such as senile dementia, myasthenia gravis, glaucomas.
Described preparation acetylcholinesteraseinhibitors inhibitors of the present invention comprises the Sutent described in the present invention (chemical compound 1) or its officinal salt and solvate thereof is combined with pharmaceutically adjuvant commonly used or carrier, prepares the pharmaceutical composition with inhibiting activity of acetylcholinesterase.Aforementioned pharmaceutical compositions can adopt agent property medicines such as tablet, granule, capsule, oral liquid, injection, aerosol; Can also adopt the known controlled release of modern pharmaceutical circle or slow release formulation or nanometer formulation.These believe that about the selection of preparation way and method those skilled in the art can be enlightened fully from prior art, the present invention repeats no more.
Description of drawings
Accompanying drawing 1 width of cloth of the present invention, Sutent is to the half suppression ratio (IC of Acetylcholinesterase
50) curve, wherein transverse axis is compound concentration (μ M), the longitudinal axis is suppression ratio percentage ratio (%).
The specific embodiment
Following non-limiting example can make those of ordinary skill in the art more fully understand the present invention; Mandatory declaration; Following embodiment is used to explain the present invention rather than limitation of the present invention, and the improvement that essence according to the present invention is carried out the present invention all belongs to the present invention and requires the scope protected.Term described in the invention like neurotransmitter, neural impulse transmission, improve the scientific terminology that understanding and memory level etc. all are professional scientific domain institute widespread usage, and limits to the scope of the invention never in any form.
Embodiment
Sutent (chemical compound 1) acetylcholine esterase inhibition activity detects
The present invention tests used Sutent (chemical compound 1) and prepares according to the method for bibliographical information: WO 99/48868 (open day: on JIUYUE 30th, 1999).
Acetylcholine esterase inhibition activity detects in the test:
Fresh Acetylcholinesterase is available from Sigma company;
Acetylthiocholine salt (ATOH) is as substrate, available from Sigma;
5,5-two sulfur two (2-nitrobenzoic acid) are developer (DTNB), available from Sigma;
0.01M phosphate buffer (pH=7.0);
Sutent is made into DMSO solution (being 20 μ mol/mL).
Detection method:
(1) Acetylcholinesterase and substrate are made into suitable concentration solution with the 0.01M phosphate buffer, and 1ml primary response system includes 0.02 unit enzyme, 0.1 μ mol substrate, 0.1 μ mol developer, the DMSO of 10 μ L;
(2) get an amount of Acetylcholinesterase and developer, add the DMSO solution of blank DMSO solution or sample, left standstill behind the mixing 20 minutes;
(3) add substrate and rapid mixing, utilize the Tecan ELIASA to detect the changing value of the absorbance of system in the 1min in the 412nm wavelength immediately;
(4) calculate enzymatic activity according to following formula: suppression ratio (%)=[(B-S)/B] * 100%, wherein B is the absorbance changing value when adding blank DMSO, S is the absorbance changing value of sample;
(5) sample of 13 variable concentrations of mensuration is drawn dosage-suppression ratio curve (data such as table 1), calculates its IC
50Value.Each sample replication three times, the result representes with meansigma methods ± standard deviation.
Table 1. variable concentrations Sutent is to the inhibitory action of Acetylcholinesterase
Testing result is shown in accompanying drawing 1, and visible Sutent (chemical compound 1) has good inhibitory action to Acetylcholinesterase, its IC
50Value is 7.15 ± 0.53 μ M.
Claims (1)
1. the application of Sutent in the preparation acetylcholinesteraseinhibitors inhibitors.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2012101537630A CN102648906A (en) | 2012-05-17 | 2012-05-17 | Application of sunitinib in preparation of acetylcholinesterase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2012101537630A CN102648906A (en) | 2012-05-17 | 2012-05-17 | Application of sunitinib in preparation of acetylcholinesterase inhibitor |
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| CN102648906A true CN102648906A (en) | 2012-08-29 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN2012101537630A Pending CN102648906A (en) | 2012-05-17 | 2012-05-17 | Application of sunitinib in preparation of acetylcholinesterase inhibitor |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101022799A (en) * | 2004-07-19 | 2007-08-22 | 约翰·霍普金斯大学 | FLT3 inhibitors for immune suppression |
| WO2010017541A2 (en) * | 2008-08-08 | 2010-02-11 | The Johns Hopkins University | Compositions and methods for treatment of neurodegenerative disease |
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2012
- 2012-05-17 CN CN2012101537630A patent/CN102648906A/en active Pending
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101022799A (en) * | 2004-07-19 | 2007-08-22 | 约翰·霍普金斯大学 | FLT3 inhibitors for immune suppression |
| WO2010017541A2 (en) * | 2008-08-08 | 2010-02-11 | The Johns Hopkins University | Compositions and methods for treatment of neurodegenerative disease |
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Application publication date: 20120829 |