CN103468680A - Novel antidiabetic medicine - Google Patents
Novel antidiabetic medicine Download PDFInfo
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- CN103468680A CN103468680A CN2013103772574A CN201310377257A CN103468680A CN 103468680 A CN103468680 A CN 103468680A CN 2013103772574 A CN2013103772574 A CN 2013103772574A CN 201310377257 A CN201310377257 A CN 201310377257A CN 103468680 A CN103468680 A CN 103468680A
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
- C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N15/00—Mutation or genetic engineering; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification; Use of hosts therefor
- C12N15/09—Recombinant DNA-technology
- C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
Abstract
The invention provides a novel antidiabetic medicine. The novel antidiabetic medicine is obtained by the steps of finding a lead compound acting on sodium-sugar transport synergistic protein with an 'antisense chemical medicine design' method and performing targeted chemical modification (for example: methylated modification of the two ends of the lead compound, synergistic design of an unmodified compound and a modified compound, and development of MgCl2 serving as a medicine efficacy enhancer). Therefore, the novel antidiabetic medicine provided by the invention can inhibited integrated sodium-sugar transport synergistic protein efficiently and specifically, has low side effects and achieves an effect which is more excellent than that of the existing sodium-sugar transport protein II inhibitor, so as to achieve an effect of effectively treating type II diabetes and fill the gap in the chemical design of antisense medicines in China.
Description
Technical field
The present invention relates to the biological medicine engineering field, be specifically related to a kind of medicine of the new chemical for diabetes and method of design thereof.
Background technology
Diabetes are that in blood, Regular Insulin definitely or relative deficiency, causes blood sugar too high, glycosuria occurs, and then cause fat and protein metabolism disorder, and be a kind of common endocrine metabolism disease.Diabetes mainly are divided into I type diabetes and II type diabetes, the I type is because beta Cell of islet can not produce due to enough Regular Insulin (Regular Insulin definitely lacks), and the II type is due to due to hypoinsulinism or insulin resistant (Regular Insulin lacks relatively).In the diabetic subject, 90-95% is II type diabetes.Along with this pathology of raising of people's living standard has become common disease and frequently-occurring disease, and age of onset also from the elderly to the young adult or even the teenager spread.
For modal diabetes (II type diabetes), mainly by the long-term taking antidiabetic medicine, treated.At present, the multiple chemicals of the anti-diabetic for various drug targets and Chinese medicine etc. have been arranged on market.But, for the effect for the treatment of diabetes, be not still very good.Trace it to its cause, " insulin resistant " is the arch-criminal.Therefore, searching out the newtype drug target spot changes antidiabetic medicine and is even more important in the problem of " aspect insulin resistant ".Oral antidiabetic thing mechanism of action is varied, but " energy balance " that also do not have clinically a kind of medicine to be based on by controlling body energy absorption and energy expenditure reaches the purpose for the treatment of diabetes.The energy of storing in body can not only be consumed by intestines and emaciation, and can in kidney, by urine, discharge unnecessary sugar.Therefore, it is feasible adopting the strategy of similar mode of motion or mode of life control agent self-energy balance.Thereby if there is medicine can stimulate the discharge impact " energy balance " of glucose in urine, balance is moved towards the direction of energy expenditure, thereby reach the purpose that reduces blood sugar in body, a kind of new class of medications is provided likely to the II diabetes mellitus type, thereby effectively improves the difficult situation of antidiabetic medicine " insulin resistant ".
In human body, glucose can't freely pass through the double-layer of lipoid structure of cytolemma, must be by means of the glucose transporter on cytolemma.Research shows, at kidney, glucose can be freely from glomerular filtration, but substantially at proximal convoluted tubule active transport (energy expenditure process), heavily absorbs.Sodium glucose co-transporter 2 plays topmost effect in vain in the heavily absorption of glucose, wherein sodium glucose co-transporter 2 white 2 the transhipment kidneys heavily absorb 90% of glucose, and sodium glucose co-transporter 2 white 1 the transhipment remaining 10%.So the inhibitor that sodium glucose co-transporter 2 is white can be blocked the heavily absorption of proximal convoluted tubule to glucose, thereby impact " energy balance " makes balance move towards the direction of energy expenditure, thereby reach, falls hypoglycemic purpose.
American I SIS pharmacy utilizes a kind of brand-new chemicals method of design---antisense drug chemistry, developed novel sodium-glucose cotransporter 2 inhibitor ISIS-388626(U.S. Patent number US20120196921A1), the expression level that it can suppress sodium glucose co-transporter 2 white 2 by specificity suppresses its function.Although ISIS-388626, due to the characteristics of " antisense drug design ", makes the specificity of medicine stronger, side effect reduces, and due to the own characteristic of such medicine, its drug potency is starkly lower than the traditional chemical medicine.
Summary of the invention
The present invention is directed to above-mentioned deficiency, a kind of antidiabetic thing is provided, this medicine is high specificity not only, can also efficiently bring into play drug effect, thereby hypoglycemic effect effectively falls in performance.
To achieve these goals, the present invention adopts following technical scheme:
The present invention finds the lead compound of the collaborative albumen of effect kidney-sugar transport by " design of antisense chemicals " method, in fact can specificity and the nucleotide sequence of the gene order RNA enzyme H formation complex body of kidney sodium glucose co-transporter 2 white 1 and the white 2 same medicine target spots of sodium glucose co-transporter 2.
It is one of following that the gene order of above-mentioned lead compound is selected from:
(1) CCCATCTCTGGTGCC
(2) CGGCCACCACACCAT
(3) CACGGGTGCAAACAG
(4) GAGGCGGATGCGGCG
(5) GGAGAGCACAGACAG
(6) CCGAGGAGCAGCGCG
(7) GGTCGCTGCACCAGT
(8) GCCAGGCAGCGCTGC
(9) CAGGCACCACGCAGG
(10)GGTAGGGATGTTGGA
A kind of novel antidiabetic medicine provided by the invention, its core texture is above-mentioned said lead compound.
Above-mentioned antidiabetic medicine, also comprise the modifier of lead compound.
The modifier of above-mentioned lead compound is that the deoxidation modification of lead compound two ends or two ends are methylated and modify " lasso trick " structure with closed at both ends formed.
The form of above-mentioned " lasso trick " structure is: not adorned base-5,5 adorned base-5 an adorned base, 4 adorned base-5 not adorned base-6 adorned base or not adorned base-4,6 adorned base-5 an adorned base.
Lead compound in above-mentioned antidiabetic medicine: the amount of substance of the compound after modification is than being 1:100 ~ 1:10.
Preferably, lead compound in above-mentioned antidiabetic medicine: the amount of substance of the compound after modification is 1:20.
In order to increase this pharmaceutical efficacy, this medicine is dissolved in MgCl
2in solution, preferred described MgCl
2the concentration of solution is 1 ~ 10mM.More preferably, MgCl
2the concentration of solution is 5mM.
Lead compound provided by the invention has following advantage: 1) effectively activator RNA enzyme H brings into play its pharmacological action; 2) medicine is synthetic simple, and cost is low; 3) nontoxicity; 4) be not easy by the nucleus enzyme liberating; 5) can not produce the side effect caused because of non-specific binding.
The present invention take " antisense drug chemistry " be criterion, be optimized modification.Antidiabetic medicine provided by the invention can significantly improve the stability of lead compound when bringing into play its pharmacological action by the chemically modified to lead compound.The medicine that the present invention adopts lead compound and the Compound Phase after modifying is mixed can significantly improve its effect and stability.Antidiabetic medicine provided by the invention has further increased the action intensity of chemicals for the specificity target spot, makes its not only high specificity, and side effect is little, can also efficiently bring into play drug effect, thereby hypoglycemic effect effectively falls in performance.
The accompanying drawing explanation
Fig. 1 is the degradation results figure of medical compounds DNA molecular;
Fig. 2 is the efficiencies figure that medical compounds suppresses the mRNA of total SGLT;
Fig. 3 is MgCl
2the efficiencies figure that suppresses the mRNA of total SGLT as the solvent of medical compounds.
Embodiment
Following examples are used for further illustrating the present invention, but should not be construed as limitation of the present invention.Under the prerequisite that does not deviate from the present invention's spirit and essence, modification made for the present invention or replacement, all belong to category of the present invention.
determining of the best cover Cable Structure of embodiment 1
By the DNA molecular by various drug candidate compounds, in immortal cell line HEK293, cultivate 1 week, then measure the degradation rate of various medical compounds DNA moleculars, 100% degradation rate means degradable, 0% degradation rate means not degrade, the degradation rate of medical compounds DNA molecular is less, and the degradation capability of pointing out the structure of this medical compounds more can resist various cell ribozymes is stronger, and its structure is more stable.
Will be wherein (1) CCCATCTCTGGTGCC, (2) CGGCCACCACACCAT, (3) CACGGGTGCAAACAG be divided into 6 experimental group according to the structure of modifying, be designated as respectively A, B, C, D, E, F, the mode of modifying selects two ends to methylate, and concrete modification structure is in Table 1.
Table 1: the concrete modification structure of each experimental group
| Experimental group | Modification structure |
| A | The |
| B | |
| 5 adorned base-10 not adorned | |
| C | |
| 10 not adorned base-5 adorned bases | |
| D | Not adorned base-5,5 adorned base-5 an adorned base |
| E | Not adorned base-6,4 adorned base-5 an adorned base |
| F | Not adorned base-4,6 adorned base-5 an adorned base |
As shown in Figure 1, its degradation rate of A group unmodified structure is respectively 96%, 95%, 92% to result, illustrates that this kind of structural compounds DNA molecular nearly all is degraded.The modification of B group and C group does not form the cover Cable Structure, the degradation rate of B group is respectively 70%, 70%, 72%, the degradation rate of C group is respectively 54%, 50%, 57%, the presentation of results of B group and C group does not have to form the Compound D NA molecule that overlaps Cable Structure fully, still being easy to by the nucleus enzyme liberating, is still unsettled chemical structure.The degradation rate of D group, E group and F group is all lower than 5%, hardly by the nucleus enzyme liberating, illustrates that these three groups is the cover Cable Structure of optimizing, and is stable medical compounds structure.
determining of the compound ratio of embodiment 2 lead compounds and modification
Following Compound C ACGGGTGCAAACAG(is called to compd A), carry out the methylated chemically modified in two ends (being called compd B) according to not adorned base-5,5 adorned base-5 an adorned base, compd A and B are mixed according to different 5 different ratios.Be specially in every group the compd B of the best lasso trick structural modification of the process that adds 10 μ M, then each group adds the compd A through chemically modified of different concns, concentration is respectively 0.1 μ M, 0.2 μ M, 0.5 μ M, 1 μ M, 2 μ M, so the ratio of A:B is followed successively by 1:100,1:50,1:20,1:10 and 1:5.Be mixed cell culture 2 weeks in MDCK by above-mentioned each group at kidney cell, then by the RT-PCR method, detect the content of SGLT1 and SGLT2, by the efficiency of the mRNA that suppresses total SGLT, show result.
Result as shown in Figure 2, the rna expression rate that suppresses SGLT is respectively 75%, 78%, 85%, 79%, 70%, wherein inhibiting rate is higher, the effect that means medicine is higher, from result, can find out, the ratio of 1:20 is can reach the ratio 85% of high suppression efficiency, the compd A of visible unmodified: the amount of substance of the compd B of modification than for 1:20 the time, can reach the effect of best medicine.
the best MgCl of embodiment 3
2
determining of concentration
Following Compound C ACGGGTGCAAACAG(is called to compd A), carry out the methylated chemically modified in two ends (being called compd B) according to not adorned base-5,5 adorned base-5 an adorned base, according to optimum proportion 1:20(A:B) mix, then it is dissolved in respectively to the MgCl of 1mM, 2mM, 5mM, 10mM, 20mM and 50mM
2solvent in, at kidney cell, be mixed cell culture 2 weeks in MDCK respectively afterwards, then by the RT-PCR method, detect the content of SGLT1 and SGLT2, show result by the efficiency of the mRNA that suppresses total SGLT.
As shown in Figure 3, this medicine is at the MgCl of 1mM, 2mM, 5mM, 10mM, 20mM and 50mM for result
2solvent in suppression efficiency be respectively 86%, 88%, 95%, 89%, 75%, 74% and 72%, wherein, suppression efficiency is higher, represents that the effect of medicine is higher.Can see that from result this medicine is dissolved in 5mM MgCl
2solvent can better bring into play its pharmaceutical efficacy.
the application of embodiment 4 antidiabetic medicines
Candidate's lead compound CCCATCTCTGGTGCC, according to 6.-5-, 4. (annotate: the base number that the circle numeral is modified, without the not adorned base number of circle numeral) method carry out the both sides modification that methylates, and according to not adorned compound: the ratio of the compound=1:100 after modification is mixed, and mixture is dissolved in to the MgCl of 10mM
2solution in, as administration group 1;
Compound after above-mentioned lead compound CCCATCTCTGGTGCC is modified is dissolved in the MgCl of 10mM
2solution in, as administration group 2;
Candidate's lead compound CGGCCACCACACCAT, according to 5.-5-, 5. (annotate: the base number that the circle numeral is modified, without the not adorned base number of circle numeral) method carry out both sides deoxidation modification, and mix according to the ratio of CGGCCACCACACCAT:CGGCCACCACACCAT=1:20, and mixture is dissolved in to the MgCl of 5mM
2in solution, as administration group 3;
Compound after above-mentioned lead compound CGGCCACCACACCAT is modified is dissolved in the MgCl of 10mM
2solution in, as administration group 4;
Select traditional antidiabetic medicine U26452, as positive controls.
Give the Wista rat that adopts disposable heavy dose (50mg/kg) injection streptozotocin (STZ) to set up the 180-220g of diabetes rat model by the formula abdominal injection in above-mentioned experimental group, after 2 weeks, detect glucose level in the rat body.As shown in table 2:
Table 2: the glucose level of each experimental group before and after administration
| Experimental group | Glucose level before experiment | Glucose level after 2 weeks |
| Normal group | 5.86±0.842 | 5.91±0.782 |
| Model control group | 22.95±3.111 | 21.86±3.881 |
| Positive controls | 22.34±1.911 | 8.71±2.781 |
| | 22.81±2.213 | 9.17±3.111 |
| | 21.91±1.578 | 12.342±2.331 |
| Administration group 3 | 22.41±3.112 | 7.21±2.332 |
| Administration group 4 | 21.71±3.122 | 11.34±2.165 |
From can draw in table, each administration group can play the hypoglycemic effect of falling, still, administration group 3 is best effecies, its effect is better than traditional chaff urine medicine.
Sequence table
<110 > Suzhou Kai En Pharmaceutical Technology Co., Ltd
<120 > a kind of novel antidiabetic medicine
<130> PN1306370-00
<160> 10
<170> PatentIn version 3.5
<210> 1
<211> 15
<212> DNA
<213 > artificial sequence
<400> 1
cccatctctg gtgcc 15
<210> 2
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<213 > artificial sequence
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cggccaccac accat 15
<210> 3
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<213 > artificial sequence
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cacgggtgca aacag 15
<210> 4
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<212> DNA
<213 > artificial sequence
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gaggcggatg cggcg 15
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ggagagcaca gacag 15
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ggtcgctgca ccagt 15
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Claims (10)
1. a lead compound, is characterized in that, is the nucleotide sequence of the gene order RNA enzyme H formation complex body of energy specificity and kidney sodium glucose co-transporter 2 white 1 and the white 2 same medicine target spots of sodium glucose co-transporter 2.
2. lead compound according to claim 1, is characterized in that, it is one of following that the gene order of its compound is selected from:
(1) CCCATCTCTGGTGCC
(2) CGGCCACCACACCAT
(3) CACGGGTGCAAACAG
(4) GAGGCGGATGCGGCG
(5) GGAGAGCACAGACAG
(6) CCGAGGAGCAGCGCG
(7) GGTCGCTGCACCAGT
(8) GCCAGGCAGCGCTGC
(9) CAGGCACCACGCAGG
(10)GGTAGGGATGTTGGA。
3. a novel antidiabetic medicine, is characterized in that, its core texture is the described lead compound of claim 1 or 2.
4. antidiabetic medicine according to claim 3, is characterized in that, also comprises the chemical modification object of lead compound claimed in claim 1.
5. antidiabetic medicine according to claim 4, is characterized in that, the modifier of described lead compound is that the deoxidation modification of lead compound two ends or two ends are methylated and modify " lasso trick " structure with closed at both ends formed.
6. antidiabetic medicine according to claim 5, it is characterized in that, the form of described " lasso trick " structure is: not adorned base-5,5 adorned base-5 an adorned base, 4 adorned base-5 not adorned base-6 adorned base or not adorned base-4,6 adorned base-5 an adorned base.
7. according to the described antidiabetic medicine of claim 3 ~ 6 any one, it is characterized in that lead compound: the amount of substance of the compound after modification is than being 1:100 ~ 1:10.
8. antidiabetic medicine according to claim 7 is characterized in that lead compound: the amount of substance of the compound after modification is than being 1:20.
9. antidiabetic medicine according to claim 8, is characterized in that, it is dissolved in MgCl
2in solution.
10. antidiabetic medicine according to claim 9, is characterized in that, described MgCl
2the concentration of solution is 1 ~ 10mM.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013103772574A CN103468680A (en) | 2013-08-27 | 2013-08-27 | Novel antidiabetic medicine |
| PCT/CN2013/091040 WO2015027652A1 (en) | 2013-08-27 | 2013-12-31 | A novel antidiabetic drug |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2013103772574A CN103468680A (en) | 2013-08-27 | 2013-08-27 | Novel antidiabetic medicine |
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| Publication Number | Publication Date |
|---|---|
| CN103468680A true CN103468680A (en) | 2013-12-25 |
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ID=49793721
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|---|---|---|---|
| CN2013103772574A Pending CN103468680A (en) | 2013-08-27 | 2013-08-27 | Novel antidiabetic medicine |
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| WO (1) | WO2015027652A1 (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015027652A1 (en) * | 2013-08-27 | 2015-03-05 | 苏州凯恩医药科技有限公司 | A novel antidiabetic drug |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120196921A1 (en) * | 2003-11-03 | 2012-08-02 | Isis Pharmaceuticals, Inc. | Modulation of sglt-2 expression |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2005038013A1 (en) * | 2003-10-07 | 2005-04-28 | Isis Pharmaceuticals, Inc. | Artisense oligonucleotides optimized for kidney targeting |
| CN103468680A (en) * | 2013-08-27 | 2013-12-25 | 苏州凯恩医药科技有限公司 | Novel antidiabetic medicine |
-
2013
- 2013-08-27 CN CN2013103772574A patent/CN103468680A/en active Pending
- 2013-12-31 WO PCT/CN2013/091040 patent/WO2015027652A1/en active Application Filing
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120196921A1 (en) * | 2003-11-03 | 2012-08-02 | Isis Pharmaceuticals, Inc. | Modulation of sglt-2 expression |
Non-Patent Citations (2)
| Title |
|---|
| EDWARD C. CHAO AND ROBERT R. HENRY: "SGLT2 inhibition — a novel strategy for diabetes treatment", 《NATURE REVIEWS》 * |
| JOHN R. WHITEET AL.: "Apple Trees to Sodium Glucose Co-Transporter Inhibitors：A Review of SGLT2 Inhibition", 《CLINICAL DIABETES》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2015027652A1 (en) * | 2013-08-27 | 2015-03-05 | 苏州凯恩医药科技有限公司 | A novel antidiabetic drug |
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| Publication number | Publication date |
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| WO2015027652A1 (en) | 2015-03-05 |
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Application publication date: 20131225 |