CN108456170A - The inhibitor of SGLT2 albumen and application - Google Patents
The inhibitor of SGLT2 albumen and application Download PDFInfo
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- CN108456170A CN108456170A CN201810237100.4A CN201810237100A CN108456170A CN 108456170 A CN108456170 A CN 108456170A CN 201810237100 A CN201810237100 A CN 201810237100A CN 108456170 A CN108456170 A CN 108456170A
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- sglt2
- compound
- inhibitor
- albumen
- diabetes
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- 0 C*(C)c1ccc(C)cc1 Chemical compound C*(C)c1ccc(C)cc1 0.000 description 3
- NVXIZLZEEOWEQU-UHFFFAOYSA-N CC(C)(C)c(ccc(F)c1)c1F Chemical compound CC(C)(C)c(ccc(F)c1)c1F NVXIZLZEEOWEQU-UHFFFAOYSA-N 0.000 description 1
- GGLWSLBFZLEDEF-UHFFFAOYSA-N CCc(ccc(F)c1)c1F Chemical compound CCc(ccc(F)c1)c1F GGLWSLBFZLEDEF-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/74—Two oxygen atoms, e.g. hydantoin with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to other ring members
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
- C07D233/78—Radicals substituted by oxygen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D233/72—Two oxygen atoms, e.g. hydantoin
- C07D233/80—Two oxygen atoms, e.g. hydantoin with hetero atoms or acyl radicals directly attached to ring nitrogen atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- G—PHYSICS
- G16—INFORMATION AND COMMUNICATION TECHNOLOGY [ICT] SPECIALLY ADAPTED FOR SPECIFIC APPLICATION FIELDS
- G16C—COMPUTATIONAL CHEMISTRY; CHEMOINFORMATICS; COMPUTATIONAL MATERIALS SCIENCE
- G16C20/00—Chemoinformatics, i.e. ICT specially adapted for the handling of physicochemical or structural data of chemical particles, elements, compounds or mixtures
- G16C20/40—Searching chemical structures or physicochemical data
Abstract
The screening technique of the inhibitor of SGLT2 albumen a kind of and compound in the application and inhibitor for preparing the drug for the treatment of diabetes.Wherein, the inhibitor includes the compound with structure shown in formula (1)：The inhibitor can be used as active primer treatment diabetes.
Description
Technical field
The present invention relates to the relevant field for the treatment of diabetes, further to a kind of SGLT2 (Na+-glucose
Cotransporter 2, OMIM：* 182381, also referred to as SLC5A2) albumen inhibitor, further relate to a kind of compound and treating
The application of diabetes further relates to the screening technique of SGLT2 protein inhibitors.
Background technology
Kidney plays an important roll in adjusting blood glucose level, and there are two class glucose transporter in kidney, wherein one
Class is the glucose transporter (Na+-glucose cotransporter, SGLT) that sodium relies on, and consumption energy is with active mode
Inverse concentration gradient transports glucose.Wells etc. is found that a kind of referred to as SGLT2 (OMIM from the cDNA library of people's kidney:*
182381, be also SLC5A2) transport protein.
Familial renal glucosuria (Familial renal Glucosuria, FRG) is with fasting blood-glucose and carbohydrate tolerance test
Normally, the disease lowered with the proximal tubular glucose re-absorption function that lasting glucose in urine is main feature, and patient is mostly
Without renal tubular function and the exception of structure, prognosis bona.In the prior art in familial renal glucosuria patient's nephridial tissue
Expression study has been carried out, it is found that wild type and saltant type SGLT2 albumen are expressed in renal cells, wherein wild type
SGLT2 can be expressed normally, and abnormal distribution and expression occur on cell membrane in SGLT2 muteins, to again
It is determined that familial renal glucosuria should be defined as codominant inheritance, and the incomplete penetrance previously thought considers and the open countries SGLT2
Raw type albumen it is compensatory related.
Research in recent years finds that the expression of the SGLT2 of diabetic and function are obviously raised, and familial renal glucosuria is suffered from
Person prognosis bona, it is therefore, special to block proximal convoluted tubule SGLT2 transport proteins, and then inhibit glucose reabsorption to control blood glucose
Level becomes the hot spot studied at present.Phloridzin (phlorizin) is that french chemist in 1835 is detached from apple bark
The first SGLT inhibitor gone out finds that phloridzin can reduce blood glucose in subsequent many diabetic animals research, restores
The sensibility of insulin, but since oral administration biaavailability is relatively low, specificity is not high, and metabolite may inhibit
The function of the albumen such as GLUT1 has some side effects, so being not applied to glycosuria in central nervous system and other systems
The clinical treatment of disease.
Invention content
(1) technical problems to be solved
In view of this, the purpose of the present invention is to provide a kind of inhibitor of SGLT2 albumen and compound to be controlled in preparation
The application of the drug of diabetes and the screening technique of SGLT2 protein inhibitors are treated, to solve at least one of above-described skill
Art problem.
(2) technical solution
According to an aspect of the present invention, a kind of inhibitor of SGLT2 albumen is provided, includes with structure shown in formula (1)
Compound：
Wherein, A is stood alone as：
B is stood alone as：
According to another aspect of the present invention, a kind of application of compound in the drug for preparing treatment diabetes is provided,
In, the compound is above-described compound.
In accordance with a further aspect of the present invention, a kind of screening technique of SGLT2 protein inhibitors is provided, including：
SGLT2 albumen and compound is arranged docks condition；
Virtual screening is carried out in the database according to docking condition；
It is carried out, to further screening and the marking of virtual screening result, obtaining the compound conduct of high score according to quasi-medicated property principle
The lead compound for the treatment of diabetes.
(3) advantageous effect
Through the above scheme, it is known that the beneficial effects of the present invention are：
Compound in the inhibitor of SGLT2 albumen through the invention can be used as active lead compound treatment sugar
Urine disease.
Compound in the inhibitor of the SGLT2 albumen of the present invention includes hydrophilic radical and hydrophobic pocket, with SGLT2 albumen
The polar pocket of active site, pocket waterborne interaction, inhibit the expression of SGLT2 albumen.
The compound of the present invention can be applied to prepare diabetes medicament.
Description of the drawings
Fig. 1 is the compound of the inhibitor of SGLT2 albumen of the embodiment of the present invention.
Fig. 2 is the compound and SGLT2 albumen action principle figures of inhibitor of the embodiment of the present invention.
Fig. 3 is the mutational site found in familial renal glucosuria patient of the embodiment of the present invention.
Fig. 4 is the structure-activity relationship figure of compound of the embodiment of the present invention and SGLT2 albumen.
Fig. 5 is the standard curve in specific example 1 of the present invention.
Specific implementation mode
To make the objectives, technical solutions, and advantages of the present invention clearer, below in conjunction with specific embodiment, and reference
Attached drawing, the present invention is described in further detail.
Since the SGLT2 expression and functional study of the past in the prior art are only found that 2 kinds of mechanism therein, the application hair
A person of good sense has found that remaining 4 kinds of mechanism plays an important roll in familial renal glucosuria pathogenic process, and specifies relevant bits
Point.C.294C inventor is further discovered that>A/p.(F98L),c.736C>T/p. (P246S) is diabetes medicament (SGLT2 albumen
Inhibitor) screening desired target point.Due to being still not very clear that medicament research and development is all sought to the exact 3D structures of SGLT2
The derivative or the like for looking for phloridzin, may be to other glucose transport proteins while inhibiting SGLT2 protein functions
Different degrees of influence is also resulted in vain, produces ill-effect, and certain difficulty is caused in the R＆D process of drug.
One side according to the ... of the embodiment of the present invention provides a kind of inhibitor of SGLT2 albumen, including following compound：
Wherein, A is stood alone as：
B is stood alone as：
The compound of formula (1) as shown in Figure 1 is the docking structure of three small molecules, shown referring to Fig.1 comprising left and right
The hydrophilic radical and hydrophobic grouping (mark in dashed rectangle) of both sides, and intermediate coupling part (dashed middle line box), (knot
It closes shown in Fig. 2, for SGLT2 as target albumen, active site has apparent polar pocket (such as residue Ser460 in Fig. 2)
With hydrophobic pocket (such as Trp289).
In Fig. 2, the combination of these compounds and SGLT2 mainly have three parts：1, the hydrophilic radical of compound with
The residues such as Ser460 form interaction of hydrogen bond；2, the coupling part of hydrophilic radical and hydrophobic grouping is formed by residue Trp289
Hydrogen bond action carrys out the combination of stable compound；3, the hydrophobic grouping of compound enters hydrophobic pocket, forms hydrophobic effect；Especially when
When hydrophobic grouping is aromatic rings, stronger pi-pi bond is formed with Trp289 residues, L286V mutation in addition can make the benzene first of small molecule
Base portion point (structure in circle in Fig. 4) has enough spatial positions and protein-interacting.
It by above-mentioned inhibitor, can specifically inhibit SGLT2 protein functions, effectively reduce empty stomach and postprandial blood
Sugar becomes the new way for the treatment of diabetes.
Above-mentioned inhibitor can do the isostructural drug of slabbing using powder as raw material.
In a further embodiment, the A can be stood alone as
Preferably, A can be stood alone asMore preferably can be
In some embodiments, the B is stood alone as Preferably, B stand alone as,
In some embodiments, more preferably, the A isB is
The embodiment of the present invention also provides a kind of application of compound in the drug for preparing treatment diabetes, wherein described
Compound has structure shown in formula (1) described above.
Another aspect according to the ... of the embodiment of the present invention provides a kind of screening technique of SGLT2 protein inhibitors, including：
SGLT2 albumen and compound is arranged docks condition；
Virtual screening is carried out in the database according to docking condition；
It is carried out, to further screening and the marking of virtual screening result, obtaining the compound conduct of high score according to quasi-medicated property principle
The lead compound for the treatment of diabetes.
In the embodiment of the present invention, it is with the SGLT2 gene mutations found in the familial renal glucosuria patient of Inner Mongolia
Basis, further to SGLT2 from gene mutation to protein expression, function progress in-depth study, for disclosing SGLT2 in family
Property renal glucosuria pathogenesis in key effect and its mechanism of action clinical and basic research evidence and theoretical foundation (ginseng are provided
As shown in Figure 3), by virtual screening, according to quasi-medicated property principle, we eliminate part the selection result, finally obtain small molecule
Compound.By the interaction relationship of small molecule and receptor protein, we analyze and select the biology that small molecule can be used for the later stage
Experimental verification.It is design, screening and the novel drugs research and development of Remedies for diabetes further by cell and animal level verification
Significant target and important clue and foundation are provided.
Screening process includes：1, drug virtual screening：The target spot that drug screening is determined using the result of functional study, into one
Walk the drug of screening treatment diabetes.SGLT2 albumen is carried out based on known antagonist phloridzin and its derivative or the like
The Inhibition test of function as a result, establish quantitative structure activity relationship model, using the method for three-dimensional pharmacophore model search, changing
It closes and carries out void in object database (commercial micromolecular compound library ACD-SC, MDDR and China Natural Product Database CNPD)
Quasi- screening, finds active lead compound.And further screened according to quasi-medicated property principle, it gives a mark, finally obtains several
Lead compound of a high score compound as treating diabetes, new clue and foundation are provided for medicament research and development.2, virtual sieve
Select scheme：It is tested by the flexible docking of albumen and three drug molecules, we tentatively can be determined that：Patent medicine small molecule and albumen
Effect maintained compared with strong interaction possibly via two parts, be on the one hand the stronger glycosyl part of hydrophily and pocket court
The amino acid residue of outer portion forms more stable hydrogen bond；On the other hand it is small molecule aromatic moiety hydrophobic with pocket higher depth
The hydrophobic interaction of pocket and π-π interactions.Virtual screening is done according to the docking condition set, in being calculated with Beijing
The virtual screening platform of the heart is screened, and the small molecule libraries selected are patent medicine database and can provisioning database C.3, pharmacophore sieves
Process is selected, is specifically included：Small molecule is selected：A/ small molecules have the general character of >=4 drug molecules, and the pharmacophore built out can be complete
Number sieve goes out 5 small molecules；B/ small molecules have specificity difference recognition site to SGLT2 and SGLT1.Pharmacophore is established and test,
5 drugs can be filtered out；One decoy test group is set again, including 5 small molecules, it is optimal that complete 5 drugs are sifted out in test.
Pharmacophore screen marketed drug library all and can the docking top30% virtual screenings of giving a mark of provisioning database c work.
The higher small molecule of pharmacophore marking is selected, the specificity combined with amino acid residue according to visualization small molecule is chosen
Select the small molecule of the embodiment of the present invention.
Fig. 4 is the structure-activity relationship figure of compound of the embodiment of the present invention and SGLT2 albumen.By existing three drug molecules pair
It is connected in SGLT2 albumen, it is found that the docking result of three small molecules has certain rule.As shown in figure 4, from albumen
Film inner region sees that the glycosyl part of three small molecules is overlapping, and small molecule is in the hydrophobic of pocket higher depth in addition to albumen depths
Qu Jun has multiple hydrophobic functional groups.Scale model shows that SGLT2 and SGLT1 has the amino acid residue of mutation in pocket locations,
Preliminary analysis finds that it may be because small molecule is more easy to be formed with hydrophobic pocket that three drug specificities, which are attached to SGLT2 pockets,
Interaction of hydrogen bond, in addition L286V mutation can make the phenylmethyl moiety of small molecule have enough spatial positions and albumen phase interaction
With (referring to Fig. 4 encircled portions).
Specific example 1 will be enumerated below, the effect of the compound of the embodiment of the present invention is verified in cellular level, find glycosuria
The lead compound of disease treatment, method are as follows：
Cellular level is verified：
One, laboratory apparatus and reagent
PBS PBS (phosphate buffer saline) phosphate buffered saline solution Shaanxi arteries and veins member
Multi-functional micropore board detector PE
DMEM basal mediums DMEM (dulbecco's modified eagle medium)
Hyclone
FBS FBS (Fetal Bovine Serum) fetal calf serum Gibco
Pen .- Strep Hyclone
0.25% trypsase Hyclone
P-transter (Mai Yuan companies make transfection reagent by oneself) Shaanxi arteries and veins member
Glucose Uptake Assay Kit Sugar intake detection kit BioAssay Systems
Two, experimental method
1., cell prepare
1. with 0.25% trypsin digestion and cell, cell suspension is prepared, adjustment cell density is 2 × 105A/ml.
2. inoculating cell suspension (500 holes μ L/) in 24 orifice plates, by culture plate put culture in the incubator (37 DEG C, 5%
CO2) overnight.
3. transfected plasmids (SGLT-2, GFP) form transfection using GFP transfection methods by transfection reagent P-transter
Plasmid cell.
4. culture plate is put culture (37 DEG C of culture environment, 5%CO in the incubator2)48h。
2., drug-treated
After 1.48h, changes free serum culture into and be based on cultivating (culture environment in incubator：37 DEG C, 5%CO2), overnight.
2. being changed to serum-free sugar-free culture-medium, and corresponding inhibitor is added, cultivates (culture environment in the incubator：
37 DEG C, 5%CO2) 40min.Here inhibitor has structure shown in formula (1)：And A isG is
, the inhibitor is labeled as T.
3. plus 2-DG (2-deoxyglucose)
1. 20 μ l 2-DG are added per hole.It is incubated that (condition is in incubator：37 DEG C, 5%CO2) 20min.
2. removing culture medium, washed 3 times with the PBS of precooling.
4. plus 2-DG
1. preparing lysis buffer：Add 1%Triton X-100 in NADP Extraction buffer (extraction bufferings
Liquid) in.Prepare 220 μ l per hole.
2. standard curve：
A. prepare 5 μM of 2-DG6P (2-deoxyglucose 6-phosphate)：5 μ l 5mM Standard (marks are added
Quasi- product) in 4995 μ l distilled water, mixing.
B. each master sample dilution process enters the following table 1
Table 1
| Serial number | Premix+H2O | 2-DG6P(μM) |
| 1 | 100μl+0μl | 5.0 |
| 2 | 60μl+40μl | 3.0 |
| 3 | 30μl+70μl | 1.5 |
| 4 | 0μl+100μl | 0 |
3. 200 μ l lysis buffers are added in the hole of 24 orifice plates, shaking table shakes 5min.
4. drawing 50 μ l cell pyrolysis liquids samples and 50 μ l master samples respectively in 1.5ml EP
Pipe, in 80 DEG C, 10min.
5. 50 μ l NADPH extraction buffer (Extraction buffer) are added in cell sample pipe, 50 μ l are added
H2O is in master sample pipe, -20 DEG C, 5min.
6. preparing WR1：Add 10 μ l Assay buffer (reaction buffer), 1 μ l G6PDH (glucose 6-
Phosphate dehydrogenase) Enzyme, in 1 μ l NADP.Often pipe prepares 12 μ l.Often 10 μ l WR1 are added in pipe, in 37
DEG C, 60min.
7. often 50 μ l NADPH extraction buffer, in 80 DEG C, 15min are added in pipe.
8. often pipe is added 50 μ l NADP extraction buffer, -20 DEG C, 5min.
9. 50 μ l are respectively drawn in cell sample and master sample, in the hole of 96 orifice plate of black.
10. preparing WR2：Add 45 μ l Assay buffer, 1 μ l Enzyme A, 1 μ l Enzyme B, 10 μ l G6P
(glucose 6-phosphate) Reagent, 5 μ l Probe.
11. 50 μ l WR2 are added per hole, 0min and 20min light absorption values are measured respectively at 530/585.
Three, experiment packet
Experiment packet situation such as the following table 2, each group is done three multiple holes.
Table 2
| Group | Details | Drug concentration |
| C1 | Transfected plasmids (GFP) cell | |
| C2 | Transfected plasmids (SGLT-2) cell | |
| C3 | Normal cell | |
| C4 | Transfected plasmids (SGLT-2) cell+solvent | |
| T | Transfected plasmids (SGLT-2) cell+inhibitor T | 1mM |
Four, experimental result and analysis
1, standard curve
Table 3
| 0(μM) | 1.5(μM) | 3(μM) | 5(μM) | |
| 0min | 13286 | 18528 | 20563 | 24000 |
| 20min | 14764 | 24054 | 31384 | 42060 |
| 20-0min | 1478 | 5526 | 10821 | 18060 |
Upper table is light absorption value as a result, linear standard curve shown in fig. 5 can be fitted to.
2. glucose uptake data analysis
4 Tukey multiple comparative tests of table
Tukey Multiple range tests verification shown in table 4 is carried out to the glucose uptake amount of group C1-C4 and T, can be seen
It is other higher than C1-C4 groups to go out the other glucose uptake amount of T groups, it, can be as sugar with preferably with preferable inhibition
The lead drug of urine disease treatment.
Particular embodiments described above has carried out further in detail the purpose of the present invention, technical solution and advantageous effect
Describe in detail bright, it should be understood that the above is only a specific embodiment of the present invention, is not intended to restrict the invention, it is all
Within the spirit and principles in the present invention, any modification, equivalent substitution, improvement and etc. done should be included in the protection of the present invention
Within the scope of.
Claims (8)
1. a kind of inhibitor of SGLT2 albumen, it is characterised in that include the compound with structure shown in formula (1)：
Wherein, A is stood alone as：
B is stood alone as：
2. inhibitor according to claim 1, which is characterized in that the A is stood alone as
3. inhibitor according to claim 1, which is characterized in that the B is stood alone as
4. inhibitor according to claim 2, which is characterized in that the A is stood alone as
5. inhibitor according to claim 3, which is characterized in that the B is stood alone as
6. inhibitor according to claim 1, which is characterized in that the A isThe B is
7. a kind of application of compound in the drug for preparing treatment diabetes, wherein the compound has knot shown in formula (1)
Structure：
Wherein, A is stood alone as：
B is stood alone as：
8. application according to claim 7, which is characterized in that the compound is used to inhibit the expression of SGLT2 albumen, institute
It is I types and type-2 diabetes mellitus to state diabetes.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810072958X | 2018-01-25 | ||
| CN201810072958 | 2018-01-25 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108456170A true CN108456170A (en) | 2018-08-28 |
Family
ID=63237245
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810237100.4A Withdrawn CN108456170A (en) | 2018-01-25 | 2018-03-21 | The inhibitor of SGLT2 albumen and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108456170A (en) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5714127A (en) * | 1992-10-08 | 1998-02-03 | Warner-Lambert Company | System for multiple simultaneous synthesis |
-
2018
- 2018-03-21 CN CN201810237100.4A patent/CN108456170A/en not_active Withdrawn
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5714127A (en) * | 1992-10-08 | 1998-02-03 | Warner-Lambert Company | System for multiple simultaneous synthesis |
Non-Patent Citations (4)
| Title |
|---|
| COGHILL,R.D.ET AL.: "Hydantoins. XLI. The synthesis of hydantoins containing phenolic groups in the glyoxaline nucleus", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
| US: "REGISTRY", 《STN COLUMBUS》 * |
| VINOD KUMAR ET AL.: "Highly efficient dialkylphosphate-mediated syntheses of hydantoins and a bicyclohydantoin under solvent-free conditions", 《TETRAHEDRON LETTERS》 * |
| 李丽晶等: "SGLT2抑制剂治疗2型糖尿病的研究进展", 《中国中西医结合肾病杂志》 * |
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