CN108721290A - Compound EPZ031686 is preparing the purposes in treating vascular ageing relevant disease drug - Google Patents
Compound EPZ031686 is preparing the purposes in treating vascular ageing relevant disease drug Download PDFInfo
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- CN108721290A CN108721290A CN201710279494.5A CN201710279494A CN108721290A CN 108721290 A CN108721290 A CN 108721290A CN 201710279494 A CN201710279494 A CN 201710279494A CN 108721290 A CN108721290 A CN 108721290A
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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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
- A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
- A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
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Abstract
The invention belongs to pharmaceutical fields, are related to EPZ031686 and are preparing anti-aging, improve the application in vascular ageing relevant disease drug.The present invention is tested by external aging model, as a result show that the EPZ031686 inhibits the protein expression of aging-related phenotype molecule, the activity of cell ageing marker-SA- β-gal can be reduced and restore cell proliferative conditions, specify the regulatory mechanism that EPZ031686 inhibits cell ageing, in vivo in diseases associated with senescence model experiment, the result shows that EPZ031686 can inhibit the protein expression of aging-related phenotype molecule, the EPZ031686 has the function of significantly slowing down aging to diseases associated with senescence, further, the compound EPZ031686 and its related inhibitors can prepare the drug for the treatment of vascular ageing relevant disease.
Description
Technical field
The invention belongs to pharmaceutical fields, are related to new applications of the compound EPZ031686 in pharmacy, and in particular to compound
The purposes of EPZ031686 and its related inhibitors in preparing treatment vascular ageing relevant disease drug, the drug contribute to
Delay vascular ageing relevant disease, improves senior health and fitness.
Background technology
Research confirms that vascular ageing is to cause cardiovascular related diseases such as.Hypertension, atherosclerosis, diabetes etc.
An important factor for one of, wherein the vascular cell of aging during its occurrence and development always with key player.This field skill
Art personnel think, intervene the continuous accumulation of aging vascular cell, will effectively prevent vascular ageing and cardiovascular related diseases
Generation.
It is a kind of sulfa drugs prior art discloses EPZ031686, is the noncompetitive inhibitor of SMYD3.It grinds
Study carefully report, in vitro experiment, EPZ031686 can effectively inhibit the bioactivity of SMYD3, be first and be identified
SMYD3 inhibitor with two nanomole grades, it is equal for 16 kinds of histone methylated transferases when using 10 μM of concentration
There are the inhibition less than 30%, SMYD3Biochem IC50=3nM, SMYD3Cell IC50=36nM；It tests in vivo
In, when taking orally the when of giving mouse EPZ031686 there is preferable bioavilability, intravenous injection concentration to need 1mg/kg.
So far, there is not yet the report that EPZ031686 is acted in terms of delaying vascular ageing pharmacology.
Present situation based on the prior art, the quasi- new use for providing compound EPZ031686 in pharmacy of present inventor
On the way, and in particular to compound EPZ031686 and its related inhibitors are preparing the use in treating vascular ageing relevant disease drug
On the way.
Invention content
The purpose of the present invention is the present situations for the prior art, provide new applications of the compound EPZ031686 in pharmacy,
The purposes in treating vascular ageing relevant disease drug is being prepared more particularly to compound EPZ031686 and its related inhibitors.
The molecular formula of compound EPZ031686 of the present invention is：C26H34CLF3N4O4S, (commercially available).
The rat aortic endothelial cells that the present invention is induced by Angiotensin II (Angiotensin II, Ang II)
Aging model observes inhibiting effect of the EPZ031686 to aging-related phenotype molecule, further pre- anti-aging related cardiovascular
The generation of disease；EPZ031686 is detected to histone methylated transferase Smyd3 (SET by western blot methods
AndMYND domain containing 3), cyclin-depended kinase inhibiting factor 1A (cyclin-
Dependent kinase inhibitor 1A, Cdkn1a/p21), vascular cell adhesion molecule (vascular cell
Adhesion molecule-1, VCAM-1) protein expression situation；Utilize cell ageing beta galactosidase staining kit
SA- β-Gal when (Senescence cells histochemical staining kit, sigma) detects cell ageing
(senescence-associated β-galactosidase) activity；Utilize keyFluor488Click-iT EdU imaging inspections
Test agent box detects cell proliferative conditions；In vivo experiment mouse aging mould is established using the micro- pump Continuous Perfusions that ooze of Ang II
Type, and be injected intraperitoneally and give mouse EPZ031686 (50mg/kg/day), pass through western blot and immunofluorescence technique
(Immunofluorescence staining) method detects influences of the EPZ031686 to aging GAP-associated protein GAP；
The result shows that the apparent inhibition of histone methylated transferase Smyd3 of the compound EPZ031686, cell week
Stage dependent protein kinase inhibitor 1A (Cdkn1a/p21), the protein expression of vascular cell adhesion molecule (VCAM-1)；?
Menses angiotensin II (Ang II) can be observed under common light microscope treated that apparent blue dye occurs in cell, i.e.,
SA- β-Gal increased activities obviously inhibit SA- β-Gal active after giving EPZ031686；It is observed under fluorescence microscope
EPZ031686 can obviously restore cell proliferative conditions；The experiment in vivo of the present invention is the results show that mouse is given in intraperitoneal injection
EPZ031686 can significantly inhibit albumen methylated transferase Smyd3, cyclin-depended kinase inhibiting factor 1A
(Cdkn1a/p21), the protein expression of vascular cell adhesion molecule (VCAM-1), the double dyes of immunofluorescence the results show that
EPZ031686 obviously inhibits the fluorescence intensity of smyd3 and p21.
The experimental results showed that EPZ031686 obviously inhibits the activity of senile cell beta galactosidase and restores cell
Proliferative capacity, EPZ031686 can inhibit the expression of aging related genes smyd3, VCAM-1, p21；Described EPZ031686 pairs
The cell ageing of Ang II inductions has significant protective effect, further, the compound EPZ031686 and its related suppression
Preparation can prepare the drug for the treatment of of vascular diseases associated with senescence.
Description of the drawings
Fig. 1 is to detect related gene Smyd3, p21, VCAM-1 protein level using western blot methods,
Wherein：control：Normal group, Ang II：Model group, EPZ031686:AngⅡ+EPZ031686.
Fig. 2 is to utilize cell ageing beta galactosidase staining kit (Senescence cells
Histochemical staining kit, Sigma) detection cell ageing when SA- β-Gal activity,
Wherein：control：Normal group, Ang II：Model group, EPZ031686:AngⅡ+EPZ031686.
Fig. 3 is to detect cell proliferative conditions using keyFluor488Click-iT EdU imaging test kits,
Wherein：control：Normal group, Ang II：Model group, EPZ031686:AngⅡ+EPZ031686.
Fig. 4 is to utilize Smyd3 in western blot methods detection mouse vascular tissue, p21 protein levels,
Wherein, data are compared with target gene with corresponding internal reference GAPDH, wherein：control：Normal group, Ang II：
Model group, EPZ031686:AngⅡ+EPZ031686.**:p<0.01.
Fig. 5 is to utilize VCAM-1 in western blot methods detection mouse vascular tissue, p-Chk2 protein levels,
Wherein, data are compared with target gene with corresponding internal reference GAPDH, wherein：control：Normal group, Ang II：
Model group, EPZ031686:AngⅡ+EPZ031686.**:p<0.01.
Fig. 6 is to utilize Smyd3, p21 tables in Immunofluorescence staining methods detection mouse vascular tissue
The fluorescence intensity reached,
Wherein：control：Normal group, Ang II：Model group, EPZ031686:AngⅡ+EPZ031686.It is wherein green
Color is Smyd3, and red is p21.
Specific implementation mode
1 EPZ031686 of embodiment prevents external rat aortic endothelial cells senescent phenotypes experiment
Grouping：1 × 105 rat aortic endothelial cells kind is entered into the culture of 6cm culture dishes and reaches 85-90% within 3 days, cell is same
Stepization 6-12h is randomly divided into 6 groups, i.e.,：1. Normal group；2. model group；EPZ031686 3. (5 μM) group；④EPZ031686
(10 μM) group；EPZ031686 5. (15 μM) group；Administration：3. 5. final concentration of 5 μM, 10 μM, 15 μM of EPZ031686 is added,
Cultivate 4h；(2 μM) culture induced rat aortic endothelial cell aging models of Ang II are added；Total protein of cell is extracted, is used
Western Blot measure the protein level of aging-related phenotype molecule, including：smyd3,VCAM-1,p21；Experimental data carries out
As a result one-way analysis of variance, p < 0.05 show that EPZ031686 can inhibit aging related genes smyd3, VCAM-1, p21
Expression；Using cell ageing beta galactosidase staining kit (Senescence cells histochemical
Staining kit, Sigma) and keyFluor488Click-iT EdU imaging test kits when detecting cell ageing respectively
SA- β-Gal activity and cell proliferative conditions, the results showed that, EPZ031686 obviously inhibits the work of senile cell beta galactosidase
Property and restore ability of cell proliferation；
The results show, the EPZ031686 have significant protective effect to the cell ageing that Ang II are induced,
The drug of prevention diseases associated with senescence can be prepared.
2 EPZ031686 of embodiment prevents vascular ageing phenotype experiment in Mice Body
Grouping：Week old 8-12W weight 22-26g male C 57 BL mouses in good condition are selected at random, are randomly divided into 6 groups,
I.e.：1. Normal group；2. model group；EPZ031686 3. (5mg/kg/day) group；④EPZ031686(15mg/kg/day)
Group；EPZ031686 5. (25mg/kg/day) group shows skin after chloral hydrate anesthesia is injected intraperitoneally using iodophor disinfection,
Mini Pump, Ang II of the embedment containing Ang II be with the rate Continuous Perfusion 4 weeks of 1.5mg/kg/day in mouse omoplate notch,
Administration：3. 5. EPZ03168650mg/kg/day is given in intraperitoneal injection daily；Conventional treatment mouse after 4 weeks, separation is actively
Arteries and veins, a part are fixed in 4% paraformaldehyde fixer, and another part is thrown into liquid nitrogen and preserved, the WB detections for after, real
Test data carry out one-way analysis of variance, p < 0.05, as a result show EPZ031686 can inhibit aging related genes smyd3,
The expression of VCAM-1, p21；Show that EPZ031686 obviously inhibits the fluorescence of smyd3 and p21 strong using immunofluorescence technique result
Degree.
Claims (4)
1.EPZ031686 the purposes in preparing treatment of vascular diseases associated with senescence drug；
The molecular formula of the EPZ031686 is：C26H34CLF3N4O4S.
2. purposes as described in claim 1, which is characterized in that the EPZ031686 is in vivo and in vitro by inhibiting to decline
The protein expression level of uneducated person correlation gene plays anti-aging effects, improves aging related cardiovascular disease symptom.
3. purposes as described in claim 1, which is characterized in that the EPZ031686 reverses SA- β-gal activation plays anti-
Aging acts on.
4. purposes as described in claim 1, which is characterized in that it is anti-that the EPZ031686 improves ability of cell proliferation performance
Aging acts on.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710279494.5A CN108721290A (en) | 2017-04-25 | 2017-04-25 | Compound EPZ031686 is preparing the purposes in treating vascular ageing relevant disease drug |
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| CN201710279494.5A CN108721290A (en) | 2017-04-25 | 2017-04-25 | Compound EPZ031686 is preparing the purposes in treating vascular ageing relevant disease drug |
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| CN201710279494.5A Pending CN108721290A (en) | 2017-04-25 | 2017-04-25 | Compound EPZ031686 is preparing the purposes in treating vascular ageing relevant disease drug |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115837022A (en) * | 2023-02-20 | 2023-03-24 | 中山大学附属第八医院（深圳福田） | Application of 1,2,4 triazolo 4,3-B pyridazine derivative in preparation of anti-aging drugs |
-
2017
- 2017-04-25 CN CN201710279494.5A patent/CN108721290A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| LH MITCHELL: "Novel Oxindole Sulfonamides and Sulfamides: EPZ031686, the First Orally Bioavailable Small Molecule SMYD3 Inhibitor", 《ACS MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115837022A (en) * | 2023-02-20 | 2023-03-24 | 中山大学附属第八医院（深圳福田） | Application of 1,2,4 triazolo 4,3-B pyridazine derivative in preparation of anti-aging drugs |
| CN115837022B (en) * | 2023-02-20 | 2023-04-25 | 中山大学附属第八医院（深圳福田） | Application of 1,2, 4-triazolo 4,3-B pyridazine derivative in preparation of anti-aging drugs |
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Application publication date: 20181102 |