CN108703971A - The comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase - Google Patents
The comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase Download PDFInfo
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- CN108703971A CN108703971A CN201810776447.6A CN201810776447A CN108703971A CN 108703971 A CN108703971 A CN 108703971A CN 201810776447 A CN201810776447 A CN 201810776447A CN 108703971 A CN108703971 A CN 108703971A
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- apelin
- platelet aggregation
- inverase
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- platelet
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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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
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Abstract
A kind of comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase, the drug can effectively inhibit platelet aggregation and inhibit the ex vivo thrombosis of artificial blood vessel.The present invention relates to drugs to have the new zealand rabbit platelet aggregation for inhibiting the ADP inductions of blood platelet derivant and artificial blood vessel ex vivo thrombosis effect than it is taken charge of；It itself can effectively inhibit the new zealand rabbit platelet aggregation and the effect of artificial blood vessel ex vivo thrombosis that APJ endogenic ligands Elabela, Apelin-12, Apelin-13 and Apelin-36 are induced.Than taking charge of its basic research in thrombotic diseases using the drug as a kind of novel platelet aggregation-against and thrombosis.
Description
Technical field
The present invention relates to drugs than it is taken charge of, the platelet aggregation that itself can effectively inhibit coagulant ADP to induce and external
Thrombosis；It also inhibits the rush blood of APJ endogenic ligands Elabela, Apelin-12, Apelin-17 and Apelin-36 small
Plate aggregation, ex vivo thrombosis effect.
Background technology
Apj receptor is a kind of transmembrane G protein coupled receptor having high homology with Angiotension type I receptor, Apelin
For its endogenic ligand.Mankind's Apelin genes are located at q25-26 sections of X chromosome, and coded product is containing 77 amino acid
Precursor peptide, can be by Isopeptidase cleavage at the active fragment of different aminoacids length：Apelin-12, Apelin-17 and Apelin-36
Deng.Apelin/APJ systems are widely distributed in the tissue, have expression in the systems such as cardiovascular, brain and kidney.ELABELA is
The novel endogenic ligand of apj receptor found in 2013, ripe ELABELA contain 32 amino acid, have with each hypotypes of Apelin
High homology.Apelin has the heart contraction effect for reducing blood pressure, enhancing in Cardiovascular regulation；In central nervous system
Have the effects that adjust pituitrin release, adjust and ingest, take the photograph water, isohydria；It can also promote in vascular function adjusting
Angiogenesis, development and maturation.Apj receptor is counted as treating the novel target spot of a variety of diseases, targets the blocking agent of apj receptor
Or agonist is likely to become the new types of therapeutic agents of relevant disease.
Thrombotic diseases be one kind by the disease caused by two kinds of pathologic processes of thrombosis and thromboembolism, internal blood is small
Plate overactivity or aggregation can accelerate the generation of thrombosis and thrombotic diseases.Platelet aggregation is thrombus and thrombotic diseases
The important link of formation, and the natural component in body blood coagulation system is (such as：ADP, collagen, arachidonic acid, fibrin ferment etc.) energy
A variety of receptors for acting on platelet membrane regulate and control the function of blood platelet.Wherein, ADP activates the adp receptor on platelet membrane,
Inhibit atpase activity and causes platelet aggregation；Fibrin ferment plays at damaged vessel and makees as the key enzyme in coagulation process
With；Collagen activation blood platelet makes it be adhered to wound, and ADP isoreactivities substance is promoted further to discharge and promote platelet aggregation
Collection；Arachidonic acid can promote to discharge thromboxane A2 and accelerate platelet aggregation and thrombosis.Early-stage study is found：APJ
Receptor endogenic ligand ELABELA, Apelin-12, Apelin-17 and Apelin-36 can effectively induce new zealand rabbit blood platelet
The effect of the ex vivo thrombosis of aggregation and artificial simulated blood vessel, it is regulation and control platelet aggregation and thrombosis to prompt apj receptor
Important target spot.Therefore, the exploitation for accelerating the drug to the blocking agent or agonist that target apj receptor, to thrombotic diseases
Treatment is of great significance.
It is that U.S. FDA listed the medicine synergist of AntiHIV1 RT activity in approval in 2012 than its (Cobisistat) is taken charge of.Medicine nothing itself
HIV-resistant activity, but can by inhibit human body metabolism's drug Major Enzymes-CYP3A come improve inverase blood concentration and
Pharmacokinetic parameters, to improve drug effect.FDA in 2015 ratify again Anti-HIV agents Atazanavir and Cobisistat (Ah
Zha Nawei-is comparable to take charge of it) compound preparation listing, it is shared in the adult trouble for the treatment of HIV-1 infection with other degeneration-resistant virus drugs that turn
Person.And at present about than department, it whether there is novel targets, new function；Whether platelet function tune AntiHIV1 RT activity other than can be participated in
Control and treatment of thrombotic disorders, at present not yet any report.In addition, the human administration that it is used as inverase than department
Dosage is generally 15mg/kg, this research used maximum concentration on blood platelet is 1 μm of ol/ml, and people is far smaller than after conversion
Body dosage.
This patent has mainly been inquired into than the functional study for taking charge of it and platelet aggregation, thrombosis.It was found that than it is taken charge of
The platelet aggregation and ex vivo thrombosis that coagulant ADP can be inhibited to induce；Effectively inhibit APJ endogenic ligands simultaneously
The rush platelet aggregation of each hypotypes of Elabela and Apelin, ex vivo thrombosis effect.
Invention content
The present invention relates to drugs than it is taken charge of, it has the new zealand rabbit blood platelet for inhibiting the ADP inductions of blood platelet derivant
Aggregation and ex vivo thrombosis effect；
Present invention finds than its new pharmacologic function is taken charge of, itself can effectively inhibit APJ endogenic ligands
The new zealand rabbit platelet aggregation and artificial blood vessel model of Elabela, Apelin-12, Apelin-13 and Apelin-36 induction
Ex vivo thrombosis effect；
The present invention relates to a kind of drug than take charge of it；It is used to prevent, improves platelet aggregation；Or the drug is expected to
Treatment is by the thrombotic diseases caused by platelet aggregation.
The advantageous effects of the present invention
The drug of the present invention has the function of ideal platelet aggregation-against than it is taken charge of, and is its anti-hiv therapy pair therefore
Effect provides foundation, would be effective for the treatment of platelet aggregation and thrombotic diseases above.
Description of the drawings：
Figure 1A is that it can not individually induce new zealand rabbit platelet aggregation rate than department
Figure 1B is than the platelet aggregation for taking charge of its inhibition ADP induction
Fig. 2 is than the platelet aggregation for taking charge of each hypotype inductions of its inhibition Apelin
Fig. 3 is than the artificial blood vessel ex vivo thrombosis for taking charge of its inhibition ADP induction
Fig. 4 is than the artificial blood vessel ex vivo thrombosis for taking charge of its inhibition Elabela induction
Fig. 5 is than the artificial blood vessel ex vivo thrombosis for taking charge of its inhibition Apelin-12 induction
Fig. 6 is than the artificial blood vessel ex vivo thrombosis for taking charge of its inhibition Apelin-17 induction
Fig. 7 is than the artificial blood vessel ex vivo thrombosis for taking charge of its inhibition Apelin-36 induction
Wherein：
In Fig. 2, A Apelin12, B Apelin17, C are Apelin36 and D is Elabela；
In Fig. 3-Fig. 7, A is ex vivo thrombosis size, and B is weight in wet base, and C is dry weight, and D is thrombus length.
Specific implementation mode
Preparation example 1
Its function is detected, shown in following examples.Implement below for illustrating the present invention, but should not be used to the limitation present invention
Range.
Embodiment 1 measures comparable influence for taking charge of it to platelet aggregation
It is small that blood is measured with platelet aggregation coagulation factor analyzer (LG-PABER-I types, Beijing Steellex Scientific Instrument Company)
Plate aggregation rate.This instrument tests platelet aggregation using photoelectric turbidimetry：Use platelet poor plasma (platelet poor
Plasma, PPP) it is used as substrate, it is measured using Platelet-rich plasm (platelet rich plasma, PRP).In magnetic
Under the stirring of power pearl, derivant is added in PRP, blood platelet is assembled, and the light transmittance of PRP increases or turbidity reduction.By light
The variation of turbidity is converted to the variation of electric signal, to calculate the aggregation rate of blood platelet.
Aggregation rate=(measurement voltage value-PPP photoelectricity voltages value)/(PRP photoelectricity voltage value-PPP photoelectricity voltages value) *
100%
1. measuring its influence to platelet aggregation of the comparable department of various concentration
Arterial blood drawing in new zealand rabbit ear is then centrifuged for sodium citrate anti-freezing, is first centrifuged 10min with 800r/min, is taken
Supernatant obtains PRP, then centrifuges 10min with 3000r/min, and supernatant is taken to obtain PPP.Accurately it is added 300 μ l's in test cup
PPP is put into TCH test channel, presses after PPP keys carry out substrate measurement and takes out.In another test cup, the accurate PRP that 300 μ l are added,
At 37 DEG C after pre-temperature 1min, using adding pearl device that 1 test pearl is added in the test cup, after starting test, divide in three seconds
Not Jia Ru various concentration (0.001,0.01,0.1,1 μm of ol/ml) test 5min than it is taken charge of, record the maximum aggregation of blood platelet
Rate (referring to Figure 1A).
2. measuring than the platelet aggregation for taking charge of its inhibition coagulant ADP induction
PPP is acquired, PRP is same as above, and coagulant ADP is added in PRP and is incubated 5min, places into the test for having mixed up baseline
Test pearl is added in Qu Zhong, and after starting test, comparable department is added in three seconds, and it tests 5min, records the maximum aggregation of blood platelet
Rate, observation test result detection promote new zealand rabbit platelet aggregation than it is taken charge of to ADP.Judged than its suppression of department with this
Platelet aggregation processed (referring to Figure 1B).
3. measuring various concentration new zealand rabbit platelet aggregation that it induces each hypotypes of Apelin than department
Acquire PPP, PRP is same as above, respectively by apj receptor endogenic ligand ELABELA, Apelin-12, Apelin-17 and
Apelin-36 is added in PRP and is incubated 5min, places into the test section for having mixed up baseline, and test pearl is added, starts to test
Afterwards, drug is added in three seconds and tests 5min than it is taken charge of, record the maximum aggregation rate of blood platelet, observation test result detection can
New zealand rabbit platelet aggregation is promoted to ELABELA, Apelin-12, Apelin-17 and Apelin-36 than taking charge of it.Sentenced with this
Disconnected comparable its inhibition platelet aggregation of department (referring to Fig. 2).
Embodiment 2 measures comparable influence for taking charge of it to ex vivo thrombosis
Thrombosis model is established with thrombometer (LMK-12 types, Zhengzhou Ming Ju scientific & technical corporation), this instrument is used
Chandler methods：Blood is injected in external rotating ring, blood flow state is to form thrombus in analogue body.
1. measuring than the influence for taking charge of the artificial blood vessel ex vivo thrombosis that it inhibits coagulant ADP to induce
Arterial blood drawing (is not added with any anti-coagulants, using straight extracting vein blood 1ml, and pays attention to inject in new zealand rabbit ear
Bubble removal in device, uses various concentration (0.001,0.01,0.1,1 μm of ol/ml) is comparable to take charge of it and 10 μm of ol/ml coagulant respectively
ADP processing after, blood sample dress fill annulus, slowly by 1m1 blood samples along the tube wall injection pipe of plastic hoop one end, connect into circle at any time
Ring is satisfied in corresponding turntable.It is 20 ± 2rpm to be put into middle rotating speed, and at 37 DEG C, after recycling 10min, removal of thromboses measures simultaneously
Record the weight in wet base and length of thrombus.By drying and processing in the above-mentioned baking oven for having claimed the thrombus of weight in wet base to be put into 60 DEG C ± 1 DEG C,
After 30min, the thrombus of drying is weighed again, record thrombus dry weight (referring to Fig. 3).
2. measuring various concentration than the influence for taking charge of the artificial blood vessel ex vivo thrombosis that it induces each hypotypes of Apelin
Thrombosis model is built using chandler methods.Respectively by various concentration (0.001,0.01,0.1,1 μm of ol/
Ml) comparable to take charge of it and 1.0 μm of ol/ml ELABELA (referring to Fig. 4), 1.0 μm of ol/ml Apelin-12 (referring to Fig. 5), 10-4 μ
The New Zealand of 1ml is added in mol/ml Apelin-17 (referring to Fig. 6) and 0.01 μm of ol/ml Apelin-36 (referring to Fig. 7) together
In rabbit blood experimental result is recorded according to the test method in 1, removal of thromboses disease.And observation lures coagulant ADP than it is taken charge of
The effect for the rabbit thrombosis led (referring to Fig. 5).
In conclusion the drug of the present invention has the function of ideal platelet aggregation-against than it is taken charge of, it is therefore, anti-for it
HIV therapy side effect provides foundation, would be effective for the treatment of platelet aggregation and thrombotic diseases above.
Claims (8)
1. a kind of inverase is than department, it is used to prepare the purposes of antithrombotic reagent, it is characterized in that being used to treat thrombotic disease
Disease.
2. the comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase according to claim 1, it is characterized in that with
The thrombotic diseases caused by treating platelet aggregation.
3. the comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase according to claim 1, it is characterized in that with
In the platelet aggregation for inhibiting blood platelet derivant ADP inductions.
4. the comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase according to claim 1, it is characterized in that with
In the platelet aggregation for inhibiting APJ endogenic ligands Elabela, Apelin-12, Apelin-13 and Apelin-36 induction.
5. the comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase according to claim 1, it is characterized in that with
In treatment thrombosis.
6. the comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase according to claim 1, it is characterized in that with
In the ex vivo thrombosis for inhibiting blood platelet derivant ADP inductions.
7. the comparable purposes taken charge of it and be used to prepare antithrombotic reagent of inverase according to claim 1, it is characterized in that with
In the ex vivo thrombosis for inhibiting APJ endogenic ligands Elabela, Apelin-12, Apelin-13 and Apelin-36 induction.
8. the comparable purposes taken charge of it and be used to prepare antithrombotic reagent of any one of claim 1-7 inverases, it is characterized in that
For treating the thrombotic diseases caused by platelet aggregation；Or prevent the platelet aggregation of body.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710563202 | 2017-07-11 | ||
| CN2017105632020 | 2017-07-11 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN108703971A true CN108703971A (en) | 2018-10-26 |
| CN108703971B CN108703971B (en) | 2023-04-07 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810776447.6A Active CN108703971B (en) | 2017-07-11 | 2018-07-10 | Application of anti-HIV (human immunodeficiency virus) medicament, namely, cobicistat, in preparation of antithrombotic medicament |
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| CN (1) | CN108703971B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5137912A (en) * | 1991-01-28 | 1992-08-11 | National Science Council Of Republic Of China | Chelerythrine inhibits platelet aggregation--a potential anti-aggregation drug |
| WO2011122899A2 (en) * | 2010-04-01 | 2011-10-06 | Kwak Soo Jong | Pharmaceutical composition for inhibiting platelet aggregation or for thrombolysis |
| CN105163720A (en) * | 2013-02-01 | 2015-12-16 | 佐尼奥尼制药股份有限公司 | Remote loading of sparingly water-soluble drugs into liposomes |
-
2018
- 2018-07-10 CN CN201810776447.6A patent/CN108703971B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5137912A (en) * | 1991-01-28 | 1992-08-11 | National Science Council Of Republic Of China | Chelerythrine inhibits platelet aggregation--a potential anti-aggregation drug |
| WO2011122899A2 (en) * | 2010-04-01 | 2011-10-06 | Kwak Soo Jong | Pharmaceutical composition for inhibiting platelet aggregation or for thrombolysis |
| CN105163720A (en) * | 2013-02-01 | 2015-12-16 | 佐尼奥尼制药股份有限公司 | Remote loading of sparingly water-soluble drugs into liposomes |
Non-Patent Citations (1)
| Title |
|---|
| 胡昊良: "靶向APJ受体的药物再评价与可比司它抑制Apelin亚型诱导的血小板聚集" * |
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| CN108703971B (en) | 2023-04-07 |
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