CN104958288B - A kind of platelet suppressant drug and its application in antiplatelet disease medicament is prepared - Google Patents
A kind of platelet suppressant drug and its application in antiplatelet disease medicament is prepared Download PDFInfo
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- CN104958288B CN104958288B CN201510360965.6A CN201510360965A CN104958288B CN 104958288 B CN104958288 B CN 104958288B CN 201510360965 A CN201510360965 A CN 201510360965A CN 104958288 B CN104958288 B CN 104958288B
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Abstract
The invention belongs to technical field of pharmaceuticals, and in particular to a kind of platelet suppressant drug and its application in antiplatelet disease medicament is prepared；KIF disclosed in this hair can suppress a variety of hematoblastic activation for causing poly- agent to induce, aggregation, more effectively suppress the formation of thrombus, and physiological haemostasis process is not influenceed, bleeding risk is small, so as to show the preventive and therapeutic action to thrombotic cardiovascular and cerebrovascular disease.
Description
Technical field
The invention belongs to medicinal chemistry art, and in particular to a kind of platelet suppressant drug and its prepare antiplatelet disease
Application in medicine.
Background technology
Cardiovascular and cerebrovascular disease has resulted in serious threat to human health in recent years, and the whole world is counted per annual 1700 according to WHO
Ten thousand people die from Cardial or cerebral vascular diseases, account for the 1/3 of global total death toll.China's cardiovascular and cerebrovascular disease also shows a rising trend, according to
The annual new people of hair cerebral apoplexy person 2,000,000 of estimation, the people of myocardial infarction person 500,000；It is annual to die from cardiovascular and cerebrovascular patient up to 2,500,000 people, its
Cardiovascular disease respectively accounts for half with cerebrovascular disease.Cardiovascular and cerebrovascular disease is the most common with thromboembolism, blood vessel internal membrane damage, blood flow
Slow down, blood coagulability rise can cause thrombosis, hematoblastic activation, be gathered in the forming process of thrombus and play
Important function, thus in order to for the blood platelet disorder triggered by platelet activation, aggregation, develop safely and effectively antiplatelet
Medicine turns into the task of top priority.
The antiplatelet drug clinically used at present mainly has the inhibitor of Cycloxygenase -1 (aspirin), ADP P2Y12
Acceptor inhibitor (clopidogrel), phosphodiesterase PDE inhibitor（Cilostazol）, a receptor antagonists of II b/ of glycoprotein GP III
(Abciximab) 4 major class.Because aspirin, clopidogrel, Cilostazol etc. can only suppress by TXA respectively2, ADP or cAMP
The platelet activation of mediation, therefore some patientss are not avoided that the generation of thrombotic episodes still；Though a receptor antagonists of II b/ of GP III
So final path of energy blocking platelet aggregation, but also counteracts that the process of physiological haemostasis simultaneously and bleeding may be caused concurrent
Disease.Therefore, finding new target and developing new antiplatelet drug has important clinical meaning and wide application prospect.
Have now been found that some micromolecular compounds can suppress platelet activation, such as AG490 can suppress collagen-induced
Hematoblastic aggregation and Ca2+Mobilization, and suppress PLC γ 2, PKC in blood platelet, AKT etc. phosphorylation；WHI-P131 can be prevented
The blood platelet pseudopodium of thrombin induction is formed, particle discharges and the function of platelet aggregation.
Although the micromolecular compound of prior art synthesis can suppress hematoblastic activity as platelet suppressant drug,
But preferably platelet suppressant drug is right outside the formation for blocking thrombus except that can suppress hematoblastic generation, activation and assemble
Hematoblastic function does not influence under physiological condition.Therefore a kind of new platelet suppressant drug of research is needed, can be to blood platelet
Activity, populated with obvious inhibiting effect, so as to develop new effective antiplatelet drug.
The content of the invention
The goal of the invention of the present invention is to provide a kind of compound as the application of platelet suppressant drug, and the compound has
Platelet activation, aggregation can be suppressed, inhibition thrombosis, while toxicity is relatively low, does not have to hematoblastic function under physiological condition
Have an impact, new antiplatelet disease medicament can be developed into.
To achieve the above object of the invention, the technical solution adopted by the present invention is：The compound of formula I is preparing blood platelet suppression
Application in agent
Formula I.
The chemical name of compound disclosed by the invention as blood platelet micromolecular inhibitor is 2- [2- (the chloro- 4- fluorine of 3-
Benzene) hydrazono-] -3- (4- chlorphenyls) -3- oxygen propionitrile, referred to as KIF.
The present invention protects applications of the above-claimed cpd KIF in antiplatelet disease medicament is prepared simultaneously.It is mainly used in blood
Platelet embolism class diseases, including arterial platelet embolism class diseases or vein blood platelet embolism class diseases；Such as coronary artery is hard
The property changed disease, myocardial infarction, pulmonary infarction or cerebral infarction.
The invention also discloses a kind of platelet suppressant drug, by the compound of effective doseWith
Pharmaceutically acceptable auxiliary material composition.
In above-mentioned technical proposal, pharmaceutically acceptable auxiliary material is selected from vitamin C, sorbierite, mannitol, xylitol, fruit
Sugar, amino acid, meglumine, dextrin, magnesium stearate, sucrose.
Preparation can be made individually or with more than one acceptable carrier auxiliary material combination agents in compound K IF of the present invention
Administration.For example, solvent, diluent etc..Can be with oral dosage form, such as tablet, capsule, dispersible powder, granule；Also may be used
It is administered with injection-type, such as freeze drying powder injection.The various formulations of pharmaceutical composition of the present invention can be according to well known in pharmaceutical field
It is prepared by method.Such as 0.05%~90% wt. Active ingredient with carrier combinations can be contained in these pharmaceutical formulations,
Active component between more conventional about 15%~60%.The compounds of this invention dosage can make 0.005~5000 mg/kg/ days,
This dosage range can be exceeded according to disease severity or the different dosages of formulation.
Because above-mentioned technical proposal is used, the present invention has following advantages compared with prior art：
The invention discloses compound K IF new application, compound K IF is low to blood platelet toxicity, under physiological condition
Hematoblastic function does not influence, and can effectively suppress a variety of platelet activations for causing poly- agent induction and aggregation, significantly inhibits
Thrombosis, so as to be expected to be developed into new antiplatelet disease medicament.
Brief description of the drawings
Fig. 1 is the aggregation curve map that the blood platelet that KIF concentration gradients are incubated causes gained after poly- agent stimulation；
Fig. 2 is the block diagram to blood platelet toxicity with AlamarBlue assay assay KIF various concentrations；
Fig. 3 is the streaming figure of the blood platelet apoptosis handled with Annexin V-FITC methods detection KIF concentration gradients；
Fig. 4 is that KIF influences the streaming figure of thrombin induction platelet activation situation；
The influence figure that Fig. 5 sprawls for KIF pairs of blood platelet；
Fig. 6 is PRP platelet plug retraction situation maps after stimulated by thrombin；
Fig. 7 is the statistical chart that KIF influences on the mouse tail vein bleeding time.
Embodiment
With reference to embodiment, the invention will be further described：
The KIF of embodiment one suppresses platelet aggregation
Wash human blood platelets (3*108 / ml) (1.25,2.5 and 5 μM) or two are incubated with 37 DEG C of the KIF of concentration gradient
Methyl sulfoxide（DMSO）10 minutes, then with the poly- agent collagen of cause（Collagen）2 μ g/ml and fibrin ferment（Thrombin）
0.02u/ml is stimulated, with platelet aggregation instrument record aggregate curve.Accompanying drawing 1 is that the blood platelet that KIF concentration gradients are incubated causes to gather
The aggregation curve of gained after agent is stimulated, shows that KIF can suppress a variety of and cause platelet aggregation caused by poly- agent.
The KIF safety of medicine Journal of Sex Research of embodiment two
Blood platelet re-suspension liquid（2.5*108/mL ）Use KIF（5、10、20μM）, 37 DEG C of incubations, 10 minutes, then each group was equal
With the μ l of AlamarBlue reagents 10（1:10）Monitor fluorescence intensity to see under 37 DEG C of incubation 4h, ELIASA 570nm, 585nm wavelength
Examine whether blood platelet survives.Accompanying drawing 2 is to blood platelet toxicity with AlamarBlue assay assay KIF various concentrations
Block diagram, it was observed that KIF does not have toxicity to blood platelet substantially.
Platelet suspension（ 2×107/mL ）100 μ l, with KIF 5,10,20, μM 37 DEG C are incubated 10 minutes, add knot
Close buffer solution（Binding Buffer) 100 μ l, Annexin V-FITC, 1 μ l processing, room temperature darkroom places 15 minutes, immediately
Progress flow cytometry quantitatively detects the ratio shared by the positive cells of Annexin V.Accompanying drawing 3 is what KIF concentration gradients were handled
Blood platelet, the streaming figure of blood platelet apoptosis is detected with Annexin V-FITC methods.It was observed that KIF does not have substantially at 5 and 10 μM
Cause blood platelet apoptosis, a small amount of apoptosis of blood platelet is made at 20 μM.Numerical value in each quadrant is hematoblastic relative percentages.
The KIF of embodiment three suppresses hematoblastic " interior-outer " signal path
Blood platelet（ 2.0X107/mL ）200 μ l are pre-processed 10 minutes with KIF 5 μM 37 DEG C, then use fibrin ferment
（Thrombin）0.05u processing, while adding the μ l of PE-CD62P, FITC-Fibrinogen antibody 1, darkroom is stored at room temperature 30 points
Clock, adds the μ l of PBS 200 resuspensions, uses flow cytomery fluorescence intensity.Accompanying drawing 4 is that KIF influences fibrin ferment
（Thrombin）The streaming figure of induced platelet Activation, it was observed that the platelet activation rate being incubated with KIF is low, shows KIF
Substantially suppress blood platelet " interior-outer " signal path.
Example IV KIF suppresses blood platelet " outer-interior " signal path
By fibrinogen（Fibrinogen）It is dissolved in 0.1M NaHCO3（PH 8.3）Solution, the μ g/ml of final concentration 10,
12mm Circular glasses piece is soaked in 24 orifice plates in 200 μ l/ holes, and 4 DEG C overnight, are then washed with PBS;Blood platelet re-suspension liquid（2.5*
106/ml）200 μ l/ holes, with KIF, 37 DEG C are incubated 30 minutes, and blood platelet re-suspension liquid then is sprawled into 37 DEG C 60 on a glass
Minute, washed afterwards with PBS 5 times, the blood platelet of adhesion fixes 30 minutes with 4% paraformaldehyde, then is washed once with PBS, finally uses
The Phalloidin (the μ g/ml of final concentration 0.1) of TRITC labels adds 100% TritonX-100（Final concentration 0.1%）,
The μ l/ holes of Phalloidin 200, room temperature lucifuge is incubated 2h, and Circular glass piece is taken out to put upside down onto slide and seen with fluorescence microscope
Examine and hematoblastic sprawl situation.The influence that accompanying drawing 5 is sprawled for KIF pairs of blood platelet.It was observed that 1.25 μM of KIF can suppress 50%
Blood platelet is sprawled, and 5 μM can suppress 80% and hematoblastic sprawl when being.Show 5 μM of KIF can substantially suppress blood platelet " it is outer-
It is interior " activation of signal path.
The KIF of embodiment five suppresses the retraction of thrombus grumeleuse
Take 250 μ l platelet rich plasmas PRP（2.0*108/ml）It is added in cuvette, with 5 μ l of KIF, 37 DEG C are incubated 10
Minute, add and cause poly- agent fibrin ferment（Thrombin）37 DEG C of 0.8u, with image technology observation 10,15,20,30 minutes blood platelets
Grumeleuse retraction situation.Accompanying drawing 6 for and without the PRP that are incubated of KIF through fibrin ferment（Thrombin）Platelet plug is returned after stimulation
Contracting situation map, as a result shows that 5 μM of KIF can substantially suppress the retraction reaction of platelet plug.Show that KIF can be in blood platelet blood
The consequent effects of bolt formation consolidate the formation of thrombus, so as to avoid the generation of platelet plug disease.
KIF or dimethyl sulfoxide (DMSO)（DMSO）In Intraperitoneal injection Mice Body, with 4% chloraldurate 150-200 μ l fiber crops after 45 minutes
Liquor-saturated mouse, and be put into warm environment（37℃）, tail protrude, cut off 5 mm of tip, 12 ml, 37 DEG C of lifes be put into immediately
Manage in salt solution 10 minutes, record bleeding stopping period.Accompanying drawing 7 is the statistical chart that KIF influences on the mouse tail vein bleeding time, it was observed that
KIF is not significantly increased the mouse tail vein bleeding time.Show that KIF has not significant impact to physiological haemostasis function, compared with it
His antiplatelet drug risk is small, there is good potential applicability in clinical practice.
To sum up, it may be said that bright KIF small molecules can suppress biologically active pdgf and gather performance, thrombus is more effectively suppressed
Formed, while not influenceed on blood platelet normal physiological activity, bleeding risk is small；So as to be prepared into antiplatelet disease,
The such as medicine of coronary arteriosclerotic disease, myocardial infarction, pulmonary infarction or cerebral infarction, there is good potential applicability in clinical practice.
Claims (4)
1. application of the compound of formula I in platelet suppressant drug is prepared
Formula I.
2. application of the compound of formula I in the medicine for preparing antiplatelet disease
Formula I,
The blood platelet disorder is platelet plug disease.
3. apply according to claim 2, it is characterised in that：The blood platelet disorder be arterial platelet embolism class diseases or
Vein blood platelet embolism class diseases.
4. apply according to claim 3, it is characterised in that：The blood platelet disorder is coronary arteriosclerotic disease, the heart
Flesh infarct, pulmonary infarction or cerebral infarction.
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| CN109010830B (en) * | 2017-06-08 | 2022-06-07 | 苏州大学 | Application of platelet related inhibitor in preparation of medicine for treating thrombocytopenia |
| CN109395059A (en) * | 2017-07-11 | 2019-03-01 | 南华大学 | Medical composition and its use containing Apelin-36 |
| CN108785659A (en) * | 2017-07-11 | 2018-11-13 | 南华大学 | Medical composition and its use containing Apelin-17 |
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Effective date of registration: 20210514 Address after: 110027 No.1-3, No.10 Road, Shenyang Economic and Technological Development Zone, Shenyang City, Liaoning Province Patentee after: SHENYANG SUNSHINE PHARMACEUTICAL Co.,Ltd. Address before: 316000 1703-0164, 17th floor, Yongyue building, 721 Haizhou Road, Donggang street, Putuo District, Zhoushan City, Zhejiang Province Patentee before: Zhoushan Putuo Baoyi Enterprise Management Studio |