CN106317198B - GRPAK-The-RGDV, preparation, activity and application - Google Patents
GRPAK-The-RGDV, preparation, activity and application Download PDFInfo
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- CN106317198B CN106317198B CN201510353112.XA CN201510353112A CN106317198B CN 106317198 B CN106317198 B CN 106317198B CN 201510353112 A CN201510353112 A CN 201510353112A CN 106317198 B CN106317198 B CN 106317198B
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- obzl
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- asp
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- 238000002360 preparation method Methods 0.000 title claims abstract description 8
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- 239000003527 fibrinolytic agent Substances 0.000 claims abstract description 4
- 229960000103 thrombolytic agent Drugs 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 60
- 238000000034 method Methods 0.000 claims description 20
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 16
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 16
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 16
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 9
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 6
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- CPMKYMGGYUFOHS-FSPLSTOPSA-N Asp-Val Chemical compound CC(C)[C@@H](C(O)=O)NC(=O)[C@@H](N)CC(O)=O CPMKYMGGYUFOHS-FSPLSTOPSA-N 0.000 claims description 2
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- 150000001875 compounds Chemical class 0.000 description 19
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 16
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- -1 dicyclohexyl carbonyl diimine Chemical compound 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
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- ODKSFYDXXFIFQN-BYPYZUCNSA-N L-arginine Chemical compound OC(=O)[C@@H](N)CCCN=C(N)N ODKSFYDXXFIFQN-BYPYZUCNSA-N 0.000 description 4
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- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 3
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- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
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- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
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- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
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- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
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- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 1
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Abstract
The invention discloses GRPAK-The-RGDV decapeptide, its preparation method is disclosed, discloses the activity that it treats ishemic stroke, antithrombotic acitivity and thrombus dissolving activity.Thus the invention discloses it treats ishemic stroke in preparation, the application in antithrombotic and thrombolytic agent.
Description
Technical field
The present invention relates to Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val decapeptides, are related to its preparation side
Method is related to the activity that it treats ishemic stroke, antithrombotic acitivity and thrombus dissolving activity.Thus the present invention relates to it controls in preparation
Treat ishemic stroke, the application in antithrombotic and thrombolytic agent.Biomedicine field of the present invention.
Background technique
Coronary heart disease, cerebral apoplexy and vasculitis etc. are very common cardiovascular and cerebrovascular diseases.With people's living standard
It is continuously improved, the number of the infected cumulative year after year of cardiovascular and cerebrovascular disease.Risk factors of cardiovascular and cerebrovascular disease is popular, China's cardiovascular and cerebrovascular
The illness rate of disease persistently rises.According to statistics, just there is 1 cardiovascular patient in every 5 adults.Thrombosis is the heart
The Important cause of disease of cranial vascular disease.Cerebral arterial thrombosis has very high lethality and disability rate.Thromboembolism treatment is common weight
One of means wanted.Existing thrombolytic drug there are bleeding, again embolism, reperfusion injury the problems such as, therefore find novel anti-lack
Hemorrhagic cerebral apoplexy new drug has important application value.In 3 years experimental studies, inventor has found Gly-Arg-Pro-Ala-
Lys-The-Arg-Gly-Asp-Val decapeptide has such activity.According to this discovery, the present invention is inventors herein proposed.
Summary of the invention
First content of the invention is to provide Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val decapeptide.
Second content of the invention is to provide Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val decapeptide
Preparation method, method includes the following steps:
(1) Boc-Asp (OBzl) and Val-OBzl are coupled to obtain Boc-Asp (OBzl)-Val-OBzl；
(2) Boc-Asp (OBzl)-Val-OBzl obtains L-Asp (OBzl)-in the ethyl acetate solution of 4N hydrogen chloride
Val-OBzl；
(3) Boc-Gly and L-Asp (OBzl)-Val-OBzl are coupled to obtain Boc-Gly-Asp (OBzl)-Val-OBzl；
(4) Boc-Gly-Asp (OBzl)-Val-OBzl obtains L-Gly-Asp in the ethyl acetate solution of 4N hydrogen chloride
(OBzl)-Val-OBzl；
(5)Boc-Arg(NO2) be coupled to obtain Boc-Arg (NO with L-Gly-Asp (OBzl)-Val-OBzl2)-Gly-Asp
(OBzl)-Val-OBzl
(6)Boc-Arg(NO2)-Gly-Asp (OBzl)-Val-OBzl obtains in the ethyl acetate solution of 4N hydrogen chloride
L-Arg(NO2)-Gly-Asp(OBzl)-Val-OBzl；
(7) Boc-The and L-Arg (NO2)-Gly-Asp (OBzl)-Val-OBzl is coupled to obtain Boc-The-Arg (NO2)-
Gly-Asp(OBzl)-Val-OBzl；
(8)Boc-The-Arg(NO2)-Gly-Asp (OBzl)-Val-OBzl is in the ethyl acetate solution of 4N hydrogen chloride
Obtain L-The-Arg (NO2)-Gly-Asp(OBzl)-Val-OBzl；
(9) Boc-Ala and Lys (Z)-OBzl are coupled to obtain Boc-Ala-Lys (Z)-OBzl；
(10) Boc-Ala-Lys (Z)-OBzl obtains L-Ala-Lys (Z)-in the ethyl acetate solution of 4N hydrogen chloride
OBzl；
(11) Boc-Pro and L-Ala-Lys (Z)-OBzl are coupled to obtain Boc-Pro-Ala-Lys (Z)-OBzl；
(12) Boc-Pro-Ala-Lys (Z)-OBzl obtains L-Pro-Ala- in the ethyl acetate solution of 4N hydrogen chloride
Lys(Z)-OBzl；
(13)Boc-Arg(NO2) be coupled to obtain L-Arg (NO with L-Pro-Ala-Lys (Z)-OBzl2)-Pro-Ala-Lys
(Z)-OBzl；
(14) Boc-Gly and L-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl is coupled to obtain Boc-Gly-Arg (NO2)-
Pro-Ala-Lys(Z)-OBzl；
(15)Boc-Gly-Arg(NO2)-Pro-Ala-Lys (Z)-OBzl 2N NaOH solution effect under obtain Boc-
Gly-Arg(NO2)-Pro-Ala-Lys(Z)；
(16)Boc-Gly-Arg(NO2)-Pro-Ala-Lys (Z) and L-The-Arg (NO2)-Gly-Asp(OBzl)-Val-
OBzl is coupled to obtain Boc-Gly-Arg (NO2)-Pro-Ala-Lys(Z)-The-Arg(NO2)-Gly-Asp(OBzl)-Val-
OBzl；
(17)Boc-Gly-Arg(NO2)-Pro-Ala-Lys(Z)-The-Arg(NO2)-Gly-Asp(OBzl)-Val-
OBzl obtains Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp- in trifluoroacetic acid/trifluoromethanesulfonic acid (4: 1) solution
Val；
Liquid phase process used above is the conventional and disclosed technology of this field.TFA is trifluoroacetic acid, and TFMSA is
Trifluoromethanesulfonic acid, HCl/EtOAc are the ethyl acetate solutions of hydrogen chloride.
Third content of the invention is that evaluation Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val treatment lacks
The activity of hemorrhagic apoplexy.
4th content of the invention is to evaluate the anti-blood of Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val
Bolt effect.
5th content of the invention is to evaluate the haemolysis of Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val
Bolt effect.
Detailed description of the invention
The synthetic route .i of Fig. 1 Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val) HOBt, DCC, NMM,
THF；ii)4N HCl/EtOAc；Iii) 2N NaOH, methanol；Iv) TFA, TFMSA.
Specific embodiment
In order to which the present invention is further explained, a series of embodiments are given below.These embodiments be entirely it is illustrative, it
Only be used to the present invention is specifically described, be not construed as limitation of the present invention.
Embodiment 1 prepares Boc-Ala-Lys (Z)-OBzl (1)
2.08g (11mmol) Boc-Ala is dissolved in 20mL anhydrous tetrahydro furan (THF), 1.35g is added under ice bath
(10mmol) I-hydroxybenzotriazole (HOBt) and 2.47g (12mmol) the dicyclohexyl carbonyl diimine dissolved with anhydrous THF
(DCC), it stirs 0.5 hour, obtains reaction solution A.After 30 minutes, by 4.07g (10mmol) HClLys (Z)-OBzl 15mLTHF
Dissolution, and pH to 9 is first adjusted with N-methylmorpholine, it is added in reaction solution A, stirs 12 hours at room temperature, TLC (solvent
CHCl3: MeOH=30: 1) show HClLys (Z)-OBzl disappear.The dicyclohexylurea (DCU) (DCU) being filtered to remove in reaction solution,
Reaction solution is concentrated to dryness, and residue 100mL ethyl acetate dissolves, and filters out insoluble matter.Filtrate successively uses unsaturated carbonate hydrogen
Sodium water solution is washed 3 times, and 5% aqueous potassium hydrogen sulfate is washed 3 times, and saturated sodium-chloride water solution is washed 3 times, and the ethyl acetate layer separated is used
Anhydrous sodium sulfate dries 12h, filtering, and the faint yellow color solid that filtrate decompression is concentrated to get chromatographs (CH by silicagel column column2Cl2∶
CH3OH=90: 1) purifying, obtain 4.0g (74%) title compound, is colorless solid.ESI-MS (m/z): 542 [M+H]+。
Embodiment 2 prepares HClAla-Lys (Z)-OBzl (2)
2.0g (3.7mmol) Boc-Ala-Lys (Z)-OBzl is dissolved in a small amount of dry ethyl acetate, is added under ice salt bath
20mL 4N hydrogen chloride-ethyl acetate solution reacts 4 hours under ice bath, TLC (CHCl3: MeOH, 30: 1) showing that raw material point disappears
It loses, fully reacting.Reaction solution is concentrated under reduced pressure, and residue with Ethyl acetate is dissolved and is concentrated under reduced pressure.The operation is repeated 3 times, cleared
Free hydrogen chloride, residue are worn away 3 times with anhydrous ether again, obtain 1.6g (90%) title compound, are colourless powder.
ESI-MS (m/z): 442 [M+H]+。
Embodiment 3 prepares Boc-Pro-Ala-Lys (Z)-OBzl (3)
Using the method for embodiment 1 from 731mg (3.4mmol) Boc-Pro and 1.8g (3.3mmol) HClAla-Lys
(Z)-OBzl obtains 1.7g (78%) title compound, is yellowish grease.ESI-MS (m/z): 639 [M+H]+。
Embodiment 4 prepares HClPro-Ala-Lys (Z)-OBzl (4)
1.4g is obtained from 1.7g (2.5mmol) Boc-Pro-Ala-Lys (Z)-OBzl using the method for embodiment 2
(91.5%) title compound is yellowish grease.ESI-MS (m/z): 539 [M+H]+。
Embodiment 5 prepares Boc-Arg (NO2)-Pro-Ala-Lys(Z)-OBzl(5)
Using the method for embodiment 1 from 798mg (2.5mmol) Boc-Arg (NO2) and 1.6g (2.4mmol) HCIPro-
Ala-Lys (Z)-OBzl obtains 1.5g (71%) title compound, is white solid.ESI-MS (m/z): 840 [M+H]+。
Embodiment 6 prepares HClArg (NO2)-Pro-Ala-Lys(Z)-OBzl(6)
Using the method for embodiment 2 from 1.5g (1.8mmol) Boc-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl obtains
1.2g (86%) title compound is white powder.ESI-MS (m/z): 740 [M+H]+
Embodiment 7 prepares Boc-Gly-Arg (NO2)-Pro-Ala-Lys(Z)-OBzl(7)
Using the method for embodiment 1 from 403mg (2.3mmol) Boc-Gly and 1.4g (2.2mmol) HCIArg (NO2)-
Pro-Ala-Lys (Z)-OBzl obtains 1.4g (68%) title compound, is white solid.ESI-MS (m/z): 897 [M+H]+。
Embodiment 8 prepares Boc-Gly-Arg (NO2)-Pro-Ala-Lys(Z)(8)
By 1.4g (1.5mmol) Boc-Gly-Arg (NO2)-Pro-Ala-Lys (Z)-OBzl is dissolved in 5mL methanol, ice bath
Lower addition 2N NaOH aqueous solution makes PH be maintained at 12, reacts 6 hours, and TLC shows that raw material point disappears.With saturation potassium acid sulfate tune
PH is 7, and methanol is removed under reduced pressure, and is 2 with saturation potassium acid sulfate tune PH, with ethyl acetate (30mL × 3) extraction solution 3 times repeatedly,
Combined ethyl acetate layer, is dried, filtered with anhydrous sodium sulfate, and filtrate decompression is concentrated to dryness, and obtains 1.0g (79%) title compound,
For white solid.ESI-MS (m/z): 805 [M-H]-。
Embodiment 9 prepares Boc-Asp (OBzl)-Val-OBzl (9)
Using the method for embodiment 1 from 3.25g (10mmol) Boc-Asp (OBzl) and 3.6g (9.5mmol) Tosh
Val-OBzl obtains 4.6g (94%) title compound, is yellow oil.ESI-MS (m/z): 513 [M+H]+。
Embodiment 10 prepares HClAsp (OBzl)-Val-OBzl (10)
4.0g (95%) is obtained from 4.8g (9.4mmol) Boc-Asp (OBzl)-Val-OBzl using the method for embodiment 2
Title compound is yellow oil.ESI-MS (m/z): 413 [M+H]+。
Embodiment 11 prepares Boc-Gly-Asp (OBzl)-Val-OBzl (11)
Using the method for embodiment 1 from 1.45g (8.3mmol) Boc-Gly and 4.5g (8.2mmol) HClAsp
(OBzl)-Val-OBzl obtains 3.5g (61%) title compound, is yellow oil.ES1-MS (m/z): 570 [M+H]+。
Embodiment 12 prepares HClGly-Asp (OBzl)-Val-OBzl (12)
3.0g is obtained from 3.5g (6.1mmol) Boc-Gly-Asp (OBzl)-Val-OBzl using the method for embodiment 2
(96%) title compound is white solid.ESI-MS (m/z): 470 [M+H]+。
Embodiment 13 prepares Boc-Arg (NO2)-Gly-Asp(OBzl)-Val-OBzl(13)
Using the method for embodiment 1 from 1.45g (5.6mmol) Boc-Arg (NO2) and 3.2g (5.5mmol) HClAsp
(OBzl)-Val-OBzl obtains 1.5g (71%) title compound, is yellow solid.ESI-MS (m/z): 771 [M+H]+。
Embodiment 14 prepares HClArg (NO2)-Gly-Asp(OBzl)-Val-OBzl(14)
Using the method for embodiment 2 from 2.5g (3.2mmol) Boc-Arg (NO2)-Gly-Asp (OBzl)-Val-OBzl obtains
It is white solid to 2.1g (91%) title compound.ESI-MS (m/z): 671 [M+H]+。
Embodiment 15 prepares Boc-The-Arg (NO2)-Gly-Asp(OBzl)-Val-OBzl(15)
Using the method for embodiment 1 from 822mg (3.0mmol) Boc-The and 716.8mg (3.48mmol) HClArg
(NO2)-Gly-Asp (OBzl)-Val-OBzl obtains 2.0g (69%) title compound, it is white solid.ESI-MS (m/z):
927[M+H]+。
Embodiment 16 prepares HClThe-Arg (NO2)-Gly-Asp(OBzl)-Val-OBzl(16)
Using the method for embodiment 2 from 2.0g (2.2mmol) Boc-The-Arg (NO2)-Gly-Asp(OBzl)-Val-
OBzl obtains 1.7g (91%) title compound, is white solid.ESI-MS (m/z): 827 [M+H]+。
Embodiment 17 prepares Boc-Gly-Arg (NO2)-Pro-Ala-Lys(Z)-The-Arg(NO2)-Gly-Asp-
(OBzl)-Val-OBzl(17)
Using the method for embodiment 1 from 890mg (1.1mmol) Boc-Gly-Arg (NO2)-Pro-Ala-Lys (Z) and
910mg (1.0mmol) HClThe-Arg (NO2)-Gly-Asp (OBzl)-Val-OBzl obtains 500mg (29%) title compound
Object is white solid.ESI-MS (m/z): 1615 [M+H]+。
Embodiment 18 prepares the synthesis (18) of Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val
By 100mg (0.06mmol) Boc-Gly-Arg (NO2)-Pro-Ala-Lys(Z)-The-Arg(NO2)-Gly-Asp
(OBzl)-Val-OBzl (17) is added in eggplant bottle, and 1mL TFA and 0.25mL TFMSA are added under ice salt bath, and TLC is being (just after 1 hour
Butanol: water: glacial acetic acid=1: 1: 1) showing that raw material point disappears, stop reaction, washed repeatedly with anhydrous ether, decompressing and extracting, so
It is dissolved afterwards with water, with 25% ammonium hydroxide tune PH to 7, with Sephadex G10Desalination, C18Column purification, freeze-drying, obtains 30mg (44%)
Title compound is white powder.Mp212-214℃；[α]20 D=-72.73 (c=0.11, H2O) .IR (KBr): vR-CH3=
2962,2873,1450,1381；vR-CH2-R=2930,1257；vCO-NH=1680,3387；vNH2=3400,600.ESI-MS (m/
E): 1111 [M+H]+.1HNMR (800MHz, D2O) δ/ppm=0.8437 (d, J=6.80Hz, 3H), 0.8191 (d, J=
6.8Hz, 3H), 1.0304 (t, J=7.28Hz, 3H), 1.3331 (d, J=7.2Hz, 3H), 1.3906 (m, 2H), 1.6006 (m,
2H), 1.6286 (m, 2H), 1.6380 (m, 2H), 1.6920 (m, 2H), 1.7665 (m, 2H), 1.8178 (m, 2H), 1.8517
(dq, J=6.72Hz, J=6.16Hz, 1H), 1.9186 (m, 2H), 1.9831 (dd, J=7.04Hz, J=6.72Hz, 2H),
2.0596 (m, H), 2.2687 (m, 2H), 2.2782 (m, 2H), 2.5815 (dd, J=8.64Hz, J=16.32Hz, 1H),
2.6767 (dd, J=8.64Hz, J=16.32Hz, 1H), 2.9328 (t, J=7.68,2H), 3.1216 (dd, J=7.28Hz, J
=9.68Hz, 2H), 3.1576 (m, 2H), 3.1642 (m, 2H), 3.5816 (m, 1H), 3.8110 ((m, 1H), 3.8230 (d,
2H), 3.9276 (s, 1H), 4.2194 (m, 1H), 4.2285 (m, 1H), 4.2362 (m, 1H), 4.2586 (q, J=5.44Hz,
1H), 4.3735 (dd, J=J=7.2Hz, 1H), 4.6010 (m, 1H), 4.6150 (m, 1H).
Experimental example 1 evaluates the antithrombotic acitivity of Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide)
It is random to be grouped by SD male rat (180-220g), it is every group 15, quiet to know raising one day, stop feeding overnight.It fills
Stomach gives the normal saline solution of Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide), and (dosage is
100nmol/kg) or the normal saline solution of aspirin (dosage be 167 μm of ol/kg) or physiological saline (dosage 10ml/
Kg) after 30min, the normal saline solution of 20% Ethylurethanm of rat is anaesthetized, and is performed the operation later.Separate rat right carotid and
The silk thread of correct amount is placed in bypass intubation by left neck vein, and left vein is inserted into one end of pipe, and another end pipe is inserted into right artrial
And it is anticoagulant to inject 0.2mL heparin sodium.So that blood flow, which flows through bypass intubation from right artrial, enters left side vein, taken after 15min
Out with thrombus silk thread weigh, calculate blood circulation before and after silk thread weight, obtain thrombus weight withIt indicates simultaneously
Antithrombotic acitivity is represented, t inspection is made.Data are included in table 1.The result shows that oral 100nmol/kgGly-Arg-Pro-Ala-Lys-
The-Arg-Gly-Asp-Val (decapeptide) can effectively inhibit thrombosis.
The antithrombotic of 1 100nmol/kg Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide) of table
Activity
N=10,167 μm of ol/kg of aspirin dose, oral administration, decapeptide dosage are 100nmol/kg；A) it indicates
With physiological saline ratio, p < 0.01, b) and aspirin ratio, p > 0.05.
The results showed that being 100nmol/kg to concentration, the wet weight of thrombus of decapeptide is 14.40 ± 2.87mg, with physiology
Brine ratio has significant difference (28.56 ± 4.12mg, p < 0.01), and decapeptide has certain anti-thrombus activity, with positive control Ah
A woods ratio is taken charge of, p > 0.05, indifference, quite, the wet weight of thrombus of aspirin is 12.97 ± 2.47mg to activity.
Experimental example 2 evaluates the thrombus dissolving activity of Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide)
SD rat (male, 200 ± 20g) is carried out by the dosage intraperitoneal injection urethane normal saline solution of 1200mg/kg
Anesthesia.Its dorsal position is fixed after anesthetized rat, its right common carotid artery is separated, clamps artery clamp at proximal part, by proximal part and
Distal end respectively penetrates surgical thread, the surgical thread ligation of distal end, and artery clamp is unclamped, takes out about 1mL artery by distal end intubation
Blood is placed in 1mL centrifuge tube.Toward vertically fixed rubber tube, (long 15mm, internal diameter 2.5mm, outer diameter 5.0mm, tube bottom rubber plug are close
Envelope, para film is tamping) in inject 0.1ml rat artery blood, the thrombus of a stainless steel material is then rapidly inserted into pipe
Fixing bolt (the fixed spiral of thrombus is coiled into the stainless steel wire that diameter is 0.2mm, and the long 10mm of spiral part includes 15 bung flanges,
The diameter of bung flange is 1.0mm, and support handle is connected with spiral, is about 7.0mm, is in question mark type).After blood clotting 45min, from glass tube
In carefully take out the fixed spiral of the thrombus wrapped up by thrombus, accurately claim its weight.
Bypass intubation is made of three parts, and interlude is long 60.0mm, the polyethylene rubber tube of internal diameter 3.5mm；Both ends are
The identical polyethylene pipe of long 100.0mm, internal diameter 1.0mm, outer diameter 2.0mm, the pipe one end pull into spike tube, are about 10.0mm and (use
In insertion rat carotid artery and vein), outer diameter 1.0mm, the outer cover one Duan Changwei 7.0mm, outer diameter 3.5mm of the other end
Polyethylene pipe (for being inserted into the polyethylene rubber tube in middle section), the inner wall of 3 sections of pipes is required to silanization (1% silicone oil ether
Solution).The fixed spiral of the thrombus of thrombus package is placed in the polyethylene rubber tube of middle section, the other both ends of sebific duct are poly- with two respectively
The overstriking end of ethylene is nested, and guarantees that blood will not be leaked during circulation.With syringe heparin will be filled by spike tube end in pipe
Normal saline solution (50IU/kg) excludes bubble, spare.
The left vena jugularis externa of rat is separated, proximal part and distal end respectively penetrate surgical thread, ligature the blood vessel of distal end,
An osculum is cut on exposed left vena jugularis externa, the above-mentioned bypass duct spike tube prepared is inserted into left vena jugularis externa by osculum and is open
Place, while far from shunt valve middle section (the fixed spiral of the thrombus containing accurate weighing) the interior fixed spiral of thrombus.Passed through with syringe another
The normal saline solution (50IU/kg) of the heparin sodium of the spike tube injection correct amount of one end, syringe not withdraw polyethylene at this time
Pipe, the hose between syringe and polyethylene pipe is clamped with artery clamp.Stop blooding in the proximal part artery clamp of right common carotid artery, ties
Distal end is pricked, right common carotid artery is nearby being cut into an osculum from artery clamp, syringe is extracted from the tip of polyethylene pipe, will gather
The proximal part of the tip insertion artery angle of ethylene tube.Arteriovenous is fixed with No. 4 sutures in the both ends of bypass duct.
With scalp acupuncture by physiological saline (3mL/kg), the normal saline solution (20000IU/kg) or Gly-Arg- of urokinase
The normal saline solution (dosage 100nmol/kg) of Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide) passes through bypass
The middle section (containing the fixed spiral of thrombus being precisely weighed) of pipe, is pierced at the nearly vein far from the fixed spiral of thrombus, opens artery clamp,
Blood flow is set to flow to vein from artery by bypass duct.Solution in syringe is slowly injected into blood, by blood circulation, is pressed
Vein-heart-artery sequential action is on the thrombus of spiral.After blood circulation 1h, fix blood is taken out from bypass duct
The spiral of bolt, accurate weighing.Calculate the weight that the spiral blood circulation front and back thrombus of thrombus is fixed in every rat bypass duct
Difference, with mean valueThrombus dissolving activity is indicated and represented, t inspection is made.Data are included in table 2.The result shows that 100nmol/kg
Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide) can effectively lysigenous thrombus.
The thrombus dissolving of 2 100nmol/kg Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide) of table
Activity
N=10, urokinase dosage are 20000IU/kg；Decapeptide dosage is 1nmol/kg；And physiological saline ratio p < a)
0.01, b) with urokinase ratio, p > 0.05
The results showed that the Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp- for being 100nmol/kg to concentration
The thrombus loss of weight of Val (decapeptide) is 38.79 ± 6.01mg, there is significant difference (27.40 ± 3.20mg, p compared with physiological saline
< 0.01), compared with positive control urokinase, p > 0.05, indifference, activity is suitable, the thrombus loss of weight of positive control urokinase
For 40.14 ± 5.43mg.
Experimental example 3 evaluates Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide) to ishemic stroke
The therapeutic effect of rat
About 2cm long notch is opened vertically at the positive middle part of the neck of male SD rat (300 ± 20g of weight), along nutator
Inside fate separates out right common carotid artery, external carotid artery and internal carotid.It is pressed from both sides respectively with noninvasive artery clamp and closes internal carotid opening
With arteria carotis communis proximal part, the distal end of external carotid artery is ligatured, an osculum is cut in external carotid artery, unclamps arteria carotis communis proximal part
Artery clamp takes 10 μ L blood, closes the proximal part of arteria carotis communis with noninvasive artery clamp folder again later.10 μ L blood of acquirement are placed on
Make blood clotting within room temperature 30 minutes in 1mL EP pipe, is then transferred in -20 DEG C of refrigerators and places 1 hour, make blood clotting
It is solid.Rat 10% chloraldurate intraperitoneal injection of anesthesia, dosage 400mg/kg.Blood clotting is taken out, 1mL physiology salt is added
Blood clotting is pounded uniform tiny thrombi with steel shovel by water, is prepared the suspension of tiny thrombus and is transferred to 1mL injection
In device.The artery clamp for unclamping arteria carotis communis proximal part slowly passes through 1mL thrombus suspension from rat external carotid artery to proximal part
Then the brain of internal carotid injection rat ligatures external carotid artery proximal part, open and obtain artery at internal carotid and arteria carotis communis
Folder restores blood flow.Wait revival.Rat presses Zealonga method after reviving 24 hours and evaluates neurological functional deficit.0 point of table
Show without any neurological deficit sign, 1 point indicate do not damage side forelimb not tensible, 2 points indicate to do not damage skidding walk, 3
Expression is divided to turn-take into shape walking of knocking into the back, 4 points of expression disturbances of consciousness without autonomous, 5 points of expressions death to side is not damaged.Rat warp
Tail vein injects 1 Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide), dosage 100nmol/ daily
kg.Continuous injection 6 days, scores daily.As a result it is included in table 3.Statistics indicate that Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-
It is 2 points and 3 points that Asp-Val (decapeptide), which is continuously treated and 24 hours Neurobiologys of whole (10) cerebral ischemia can be scored for 6 days,
It is 1 point that rat, which improves,.Because rear 5 maintenance doses need 2 unlike the compound initial dose having disclosed needs 5 μm of ol/kg
μm ol/kg, 6 dosage of Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val (decapeptide) are 100nmol/kg.This
Sample one, initial dose and maintenance dose reduce 50 times and 20 times respectively.
3 Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val of table (decapeptide) continuously treats 6 days to cerebral ischemia
The influence of 24 hours rat nerve biology scoring
N=10.
Claims (5)
1.Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val decapeptide.
2. the preparation method of the Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val of claim 1, this method packet
It includes:
(1) Boc- β-carboxyl-OBzl-Asp and Val-OBzl are coupled to obtain Boc- β-carboxyl-OBzl-Asp-Val-OBzl；
(2) Boc- β-carboxyl-OBzl-Asp-Val-OBzl obtains L- β-carboxyl-in the ethyl acetate solution of 4N hydrogen chloride
OBzl-Asp-Val-OBzl；
(3) Boc-Gly and L- β-carboxyl-OBzl-Asp-Val-OBzl are coupled to obtain Boc-Gly- β-carboxyl-OBzl-Asp-
Val-OBzl；
(4) Boc-Gly- β-carboxyl-OBzl-Asp-Val-OBzl obtains L-Gly- β-in the ethyl acetate solution of 4N hydrogen chloride
Carboxyl-OBzl-Asp-Val-OBzl；
(5)Boc-NG-NO2- Arg and L-Gly- β-carboxyl-OBzl-Asp-Val-OBzl are coupled to obtain Boc-NG-NO2-Arg-
Gly- β-carboxyl-OBzl-Asp-Val-OBzl；
(6)Boc-NG-NO2- Arg-Gly- β-carboxyl-OBzl-Asp-Val-OBzl is obtained in the ethyl acetate solution of 4N hydrogen chloride
To NG-NO2- Arg-Gly- β-carboxyl-OBzl-Asp-Val-OBzl；
(7) Boc-The and NG-NO2- Arg-Gly- β-carboxyl-OBzl-Asp-Val-OBzl is coupled to obtain Boc-The-NG-NO2-
Arg-Gly- β-carboxyl-OBzl-Asp-Val-OBzl；
(8)Boc-The-NG-NO2Ethyl acetate solution of-Arg-Gly- β-carboxyl-the OBzl-Asp-Val-OBzl in 4N hydrogen chloride
In obtain L-The-NG-NO2- Arg-Gly- β-carboxyl-OBzl-Asp-Val-OBzl；
(9) Boc-Ala and Nω- Z-Lys-OBzl is coupled to obtain Boc-Ala-Nω-Z-Lys-OBzl；
(10)Boc-Ala-Nω- Z-Lys-OBzl obtains L-Ala-N in the ethyl acetate solution of 4N hydrogen chlorideω-Z-Lys-
OBzl；
(11) Boc-Pro and L-Ala-Nω- Z-Lys-OBzl is coupled to obtain Boc-Pro-Ala-Nω-Z-Lys-OBzl；
(12)Boc-Pro-Ala-Nω- Z-Lys-OBzl obtains L-Pro-Ala--N in the ethyl acetate solution of 4N hydrogen chlorideω-
Z-Lys--OBzl；
(13)Boc-NG-NO2- Arg and L-Pro-Ala-Nω- Z-Lys-OBzl is coupled to obtain L-NG-NO2-Arg-Pro-Ala-Nω-
Z-Lys-OBzl；
(14) Boc-Gly and L-NG-NO2-Arg-Pro-Ala-Nω- Z-Lys-OBzl is coupled to obtain Boc-Gly-NG-NO2-Arg-
Pro-Ala-Nω-Z-Lys-OBzl；
(15)Boc-Gly-NG-NO2-Arg-Pro-Ala-Nω- Z-Lys-OBzl obtains Boc- under the effect of 2N NaOH solution
Gly-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys；
(16)Boc-Gly-NG-NO2-Arg-Pro-Ala-Nω- Z-Lys and L-The-NG-NO2- Arg-Gly- β-carboxyl-OBzl-
Asp-Val-OBzl is coupled to obtain Boc-Gly-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-The-NG-NO2-Arg-Gly-β-
Carboxyl-OBzl-Asp-Val-OBzl；
(17)Boc-Gly-NG-NO2-Arg-Pro-Ala-Nω-Z-Lys-The-NG-NO2- Arg-Gly- β-carboxyl-OBzl-Asp-
Val-OBzl is in trifluoroacetic acid/trifluoromethanesulfonic acid=4: obtaining Gly-Arg-Pro-Ala-Lys-The-Arg-Gly- in 1 solution
Asp-Val。
3. the application that the Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val of claim 1 prepares antithrombotic reagent.
4. the application that the Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val of claim 1 prepares thrombolytic agent.
5. the Gly-Arg-Pro-Ala-Lys-The-Arg-Gly-Asp-Val of claim 1 prepares ishemic stroke drug
Using.
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| CN102702312A (en) * | 2006-11-30 | 2012-10-03 | 首都医科大学 | RGDVYIGSK with targeting antithrombotic activity, preparation and applications thereof |
| CN102875644A (en) * | 2012-09-05 | 2013-01-16 | 永光制药有限公司 | GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof |
| CN103665107A (en) * | 2012-09-05 | 2014-03-26 | 永光制药有限公司 | Novel compound combining functions of dissolving thrombus, scavenging free radicals and targeting thrombus, as well as preparation method and application thereof |
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| CN102875644A (en) * | 2012-09-05 | 2013-01-16 | 永光制药有限公司 | GRPAK/tetrahydroglyoxaline/RGD ternary conjugate as well as preparation method and application thereof |
| CN103665107A (en) * | 2012-09-05 | 2014-03-26 | 永光制药有限公司 | Novel compound combining functions of dissolving thrombus, scavenging free radicals and targeting thrombus, as well as preparation method and application thereof |
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| 茶氨酸对脑缺血损伤大鼠自由基代谢的影响;王庆利等;《实用医学杂志》;20081231;第24卷(第11期);摘要，第1899-1900 3讨论部分 |
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| CF01 | Termination of patent right due to non-payment of annual fee |