CN104193807B - 凝血酶抑制多肽及其制备方法、应用 - Google Patents
凝血酶抑制多肽及其制备方法、应用 Download PDFInfo
- Publication number
- CN104193807B CN104193807B CN201410509069.7A CN201410509069A CN104193807B CN 104193807 B CN104193807 B CN 104193807B CN 201410509069 A CN201410509069 A CN 201410509069A CN 104193807 B CN104193807 B CN 104193807B
- Authority
- CN
- China
- Prior art keywords
- polypeptide
- thrombin
- relevant disease
- suppresses
- atherosclerosis
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
- 229920001184 polypeptide Polymers 0.000 title claims abstract description 25
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 25
- 102000004196 processed proteins & peptides Human genes 0.000 title claims abstract description 25
- 108090000190 Thrombin Proteins 0.000 title claims abstract description 18
- 229960004072 thrombin Drugs 0.000 title claims abstract description 18
- 238000002360 preparation method Methods 0.000 title claims description 4
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 19
- 239000003814 drug Substances 0.000 claims abstract description 11
- 201000010099 disease Diseases 0.000 claims abstract description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 10
- 206010020772 Hypertension Diseases 0.000 claims abstract description 6
- 206010002383 Angina Pectoris Diseases 0.000 claims abstract description 5
- 208000024806 Brain atrophy Diseases 0.000 claims abstract description 5
- 208000001647 Renal Insufficiency Diseases 0.000 claims abstract description 5
- 230000006793 arrhythmia Effects 0.000 claims abstract description 5
- 206010003119 arrhythmia Diseases 0.000 claims abstract description 5
- 201000006370 kidney failure Diseases 0.000 claims abstract description 5
- 208000010125 myocardial infarction Diseases 0.000 claims abstract description 5
- 206010008190 Cerebrovascular accident Diseases 0.000 claims abstract description 4
- 208000006011 Stroke Diseases 0.000 claims abstract description 4
- 230000003143 atherosclerotic effect Effects 0.000 abstract description 6
- 229940079593 drug Drugs 0.000 abstract description 5
- 230000002265 prevention Effects 0.000 abstract description 5
- 239000002671 adjuvant Substances 0.000 abstract description 4
- 238000000034 method Methods 0.000 abstract description 4
- 125000003088 (fluoren-9-ylmethoxy)carbonyl group Chemical group 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 3
- 231100000915 pathological change Toxicity 0.000 abstract description 3
- 230000036285 pathological change Effects 0.000 abstract description 3
- 238000010532 solid phase synthesis reaction Methods 0.000 abstract description 3
- 108091003079 Bovine Serum Albumin Proteins 0.000 abstract description 2
- 108091006905 Human Serum Albumin Proteins 0.000 abstract description 2
- 102000008100 Human Serum Albumin Human genes 0.000 abstract description 2
- 239000002202 Polyethylene glycol Substances 0.000 abstract description 2
- 230000023555 blood coagulation Effects 0.000 abstract description 2
- 229940098773 bovine serum albumin Drugs 0.000 abstract description 2
- 239000002775 capsule Substances 0.000 abstract description 2
- 230000005764 inhibitory process Effects 0.000 abstract description 2
- 238000001990 intravenous administration Methods 0.000 abstract description 2
- 238000010253 intravenous injection Methods 0.000 abstract description 2
- 239000007922 nasal spray Substances 0.000 abstract description 2
- 229940097496 nasal spray Drugs 0.000 abstract description 2
- 239000006187 pill Substances 0.000 abstract description 2
- 229920001223 polyethylene glycol Polymers 0.000 abstract description 2
- 108010023302 HDL Cholesterol Proteins 0.000 description 5
- 240000008042 Zea mays Species 0.000 description 4
- 235000005824 Zea mays ssp. parviglumis Nutrition 0.000 description 4
- 235000002017 Zea mays subsp mays Nutrition 0.000 description 4
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 235000005822 corn Nutrition 0.000 description 4
- 235000013305 food Nutrition 0.000 description 4
- 150000002632 lipids Chemical class 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 208000037260 Atherosclerotic Plaque Diseases 0.000 description 3
- 108010028554 LDL Cholesterol Proteins 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 241000283973 Oryctolagus cuniculus Species 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 235000001014 amino acid Nutrition 0.000 description 3
- 150000001413 amino acids Chemical class 0.000 description 3
- 125000003277 amino group Chemical group 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 235000021590 normal diet Nutrition 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 2
- 229940122388 Thrombin inhibitor Drugs 0.000 description 2
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 2
- 125000000539 amino acid group Chemical group 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 210000004204 blood vessel Anatomy 0.000 description 2
- 238000005859 coupling reaction Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 1
- MCTWTZJPVLRJOU-UHFFFAOYSA-N 1-methyl-1H-imidazole Chemical compound CN1C=CN=C1 MCTWTZJPVLRJOU-UHFFFAOYSA-N 0.000 description 1
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 206010059245 Angiopathy Diseases 0.000 description 1
- 206010065558 Aortic arteriosclerosis Diseases 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 208000009084 Cold Injury Diseases 0.000 description 1
- 102000009123 Fibrin Human genes 0.000 description 1
- 108010073385 Fibrin Proteins 0.000 description 1
- BWGVNKXGVNDBDI-UHFFFAOYSA-N Fibrin monomer Chemical compound CNC(=O)CNC(=O)CN BWGVNKXGVNDBDI-UHFFFAOYSA-N 0.000 description 1
- 108010049003 Fibrinogen Proteins 0.000 description 1
- 102000008946 Fibrinogen Human genes 0.000 description 1
- 206010017711 Gangrene Diseases 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 206010060378 Hyperinsulinaemia Diseases 0.000 description 1
- 206010022562 Intermittent claudication Diseases 0.000 description 1
- 208000008574 Intracranial Hemorrhages Diseases 0.000 description 1
- 206010065560 Mesenteric arteriosclerosis Diseases 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 1
- NPGIHFRTRXVWOY-UHFFFAOYSA-N Oil red O Chemical compound Cc1ccc(C)c(c1)N=Nc1cc(C)c(cc1C)N=Nc1c(O)ccc2ccccc12 NPGIHFRTRXVWOY-UHFFFAOYSA-N 0.000 description 1
- 241000283977 Oryctolagus Species 0.000 description 1
- 208000031481 Pathologic Constriction Diseases 0.000 description 1
- 208000004531 Renal Artery Obstruction Diseases 0.000 description 1
- 206010038378 Renal artery stenosis Diseases 0.000 description 1
- 239000012190 activator Substances 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 201000001962 aortic atherosclerosis Diseases 0.000 description 1
- 208000011775 arteriosclerosis disease Diseases 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 230000002595 cold damage Effects 0.000 description 1
- 210000002808 connective tissue Anatomy 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 230000008034 disappearance Effects 0.000 description 1
- 210000003017 ductus arteriosus Anatomy 0.000 description 1
- 229950003499 fibrin Drugs 0.000 description 1
- 229940012952 fibrinogen Drugs 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 208000035861 hematochezia Diseases 0.000 description 1
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 description 1
- 201000008980 hyperinsulinism Diseases 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 208000021156 intermittent vascular claudication Diseases 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 208000028867 ischemia Diseases 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000003141 lower extremity Anatomy 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 206010029446 nocturia Diseases 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 230000002980 postoperative effect Effects 0.000 description 1
- 230000010349 pulsation Effects 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 description 1
- 229960000672 rosuvastatin Drugs 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000036262 stenosis Effects 0.000 description 1
- 208000037804 stenosis Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 231100000216 vascular lesion Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
Abstract
本发明涉及药物领域，具体涉及预防和治疗或预防动脉粥样硬化的多肽化合物。凝血酶抑制多肽2，其特征在于：其序列为RGDLFRKSADGFIALMKLKK。采用Fmoc保护的固相合成技术制备。可共价连接一个佐剂，佐剂是牛血清白蛋白，人血清白蛋白，或聚乙二醇。凝血酶抑制多肽2在治疗动脉粥样硬化相关疾病中的应用。所述的动脉粥样硬化相关疾病是心绞痛、心肌梗塞、心律失常、脑卒中、脑萎缩、顽固性高血压、肾功能不全等病变。可通过多种给药方式治疗动脉粥样硬化相关疾病，包括皮下或肌肉注射，静脉注射或者静脉滴注，口服给药如药丸、胶囊等，鼻喷剂等。本发明中的凝血酶抑制多肽2可以靶向抑制凝血酶，抑制凝血，达到预防或治疗动脉粥样硬化的作用。
Description
技术领域：
本发明涉及药物领域，具体涉及用于预防和治疗或预防动脉粥样硬化的多肽化合物。
背景技术：
动脉粥样硬化(Atherosclerosis)是由于脂肪、血栓、结缔组织和碳酸钙在血管(主要是动脉，但也包括静脉)沉积所造成的一种对人体有害的状态。其特点是动脉管壁增厚变硬、失去弹性和管腔缩小。动脉粥样硬化的症状主要决定于血管病变及受累器官的缺血程度，主动脉粥样硬化常无症状，冠状动脉粥样硬化者，若管径狭窄达75％以上,则可发生心绞痛、心肌梗塞、心律失常，甚至猝死。脑动脉硬化可引起脑缺血、脑萎缩，或造成脑血管破裂出血，肾动脉粥样硬化常引起夜尿、顽固性高血压、严重者可有肾功能不全。肠系膜动脉粥样硬化可表现为饱餐后腹痛便血等症状。下肢动脉粥样硬化引起血管腔严重狭窄者可出现间歇性跛行、足背动脉搏动消失，严重者甚至可发生坏疽。动脉粥样硬化是一组称为动脉硬化的血管病中最常见、最重要的一种。
目前预防和治疗动脉粥样硬化的药物，主要为针对控制易患因素。如患有糖尿病、应及时控制血糖，包括饮食控制。2型糖尿病的降糖药物应以不引起高胰岛素血症为宜如达美康等；如有高血压则应给降压药，使血压降至适当水平，如有血胆固醇增高，则应控制高胆固醇适当给予降脂药物。
凝血酶能使纤维蛋白原转化成纤维蛋白。血管内促进血栓的形成，引起动脉粥样硬化。我们的实验表明，采用凝血酶抑制剂可以控制血管内动脉粥样硬化血栓的形成，能有效抑制动脉粥样硬化斑块的形成。这是一个治疗动脉粥样硬化的新靶点。
现阶段，没有成熟开发的凝血酶抑制剂问世，用于治疗动脉粥样硬化。
发明内容：
本发明目的是针对现有治疗动脉粥样硬化药物的特点，设计一种多肽化合物，能有效治疗或预防动脉粥样硬化。
技术方案
凝血酶抑制多肽2，其特征在于：其序列为RGDLFRKSADGFIALMKLKK。采用Fmoc保护的固相合成技术制备。可共价连接一个佐剂，佐剂是牛血清白蛋白，人血清白蛋白，或聚乙二醇。凝血酶抑制多肽2在治疗动脉粥样硬化相关疾病中的应用。所述的动脉粥样硬化相关疾病是心绞痛、心肌梗塞、心律失常、脑卒中、脑萎缩、顽固性高血压、肾功能不全等病变。可通过多种给药方式治疗动脉粥样硬化相关疾病，包括皮下或肌肉注射，静脉注射或者静脉滴注，口服给药如药丸、胶囊等，鼻喷剂等。
有益结果：
本发明中的凝血酶抑制多肽2可以靶向抑制凝血酶，抑制凝血，达到预防或治疗动脉粥样硬化的作用。更优选是治疗动脉粥样硬化相关疾病药物中的用途。所述的脉粥样硬化相关疾病包括心绞痛、心肌梗塞、心律失常、脑卒中、脑萎缩、顽固性高血压、肾功能不全等病变。
具体实施方式
实施例1
多肽的化学合成方法
多肽2用Fmoc保护的固相合成技术制备。合成反应按照多肽2序列从C端向N端进行，Rink介质(可在AdvancedChemTech公司购得)上有自由氨基。每一步连接过程中，氨基酸残基都要活化，活化混合物中有4倍于介质上自由氨基的HBTU，HOBt，DIEA和Fmoc-氨基酸。每次氨基酸的连接反应之后，都用一个吡啶/醋酸/N-甲基咪唑(3:2:0.5)的混合物来封闭未连接的自由氨基，封闭反应10分钟。每次氨基酸的连接反应之后，下一个氨基酸连接之前，都要把介质上的Fmoc-基团去掉，去Fmoc-基团使用含20％哌啶的二甲基甲酰胺，需15分钟。最后，当所有氨基酸残基顺序连接之后，多肽2用98％三氟乙酸从介质上切割下来，切割在室温下进行2小时。
应用上述化学条件可合成并获得多肽2，序列为RGDLFRKSADGFIALMKLKK，该序列为全新序列。
实施例2
凝血酶抑制多肽2对家兔动脉粥样硬化模型的影响
建立家兔动脉粥样硬化模型动物模型。雄性新西兰白兔40只，随机分为4组，分别为：A组为空白对照组：普通饲料喂养；B组为模型对照组：造模+高脂饲料喂养；C组为药物干预组：造模+高脂饲料+凝血酶抑制多肽2(2.5mg/kg/d)；D为阳性药干预组：造模+高脂饲料+瑞舒伐他汀片(2.5mg/kg/d)。普通饲料适应性喂养7天后，对模型对照组、药物干预组及阳性药干预组实施右颈动脉内膜液氮冻伤术，术后模型对照组、药物干预组及阳性药干预组高脂饲料喂养，同时灌胃给药，进行药物干预治疗，连续13周后处死。空白对照组一直给予普通饲料喂养。检测血清总胆固醇(totalcholesterol,TC)、甘油三酯(tryglyeride,TG)、高密度脂蛋白胆固醇(highdensitylipoproteincholesterol,HDL-C)和低密度脂蛋白胆固醇(lowdensitylipoproteincholesterol,HDL-C)的水平。对家兔主动脉大体和主动脉根部冰冻切片行油红O染色，对动脉粥样斑块面积进行定量。
结果：多肽2组与高脂高胆固醇喂养的模型家兔组相比，TG、TC、HDL-C、LDL-C水平显著降低(P<0.01，见表1)，动脉粥样斑块面积显著性减小(P<0.01，见表2)，与模型对照组比较差异均有统计学意义。
表1凝血酶抑制多肽2对家兔动脉粥样硬化模型小鼠胆固醇的影响
*p<0.05，**p<0.01与模型组相比
表2凝血酶抑制多肽2对家兔动脉粥样硬化模型小鼠动脉粥样硬化面积的影响
*p<0.05，**p<0.01与模型组相比
结论：凝血酶抑制多肽2对家兔动脉粥样硬化具有治疗作用。
SEQUENCELISTING
<110>苏州普罗达生物科技有限公司
<120>凝血酶抑制多肽及其制备方法、应用
<130>
<160>1
<170>PatentInversion3.3
<210>1
<211>20
<212>PRT
<213>人工序列
<400>1
ArgGlyAspLeuPheArgLysSerAlaAspGlyPheIleAlaLeuMet
151015
LysLeuLysLys
20
Claims (2)
1.一种凝血酶抑制多肽，其特征在于：其序列为RGDLFRKSADGFIALMKLKK。
2.根据权利要求1所述的多肽在制备治疗动脉粥样硬化相关疾病药物中的应用，所述的动脉粥样硬化相关疾病是心绞痛、心肌梗塞、心律失常、脑卒中、脑萎缩、顽固性高血压、肾功能不全。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410509069.7A CN104193807B (zh) | 2014-09-28 | 2014-09-28 | 凝血酶抑制多肽及其制备方法、应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410509069.7A CN104193807B (zh) | 2014-09-28 | 2014-09-28 | 凝血酶抑制多肽及其制备方法、应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104193807A CN104193807A (zh) | 2014-12-10 |
| CN104193807B true CN104193807B (zh) | 2016-06-15 |
Family
ID=52079203
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410509069.7A Active CN104193807B (zh) | 2014-09-28 | 2014-09-28 | 凝血酶抑制多肽及其制备方法、应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104193807B (zh) |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11643439B2 (en) * | 2015-08-05 | 2023-05-09 | Shaanxi Micot Technology Limited Company | Multi-target compound with anticoagulation and antiplatelet activity, preparation method therefor, and use thereof |
| CN105175503A (zh) * | 2015-09-08 | 2015-12-23 | 苏州普罗达生物科技有限公司 | 因子viii抑制多肽及其应用 |
| CN105175505A (zh) * | 2015-09-08 | 2015-12-23 | 苏州普罗达生物科技有限公司 | 瘦素激动多肽及其应用 |
| CN105175504A (zh) * | 2015-09-08 | 2015-12-23 | 苏州普罗达生物科技有限公司 | 血管性血友病因子抑制多肽及其应用 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IL101062A0 (en) * | 1991-02-28 | 1992-11-15 | Erba Carlo Spa | Anti-thrombin polypeptides and their preparation |
| DE4323754C1 (de) * | 1993-07-15 | 1994-12-01 | Gruenenthal Gmbh | Bifunktionelle Urokinasevarianten mit verbesserten fibrinolytischen Eigenschaften und thrombinhemmender Wirkung |
| CN1194009C (zh) * | 2000-09-12 | 2005-03-23 | 南京大学 | 人胎盘抗凝蛋白介导的抗凝蛋白 |
| CN102702325B (zh) * | 2012-06-19 | 2015-09-23 | 深圳翰宇药业股份有限公司 | 一种抗凝血多肽的制备方法 |
-
2014
- 2014-09-28 CN CN201410509069.7A patent/CN104193807B/zh active Active
Also Published As
| Publication number | Publication date |
|---|---|
| CN104193807A (zh) | 2014-12-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN104193807B (zh) | 凝血酶抑制多肽及其制备方法、应用 | |
| HU230773B1 (hu) | Benzamidok és rokon Xa faktor inhibitorok | |
| CN104736552B (zh) | 用于预防或治疗心血管疾病的、包含对血管紧张素‑i转换酶表现出抑制活性的肽作为活性成分的药物组合物 | |
| CN105339010A (zh) | 使用因子xii抑制剂和c1-抑制剂的联合疗法 | |
| CN104193809B (zh) | 一种凝血酶抑制及其制备方法、应用 | |
| WO2018006667A1 (zh) | 降血压肽和降血压蛋白质及其应用 | |
| JPS6357407B2 (zh) | ||
| CN112898380B (zh) | 二氧六环修饰的四氢咔啉-3-甲酰-The-HGK、其制备、抗血栓活性和应用 | |
| CN102516358A (zh) | 源于鱼鳞胶原蛋白的血管紧张素ⅰ转换酶抑制剂及其应用 | |
| WO2001077673A1 (en) | Hypotensors | |
| CN105175504A (zh) | 血管性血友病因子抑制多肽及其应用 | |
| CN105175503A (zh) | 因子viii抑制多肽及其应用 | |
| CN108815171B (zh) | 25-羟基胆固醇在制备治疗或预防心肌梗死的药物中的应用 | |
| BE1013958A6 (fr) | Antagonistes glycoproteiques. | |
| CN105175505A (zh) | 瘦素激动多肽及其应用 | |
| WO2007088681A1 (ja) | グレリン産生促進剤 | |
| Giraldo-Grueso et al. | Mitral Valve Replacement in a Patient With Systemic Mastocytosis | |
| CN101185506B (zh) | 一种降血压食品及其制备方法 | |
| JPH03141297A (ja) | イミダゾール化合物およびトランスグルタミナーゼ阻害剤としてのその使用 | |
| KR101693713B1 (ko) | 혈소판 응집 억제용 조성물 | |
| Li et al. | A 63-year-old man who developed severe abdominal pain after thrombolytic therapy. | |
| Adam Cartwright et al. | Advances in drug safety | |
| TWI516273B (zh) | 一種篩選自苦瓜籽蛋白之具降血壓活性胜肽及其製備方法 | |
| Markos' yan et al. | Effect of intraoperative heparin administration on some indices of the blood coagulatory-lytic system in the ischemic region of the small intestine with anastomosis | |
| CN105131088A (zh) | 一种雪莲果蛋白多肽及其应用 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| C41 | Transfer of patent application or patent right or utility model | ||
| CB03 | Change of inventor or designer information |
Inventor after: Guo Rui Inventor after: Lan Yong Inventor after: Liu Yu Inventor before: Luo Ruixue |
|
| COR | Change of bibliographic data | ||
| GR01 | Patent grant | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20160524 Address after: High tech Industrial Development Zone, Guangzhou City, Guangdong province 510663 Science City skim Springs Road No. 3, Guangzhou international business incubator A A506 Applicant after: GUANGZHOU BEOGENE BIOTECH Co.,Ltd. Address before: 215000 Jiangsu City, Suzhou hi tech Zone Jinfeng Road, building 8, No. 15 Applicant before: SUZHOU PULUODA BIOLOGICAL SCIENCE AND TECHNOLOGY Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| CP03 | Change of name, title or address |
Address after: 510663 second floor, building C, No.2 Ruitai Road, Guangzhou hi tech Industrial Development Zone, Guangzhou City, Guangdong Province Patentee after: Guangzhou bioscience Co.,Ltd. Address before: 510663 a506, zone a, Guangzhou International Business Incubator, No.3, Juquan Road, Science City, Guangzhou hi tech Industrial Development Zone, Guangdong Province Patentee before: GUANGZHOU BEOGENE BIOTECH Co.,Ltd. |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Thrombin inhibitory peptide and its preparation and Application Effective date of registration: 20210407 Granted publication date: 20160615 Pledgee: Zhongda sub branch of Bank of Guangzhou Co.,Ltd. Pledgor: Guangzhou bioscience Co.,Ltd. Registration number: Y2021440000120 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right | ||
| PC01 | Cancellation of the registration of the contract for pledge of patent right |
Date of cancellation: 20220713 Granted publication date: 20160615 Pledgee: Zhongda sub branch of Bank of Guangzhou Co.,Ltd. Pledgor: Guangzhou bioscience Co.,Ltd. Registration number: Y2021440000120 |
|
| PC01 | Cancellation of the registration of the contract for pledge of patent right | ||
| PE01 | Entry into force of the registration of the contract for pledge of patent right |
Denomination of invention: Thrombin inhibitory polypeptide and its preparation method and Application Effective date of registration: 20220713 Granted publication date: 20160615 Pledgee: Zhongda sub branch of Bank of Guangzhou Co.,Ltd. Pledgor: Guangzhou bioscience Co.,Ltd. Registration number: Y2022980010456 |
|
| PE01 | Entry into force of the registration of the contract for pledge of patent right |