CN108272784A - Application of the Propionamides compound in treating enteric flora disturbance relevant disease - Google Patents
Application of the Propionamides compound in treating enteric flora disturbance relevant disease Download PDFInfo
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- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 title claims abstract description 40
- 201000010099 disease Diseases 0.000 title claims abstract description 23
- -1 Propionamides compound Chemical class 0.000 title claims description 21
- 239000003814 drug Substances 0.000 claims abstract description 20
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims abstract description 16
- 229940079593 drug Drugs 0.000 claims abstract description 16
- 150000004666 short chain fatty acids Chemical class 0.000 claims abstract description 11
- 235000021391 short chain fatty acids Nutrition 0.000 claims abstract description 5
- 210000004369 blood Anatomy 0.000 claims description 13
- 239000008280 blood Substances 0.000 claims description 13
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 9
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 8
- 206010020772 Hypertension Diseases 0.000 claims description 6
- 208000022559 Inflammatory bowel disease Diseases 0.000 claims description 6
- 208000001145 Metabolic Syndrome Diseases 0.000 claims description 6
- 208000008589 Obesity Diseases 0.000 claims description 6
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 claims description 6
- 239000001257 hydrogen Substances 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 6
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 6
- 235000020824 obesity Nutrition 0.000 claims description 6
- 125000005037 alkyl phenyl group Chemical group 0.000 claims description 5
- 125000006383 alkylpyridyl group Chemical group 0.000 claims description 5
- 125000004076 pyridyl group Chemical group 0.000 claims description 5
- 208000017170 Lipid metabolism disease Diseases 0.000 claims description 4
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 125000000217 alkyl group Chemical group 0.000 claims description 3
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 3
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- 230000002547 anomalous effect Effects 0.000 claims 1
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- QLNJFJADRCOGBJ-UHFFFAOYSA-N propionamide Chemical class CCC(N)=O QLNJFJADRCOGBJ-UHFFFAOYSA-N 0.000 abstract description 17
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- 229940080818 propionamide Drugs 0.000 description 10
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- 208000032928 Dyslipidaemia Diseases 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
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- ZSJLQEPLLKMAKR-UHFFFAOYSA-N Streptozotocin Natural products O=NN(C)C(=O)NC1C(O)OC(CO)C(O)C1O ZSJLQEPLLKMAKR-UHFFFAOYSA-N 0.000 description 2
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- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 1
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Classifications
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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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- 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
- A61K31/16—Amides, e.g. hydroxamic acids
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
- A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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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
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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
- A61K31/4402—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 2, e.g. pheniramine, bisacodyl
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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
- A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
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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
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- 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
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
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Abstract
本发明提供了丙酰胺类化合物在制备用于治疗与肠道菌群紊乱相关的疾病的药物中的应用，丙酰胺类化合物通过调节肠道菌群组成，可以有效改善肠道菌群紊乱的状态，提高肠道中短链脂肪酸含量，尤其是肠道中丁酸的含量，进而用于治疗与肠道菌群紊乱相关的疾病，本发明还提供了一种治疗与肠道菌群紊乱相关的疾病的药物。The present invention provides the application of propionamide compounds in the preparation of medicines for treating diseases related to intestinal flora disorders. The propionamide compounds can effectively improve the state of intestinal flora disorders by regulating the composition of intestinal flora , increase the content of short-chain fatty acids in the intestine, especially the content of butyric acid in the intestine, and then be used to treat diseases related to intestinal flora disorders, and the present invention also provides a method for treating diseases related to intestinal flora disorders drug.
Description
技术领域technical field
本发明涉及药物领域，具体而言，涉及丙酰胺类化合物在治疗与肠道菌群紊乱相关的疾病中的应用。The invention relates to the field of medicines, in particular to the application of propionamide compounds in the treatment of diseases related to intestinal flora disturbance.
背景技术Background technique
人体肠道内寄居着大量微生物，构成了肠道的微生态系统。人在健康状况时的微生态系统保持相对稳定的平衡状态。因受宿主的基因遗传、生活环境、饮食习惯等的影响，使得肠道菌群具有多样性和特异性。种类繁多的肠道菌群在人体的营养吸收、免疫调节、脂肪代谢等诸多方面起着重要作用。因此，以肠道菌群为代表的人体微生物组在维持人体健康中具有不可替代的作用。肠道菌群紊乱导致机体健康状况受损，主要指机体肠道菌群各菌种间比例发生较大幅度变化而超出正常范围的状态，由此产生的病症。肠道菌群紊乱的本质是有益微生物与有害微生物的失衡。与肠道菌群紊乱相关的疾病包括糖尿病，肥胖症，血脂紊乱，炎性肠病、高血压、代谢综合征等。因此改善肠道菌群紊乱对于改善与肠道菌群紊乱相关疾病(糖尿病，肥胖症，血脂紊乱，炎性肠病、高血压、代谢综合征等)有着重要的作用。There are a large number of microorganisms living in the human intestinal tract, which constitute the intestinal micro-ecosystem. When a person is in a healthy state, the micro-ecosystem maintains a relatively stable balance. Due to the influence of the host's genetic inheritance, living environment, and eating habits, the intestinal flora has diversity and specificity. A wide variety of intestinal flora play an important role in many aspects such as nutrient absorption, immune regulation, and fat metabolism in the human body. Therefore, the human microbiome represented by intestinal flora plays an irreplaceable role in maintaining human health. The disorder of intestinal flora leads to the impairment of the health of the body, which mainly refers to the state in which the proportion of various species of intestinal flora in the body changes greatly and exceeds the normal range, and the resulting disease. The essence of intestinal flora disorder is the imbalance between beneficial microorganisms and harmful microorganisms. Diseases related to intestinal flora disturbance include diabetes, obesity, dyslipidemia, inflammatory bowel disease, hypertension, metabolic syndrome, etc. Therefore, improving intestinal flora disorder plays an important role in improving diseases related to intestinal flora disorder (diabetes, obesity, dyslipidemia, inflammatory bowel disease, hypertension, metabolic syndrome, etc.).
目前肠道菌群已经作为一个重要的药物筛选靶标用于调节多种与肠道菌群紊乱相关疾病的糖尿病、肥胖症、炎性肠病、代谢综合征、高血压和癌症等，调节肠道菌的平衡，改善疾病状态。针对肠道菌群调节的治疗方式主要为饮食调整、活菌制剂、菌群促进剂等。因此迫切需要开发新型的以肠道菌群为靶点的药物，通过改变它们与宿主间相互作用，纠正紊乱的菌群结构，从而达到治疗肠道菌群紊乱相关疾病的目的。At present, intestinal flora has been used as an important drug screening target to regulate a variety of diseases related to intestinal flora disorders, such as diabetes, obesity, inflammatory bowel disease, metabolic syndrome, hypertension and cancer, etc. Bacteria balance, improve disease state. The treatment methods for the regulation of intestinal flora mainly include diet adjustment, live bacterial preparations, flora promoters, etc. Therefore, there is an urgent need to develop new drugs that target the intestinal flora, and correct the disordered flora structure by changing the interaction between them and the host, so as to achieve the purpose of treating diseases related to intestinal flora disorders.
发明内容Contents of the invention
针对相关技术中的问题，本发明提供了丙酰胺类化合物在制备用于治疗与肠道菌群紊乱相关的疾病的药物中的应用，其特征在于，丙酰胺类化合物的通式为：In view of the problems in the related art, the present invention provides the application of propionamide compounds in the preparation of medicines for treating diseases related to intestinal flora disturbance, characterized in that the general formula of propionamide compounds is:
其中，R1选自氢、乙酰基、苯甲酰基、C1-C2烷基、苯基、苯烷基中的一种或多种的组合；以及R2、R3选自氢、C1-C3烷基、C1-C2烷基嘧啶基、C1-C2烷基环戊二烯基、C1-C2烷基呋喃基、C1-C2烷基噻吩基、C1-C2烷基苯基、C1-C2烷基吡啶基，其中，所述C1-C2烷基苯基中的苯基和所述C1-C2烷基吡啶基中的吡啶基是未取代的或用羟基、乙酯基、C1-C2烷氧基、苄氧基中的一个或多个基团取代的苯基和吡啶基。Wherein, R 1 is selected from one or more combinations of hydrogen, acetyl, benzoyl, C 1 -C 2 alkyl, phenyl, phenylalkyl; and R 2 and R 3 are selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkylpyrimidinyl, C 1 -C 2 alkylcyclopentadienyl, C 1 -C 2 alkylfuryl, C 1 -C 2 alkylthienyl, C 1 -C 2 alkylphenyl, C 1 -C 2 alkylpyridyl, wherein, the phenyl in the C 1 -C 2 alkylphenyl and the C 1 -C 2 alkylpyridyl The pyridyl group is phenyl and pyridyl which are unsubstituted or substituted with one or more groups in hydroxyl, ethyl carboxy, C 1 -C 2 alkoxy, benzyloxy.
在上述应用中，所述丙酰胺类化合物选自以下化学式所示的化合物中的一种或多种：In the above application, the propionamide compound is selected from one or more of the compounds shown in the following chemical formula:
在上述应用中，所述丙酰胺类化合物可以调节肠道菌群组成，提高肠道中短链脂肪酸含量，进而改善肠道菌群紊乱。In the above application, the propionamide compound can regulate the composition of the intestinal flora, increase the content of short-chain fatty acids in the intestinal tract, and then improve the disorder of the intestinal flora.
在上述应用中，所述丙酰胺类化合物可以调节肠道菌群组成，提高肠道中丁酸的含量，进而改善肠道菌群紊乱。In the above application, the propionamide compound can regulate the composition of the intestinal flora, increase the content of butyric acid in the intestinal tract, and then improve the disorder of the intestinal flora.
在上述应用中，所述与肠道菌群紊乱相关的疾病包括II型糖尿病、脂代谢异常、高血压、血脂紊乱、肥胖症和炎性肠病、代谢综合征中的一种或多种。In the above application, the diseases related to intestinal flora disturbance include one or more of type II diabetes, abnormal lipid metabolism, hypertension, blood lipid disorder, obesity, inflammatory bowel disease, and metabolic syndrome.
本发明还提供了一种治疗与肠道菌群紊乱相关的疾病的药物，其中，所述药物包括丙酰胺类化合物、所述丙酰胺类化合物在药学上可接受的盐、酯、水合物或它们的组合以及辅料。The present invention also provides a drug for treating diseases related to intestinal flora disturbance, wherein the drug includes propionamide compounds, pharmaceutically acceptable salts, esters, hydrates or Their combinations and accessories.
本发明提供了丙酰胺类化合物在制备用于治疗与肠道菌群紊乱相关的疾病的药物中的应用，丙酰胺类化合物通过调节肠道菌群组成，有效改善肠道菌群紊乱状态，提高肠道中短链脂肪酸含量，尤其是肠道中丁酸的含量，同时可以具有降低血糖及血清中甘油三酯(TG)、总胆固醇(TC)的作用。The invention provides the application of propionamide compounds in the preparation of medicines for treating diseases related to intestinal flora disorders. The propionamide compounds can effectively improve the disordered state of intestinal flora by regulating the composition of intestinal flora, and improve the The content of short-chain fatty acids in the intestine, especially the content of butyric acid in the intestine, can also reduce blood sugar, triglyceride (TG) and total cholesterol (TC) in serum.
具体实施方式Detailed ways
下面将结合本发明的实施例，对本发明实施例中的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员所获得的所有其他实施例，都属于本发明保护的范围。The technical solutions in the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some of the embodiments of the present invention, not all of them. All other embodiments obtained by persons of ordinary skill in the art based on the embodiments of the present invention belong to the protection scope of the present invention.
本发明提供了丙酰胺类化合物在制备用于治疗与肠道菌群紊乱相关的疾病的药物中的应用，其中，与肠道菌群紊乱相关的疾病II型糖尿病、脂代谢异常、高血压、血脂紊乱、肥胖症和炎性肠病、代谢综合征等疾病中的一种或多种，丙酰胺类化合物的通式为：The present invention provides the application of propionamide compounds in the preparation of medicines for treating diseases related to intestinal flora disorders, wherein the diseases related to intestinal flora disorders are type II diabetes, abnormal lipid metabolism, hypertension, One or more of diseases such as dyslipidemia, obesity, inflammatory bowel disease, and metabolic syndrome, the general formula of the propionamide compound is:
其中，R1选自氢、乙酰基、苯甲酰基、C1-C2烷基、苯基、苯烷基中的一种或多种的组合；以及R2、R3选自氢、C1-C3烷基、C1-C2烷基嘧啶基、C1-C2烷基环戊二烯基、C1-C2烷基呋喃基、C1-C2烷基噻吩基、C1-C2烷基苯基、C1-C2烷基吡啶基，其中，所述C1-C2烷基苯基中的苯基和所述C1-C2烷基吡啶基中的吡啶基是未取代的或用羟基、乙酯基、C1-C2烷氧基、苄氧基中的一个或多个基团取代的苯基和吡啶基。Wherein, R 1 is selected from one or more combinations of hydrogen, acetyl, benzoyl, C 1 -C 2 alkyl, phenyl, phenylalkyl; and R 2 and R 3 are selected from hydrogen, C 1 -C 3 alkyl, C 1 -C 2 alkylpyrimidinyl, C 1 -C 2 alkylcyclopentadienyl, C 1 -C 2 alkylfuryl, C 1 -C 2 alkylthienyl, C 1 -C 2 alkylphenyl, C 1 -C 2 alkylpyridyl, wherein, the phenyl in the C 1 -C 2 alkylphenyl and the C 1 -C 2 alkylpyridyl The pyridyl group is phenyl and pyridyl which are unsubstituted or substituted with one or more groups in hydroxyl, ethyl carboxy, C 1 -C 2 alkoxy, benzyloxy.
丙酰胺类化合物选自以下化学式所示的化合物中的一种或多种：Propionamide compounds are selected from one or more of the compounds shown in the following chemical formulas:
本发明还提供了一种治疗与肠道菌群紊乱相关的疾病的药物，该药物包括具有上述结构通式的丙酰胺类化合物、丙酰胺类化合物在药学上可接受的盐、酯、水合物或它们的组合以及辅料。The present invention also provides a medicament for treating diseases related to intestinal flora disturbance, the medicament includes the propionamide compound having the above general structural formula, the pharmaceutically acceptable salt, ester and hydrate of the propionamide compound Or their combination and accessories.
在本发明中，使用的试验材料及其来源包括：匹格列酮piogitazone(ACTOS)，为sigma公司产品；高糖高脂饲料，为丰硕实验仪器有限公司产品；长寿花玉米油，为山东三星玉米科技产业有限公司产品；Wistar大鼠，由中国人民解放军军事医学科学院试验动物中心和北京维通利华实验动物技术有限公司提供；链脲佐菌素(STZ)，购自大连美仑公司；以及丙酰胺类化合物，来自天津国际生物医药联合研究院高通量药物筛选中心。In the present invention, the test materials used and their sources include: piogitazone (ACTOS), a product of sigma; high-sugar and high-fat feed, a product of Fengshuo Experimental Instrument Co., Ltd.; Changshouhua corn oil, a product of Shandong Sanxing Products from Corn Science and Technology Industry Co., Ltd.; Wistar rats, provided by the Experimental Animal Center of the Academy of Military Medical Sciences of the Chinese People's Liberation Army and Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.; streptozotocin (STZ), purchased from Dalian Meilun Company; And propionamide compounds, from the High-throughput Drug Screening Center of Tianjin International Joint Research Institute of Biomedicine.
采用II型糖尿病动物模型对丙酰胺类化合物进行药效检测Drug efficacy testing of propionamide compounds using type II diabetes animal model
实验步骤：Experimental steps:
A.大鼠II型糖尿病模型的建立：利用高糖高脂饮食联合链脲佐菌素(STZ)诱发大鼠产生II型糖尿病。阴性对照组喂食标准饲料，仅注射柠檬酸缓冲液。实验组喂食高脂饲料(20％蔗糖、10％猪油、10％蛋黄粉、1.5％胆固醇、0.2％胆酸、58.3％标准饲料)，喂养2周后，腹腔注射STZ(40mg/kg，用0.1M无菌柠檬酸缓冲液pH 4.5配制，0.2μM微孔滤膜过滤)。STZ注射两天后，尾静脉取血测空腹血糖(测血糖前隔夜禁食，用罗氏血糖仪进行血糖测定)。空腹血糖高于16.89mmol/L判定为II型糖尿病。造模成功的II型糖尿病大鼠随机分组，每组5只，分别为模型组(未给药)、丙酰胺类化合物组(分别给予不同的丙酰胺类化合物，30mg/kg/天)，其中，丙酰胺类化合物组每天灌胃给药，给药4周。A. Establishment of type II diabetes model in rats: high-sugar and high-fat diet combined with streptozotocin (STZ) was used to induce type II diabetes in rats. The negative control group was fed with standard diet and only injected with citrate buffer. The experimental group was fed with high-fat feed (20% sucrose, 10% lard, 10% egg yolk powder, 1.5% cholesterol, 0.2% cholic acid, 58.3% standard feed), and after 2 weeks of feeding, intraperitoneal injection of STZ (40mg/kg, with 0.1M sterile citric acid buffer pH 4.5 preparation, 0.2μM microporous membrane filtration). Two days after STZ injection, blood was taken from the tail vein to measure fasting blood glucose (fasting overnight before blood glucose measurement, blood glucose measurement was performed with a Roche blood glucose meter). Fasting blood glucose higher than 16.89mmol/L was judged as type II diabetes. Successfully modeled type II diabetic rats were divided into random groups, 5 in each group, respectively model group (no administration), propionamide compound group (respectively given different propionamide compounds, 30mg/kg/day), wherein , the propionamide compound group was intragastrically administered every day for 4 weeks.
B.大鼠血清中TG(甘油三酯)、TC(总胆固醇)水平：给药4周后处死大鼠，心脏取血及收集新鲜粪便。利用ELISA试剂盒检测上述各项参数。B. Levels of TG (triglyceride) and TC (total cholesterol) in serum of rats: the rats were sacrificed after 4 weeks of administration, blood was collected from the heart and fresh feces were collected. ELISA kits were used to detect the above parameters.
C.实验快结束时，取各组大鼠的粪便，进行16s rRNA肠道菌群测序，观察给药后肠道菌群变化。C. At the end of the experiment, the feces of the rats in each group were taken, and the 16s rRNA intestinal flora was sequenced to observe the changes of the intestinal flora after administration.
结果如下表所示，表1为药物对拟杆菌门/厚壁菌门比例(B/F)、产丁酸盐菌含量的改善作用，其中，所注射的药物中丙酰胺类化合物的浓度为30mg/kg；表2为药物对肠道菌群紊乱的改善作用，其中，所注射的药物中丙酰胺类化合物浓度为30mg/kg，SCFA表示短链脂肪酸；表3为药物对II型糖尿病的治疗效果，其中，所注射的药物中丙酰胺类化合物的浓度为30mg/kg，FSG表示空腹血糖，TC表示总胆固醇，TG表示甘油三酯。The results are shown in the following table. Table 1 shows the improvement effect of the medicine on the Bacteroidetes/Firmicutes ratio (B/F) and the content of butyrate-producing bacteria. Wherein, the concentration of propionamides in the injected medicine is 30mg/kg; Table 2 shows the improvement effect of the drug on intestinal flora disorder, wherein the concentration of propionamides in the injected drug is 30mg/kg, and SCFA means short-chain fatty acid; Table 3 shows the effect of the drug on type II diabetes Therapeutic effect, wherein the concentration of propionamide compound in the injected drug is 30 mg/kg, FSG means fasting blood glucose, TC means total cholesterol, and TG means triglyceride.
表1Table 1
表2Table 2
表3table 3
实验结果：Experimental results:
如表1所示，给药4周后，对糖尿病大鼠粪便菌群测序结果进行分析。门水平物种丰度层面，糖尿病模型组拟杆菌门/厚壁菌门比例(B/F)显著升高，产丁酸菌含量降低，给药上述丙酰胺类化合物后，拟杆菌门/厚壁菌门比例均有不同程度的降低，同时产丁酸菌的含量均有不同程度的提高。As shown in Table 1, after 4 weeks of administration, the sequencing results of fecal flora of diabetic rats were analyzed. At the level of species abundance at the phylum level, the proportion of Bacteroides/Firmicutes (B/F) in the diabetes model group was significantly increased, and the content of butyrate-producing bacteria was decreased. The proportion of bacterial phyla decreased to varying degrees, while the content of butyric acid-producing bacteria increased to varying degrees.
利用气相色谱测定粪便中短链脂肪酸(SCFA)含量，如表2所示，模型组SCFA显著降低，而给药上述丙酰胺类化合物后，各组粪便中检测出的短链脂肪酸含量，尤其是丁酸的含量均有不同程度的升高。Utilize gas chromatography to measure short-chain fatty acid (SCFA) content in feces, as shown in Table 2, model group SCFA significantly reduces, and after administering above-mentioned propionamide compound, the short-chain fatty acid content detected in each group feces, especially The content of butyric acid increased to varying degrees.
从表3可以看出，模型组的FSG、TC、TG的含量相对较高，而给药上述丙酰胺类化合物后，FSG、TC、TG的含量均有不同程度的下降。It can be seen from Table 3 that the contents of FSG, TC, and TG in the model group were relatively high, but after administration of the above-mentioned propionamide compounds, the contents of FSG, TC, and TG all decreased to varying degrees.
综上所述，本发明所提供的丙酰胺类化合物通过调节肠道菌群组成，可以有效地改善肠道菌群紊乱的状况，提高肠道中短链脂肪酸含量，尤其是肠道中丁酸的含量，同时可以降低空腹血糖，并降低血糖及血清中甘油三酯(TG)、总胆固醇(TC)的含量，进而用于治疗与肠道菌群紊乱相关的疾病。In summary, the propionamide compounds provided by the present invention can effectively improve the disordered intestinal flora and increase the content of short-chain fatty acids in the intestinal tract, especially the content of butyric acid in the intestinal tract, by regulating the composition of the intestinal flora. At the same time, it can reduce fasting blood sugar, lower blood sugar and serum triglyceride (TG), total cholesterol (TC) content, and then be used to treat diseases related to intestinal flora disturbance.
以上仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。The above are only preferred embodiments of the present invention, and are not intended to limit the present invention. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present invention shall be included in the protection scope of the present invention within.
Claims (6)
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| CN105287483A (en) * | 2014-06-05 | 2016-02-03 | 天津国际生物医药联合研究院 | Application of propionamide compounds |
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