CN113750088B - Application of heterocyclic compound in preparation of medicine for treating ulcerative colitis - Google Patents
Application of heterocyclic compound in preparation of medicine for treating ulcerative colitis Download PDFInfo
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- CN113750088B CN113750088B CN202111088303.XA CN202111088303A CN113750088B CN 113750088 B CN113750088 B CN 113750088B CN 202111088303 A CN202111088303 A CN 202111088303A CN 113750088 B CN113750088 B CN 113750088B
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/415—1,2-Diazoles
- A61K31/4155—1,2-Diazoles non condensed and containing further heterocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Pain & Pain Management (AREA)
- Rheumatology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses application of a heterocyclic compound in preparation of a medicament for treating ulcerative colitis. The heterocyclic compound of the invention can effectively treat and relieve symptoms of ulcerative colitis such as weight loss, diarrhea, hematochezia and the like, inhibit the production of inflammatory mediators such as TNF-alpha, IL-6 or IL-1 beta and the like, regulate intestinal flora composition and promote flora recovery, and can further protect mucosal barrier and improve DSS-induced colon injury. Therefore, the heterocyclic compound can be used as an effective therapeutic drug for ulcerative colitis, and can be prepared into various dosage forms or pharmaceutical compositions for treating ulcerative colitis.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of a heterocyclic compound in preparation of a medicament for treating ulcerative colitis.
Background
Ulcerative colitis (Ulcerative Colitis, UC) is a major type of inflammatory bowel disease (inflammatory bowel disease, IBD), one of the refractory diseases in the digestive system, with a high incidence worldwide, especially in young and middle-aged 30-40 years and brain workers as the major morbidity population. UC is typically clinically manifested as symptoms such as hematochezia, diarrhea, abdominal pain, tenesmus, fever and the like, is difficult to cure, has long recurrence and disease course, finally leads to increased risk of colorectal cancer, seriously influences the work and life of patients, and reduces the life quality of the patients.
At present, the pathogenesis of UC is not well defined, and it is mainly believed that its occurrence and development are caused by a variety of factors and interactions, such as inducible nitric oxide synthase, COX2, apoptosis, cytokines and diet. The inflammatory immune factors play a key role in the development of ulcerative colitis, and are mainly characterized in that a large number of inflammatory cells infiltrate colon tissues, abnormal IgM and IgG are increased in humoral immunity, and the balance of pro-inflammatory cytokines and anti-inflammatory cytokines is disregulated, so that the body develops towards the direction of pro-inflammatory action, and serious pathological manifestations are caused.
Cure of UC is very difficult, and currently the main therapeutic measures for UC include both drug therapy and surgical therapy, but there are many shortcomings in the existing therapeutic methods. UC is generally considered incurable as a chronic disease, and at present, few patients who undergo surgery and resect diseased colorectal may be cured, but the quality of life after curing is seriously affected. Thus, the main goal of clinical treatment is to induce and maintain remission while preventing the occurrence of undesirable consequences such as colorectal resection and cancer caused by ulcerative colitis. The current therapeutic drugs mainly include: 5-aminosalicylic acids such as mesalamine, steroid hormones, azathioprine, biological agents (infliximab, vedolizumab, etc.), tacrolimus, and the like. In terms of induction relief, the primary drug for mild UC is mesalamine; for moderate to severe UC or mild ulcerative colitis that is unresponsive to mesalamine, the induction remission treatment may take the form of a glucocorticoid; thiopurine and anti-TNF-alpha preparations, tacrolimus and the like are generally employed for severe UC and for mild and moderate UC that is non-responsive to hormones.
However, no medicine capable of effectively curing ulcerative colon exists in clinic so far, and the main problems are that partial patients fail to be treated due to unresponsiveness or unsustainable responsiveness to the medicine, colorectal resection treatment is needed, the patients with larger side effects of the medicine cannot tolerate the medicine, the patient has poor compliance, the economic burden of the patient is heavy, and the treatment cannot be maintained. Therefore, there is a great need to develop new drugs for treating ulcerative colitis to meet the urgent clinical demands.
Disclosure of Invention
The present invention aims to solve at least one of the technical problems in the prior art described above. Therefore, the invention provides application of a heterocyclic compound in preparing a medicament for treating ulcerative colitis, wherein the structural formula of the heterocyclic compound is shown as a formula (I):
According to a specific embodiment of the invention, it has at least the following advantageous effects: the heterocyclic compound disclosed by the invention can effectively treat and relieve the symptoms of ulcerative colitis: including weight loss, diarrhea, and hematochezia; can inhibit the production of inflammatory mediators: inflammatory molecules including TNF-alpha, IL-6 or IL-1 beta, etc., to alleviate inflammatory symptoms and intestinal symptoms; can regulate intestinal flora composition, promote flora recovery, and regulate intestinal health; can further protect the mucosal barrier and repair colon lesions; therefore, the heterocyclic compound can be used as an effective therapeutic agent for ulcerative colitis.
In some embodiments of the invention, the treating ulcerative colitis comprises alleviating at least one of the symptoms of ulcerative colitis of weight loss, diarrhea, and hematochezia.
In some embodiments of the invention, the heterocyclic compound is capable of inhibiting inflammatory mediators.
In some preferred embodiments of the invention, the inflammatory mediator comprises at least one of TNF- α, IL-6 or IL-1β.
In some embodiments of the invention, the heterocyclic compound is capable of protecting the colonic mucosal barrier and/or repairing DSS-induced colonic lesions.
In some embodiments of the invention, the heterocyclic compound is capable of modulating gut flora composition and/or promoting flora recovery.
In some embodiments of the invention, the pharmaceutical dosage form is a capsule, tablet, pill, granule, oral liquid formulation, or injection.
In some embodiments of the invention, the medicament further comprises a pharmaceutically acceptable carrier.
In some preferred embodiments of the invention, the pharmaceutically acceptable carrier refers to a pharmaceutical carrier conventional in the pharmaceutical arts, such as: diluents, excipients such as water, etc., fillers such as starch, sucrose, etc.; binders such as cellulose derivatives, alginates, gelatin and polyvinylpyrrolidone; humectants such as glycerol; disintegrants such as agar, calcium carbonate and sodium bicarbonate; absorption promoters such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and soap clay; lubricants such as talc, calcium stearate and magnesium stearate, polyethylene glycol, and the like. Other adjuvants such as sweetener, flavoring agent, etc. can also be added into the composition.
In some embodiments of the invention, the heterocyclic compound is administered in an amount of 10mg to 20mg per kg of body weight of the subject.
By "pharmaceutically acceptable carrier" is meant a diluent, adjuvant, excipient or vehicle with which the active ingredient is administered, and which is suitable for contacting the tissues of humans and/or other animals without undue toxicity, irritation, allergic response, complications, or other problem commensurate with a reasonable benefit/risk ratio, within the scope of sound medical judgment.
In the present invention, the term "treatment" is used to include alleviation, inhibition or amelioration of symptoms or conditions of a disease; inhibiting the generation of complications: improving or preventing underlying metabolic syndrome; inhibiting the occurrence of a disease or condition, such as controlling the progression of a disease or condition; alleviating a disease or symptom; causing the disease or symptom to subside; alleviating complications caused by diseases or symptoms, or preventing or treating signs caused by diseases or symptoms. As used herein, administration may result in an improvement in a disease, symptom, or condition, particularly an improvement in severity, a delay in onset, a slowing in progression, or a reduction in duration of the condition.
Drawings
The invention is further described with reference to the accompanying drawings and examples, in which:
FIG. 1 is a graph showing the effect of BE-7-131 on DSS-induced body weight of mice in an embodiment of the present invention;
FIG. 2 is a graph showing the effect of BE-7-131 on fecal trait scores of DSS-induced mice in an embodiment of the present invention;
FIG. 3 is a graph showing the effect of BE-7-131 on the average fecal blood fraction of DSS-induced mice in an embodiment of the present invention;
FIG. 4 is a graph showing the effect of BE-7-131 on DAI values in DSS-induced mice in accordance with an embodiment of the present invention;
FIG. 5 is a graph showing the effect of BE-7-131 on DSS-induced colon length in mice in accordance with an embodiment of the present invention;
FIG. 6 is a graph showing the staining of DSS-induced colon HE and AB-PAS by BE-7-131 in an embodiment of the present invention;
FIG. 7 is a graph showing the effect of BE-7-131 on the pathological histological scoring of the colon of DSS-induced mice in an embodiment of the present invention;
FIG. 8 is a graph showing the effect of BE-7-131 on TNF- α, IL-6, IL-1β in DSS-induced colon tissue of mice in accordance with an embodiment of the present invention;
FIG. 9 is a schematic diagram showing the effect of BE-7-131 on the structure of DSS-induced intestinal flora in mice according to an embodiment of the present invention;
FIG. 10 is a schematic diagram showing the analysis of diversity of intestinal flora alpha of mice induced by BE-7-131 on DSS in the examples of the present invention;
FIG. 11 is a schematic diagram showing PCoA (2D) analysis of DSS-induced intestinal flora of mice by BE-7-131 in the present embodiment;
FIG. 12 is a schematic diagram showing the analysis of the species variability of the intestinal flora of mice induced by BE-7-131 in the present invention.
Detailed Description
The conception and the technical effects produced by the present invention will be clearly and completely described in conjunction with the embodiments below to fully understand the objects, features and effects of the present invention. It is apparent that the described embodiments are only some embodiments of the present invention, but not all embodiments, and that other embodiments obtained by those skilled in the art without inventive effort are within the scope of the present invention based on the embodiments of the present invention. The test methods used in the examples are conventional methods unless otherwise specified; the materials, reagents and the like used, unless otherwise specified, are those commercially available.
In the following examples, the heterocyclic compound used was BE-7-131 having the formula: c 16H23N3O2 S, the structural formula is as follows:
Examples: investigation of the Effect of BE-7-131 on ulcerative colitis in mice
1. Grouping and dosing regimen for animals
C57BL/6 mice, male, 6 weeks old, 20+ -2 g mass, SPF grade, purchased from navy specialty medical center animal center. After 5 days of adaptive feeding, the mice were randomly divided into 4 groups of 10 mice each, control group, model group, BE-7-131 treated group (500 mg/kg), positive drug group (mesalamine 600 mg/kg) with SPSS software. Establishing a ulcer model by adopting a DSS induction method: the mice were free to drink 3% dss solution for seven consecutive days, except for the control group. From the first day of molding, the administration is continuous, once a day, for nine days, the BE-7-131 treatment group is given by gastric lavage 10mg/kgBE-7-131 daily, the positive drug group is given by gastric lavage 600mg/kg, and the control group and the model group are given by gastric lavage with equal volumes of distilled water.
For the construction of the colitis model, dextran sodium sulfate salt (Dextran Sulfate Sodium Salt, DSS) colitis (ulcerative colitis, UC) model is most widely used.
2. Experimental method and data processing
2.1 Disease Activity Index (DAI) scoring
Mice were observed daily and recorded for body weight, diet, stool consistency, and hematochezia. Scoring according to DAI scoring criteria, wherein the scoring criteria for fecal trait scores are: the normal score is 0, the score is 1 between the normal score and the loose score, the loose score is 2, the score is 3 between the loose score and the loose score, and the loose score is 4; the scoring criteria for the occult blood level score were: the non-hematochezia is 0 score, 1 score between non-hematochezia and occult blood, the occult blood positive is 2 score, 3 score between occult blood and macroscopic hematochezia, the macroscopic hematochezia is 4 score, dai= (mass reduction rate score + fecal character score + occult blood degree score)/3.
2.2 Colon Length
On day 9 of the experiment, each group of mice was sacrificed by cervical dislocation, the whole colon tissue was isolated, and the colon length of each group of mice was measured with a ruler for statistical analysis.
2.3 Colonography histopathological observations and scoring
The normal paraffin embedding, slicing, HE and AB-PAS staining of the colon tissue of each group of mice was taken. Referring to the standard blind scoring of Boirivant and the like, according to the forms of epithelial cells, the infiltration conditions of inflammatory cells and the like, 2 pathologists read the tablets in double blind mode respectively, and the results are averaged for scoring.
2.4 Detection of inflammatory factors in colon tissue
200Mg of colon tissue is taken, 2mL of physiological saline is added for homogenization, the supernatant is taken after centrifugation for 10min at 4000r/min, and the IL-1 beta, IL-6 and TNF-alpha contents are determined according to the steps of a kit instruction book.
2.5 Fecal sample collection and treatment
On the 9 th day of the experiment, the mice are sacrificed, the abdominal cavity is dissected, the complete colon tissue from the anus to the tail end of the cecum is taken out and placed on an ice tray, the colon tissue is dissected longitudinally along the mesentery, fecal particles (2-3 particles) in the colon are taken out and collected in a freezing tube, and the frozen tube is immediately placed in liquid nitrogen for preservation, and the DNA of bacteria in the fecal is extracted.
2.6 Extraction and sequencing of bacterial DNA in feces
2.6.1DNA extraction and detection
Total DNA in the feces was extracted using a DNA extraction kit, DNA concentration and purity were detected using NanoDrop2000, and DNA extraction quality was detected using 1% agarose gel electrophoresis.
2.6.2 PCR amplification and product recovery
PCR amplification was performed using the V3-V4 variable region sequence of the bacterial 16S rRNA gene as a target and 338F-806R with the barcode sequence as a primer to obtain a PCR product, the PCR product was recovered using 2% agarose gel, purified using AxyPrep DNA Gel Extraction Kit (Axygen Biosciences, USA), eluted with Tris-HCl, and detected by 2% agarose electrophoresis.
2.6.3 Fluorescent quantitation
Referring to the result of the preliminary quantification by electrophoresis, detection and quantification were performed using QuantiFluorTM-ST (Promega, USA). Then mixing according to the sequencing requirement of each sample in a corresponding proportion.
2.6.4 Sequencing analysis
Samples were sequenced on the Illumina NovaSeq platform as suggested by the manufacturer and supplied by LC-Bio. The paired-end sequences were assigned to the samples based on their unique barcodes, and the pool-built introduced barcode and primer sequences were removed. And combining the matched end reading by using FLASH. According to fqtrim (v 0.94), the raw read data is quality filtered under specific filtering conditions to obtain a clean tag of high quality. The chimeric sequences were filtered using Vsearch software (v2.3.4). And demodulating by using DADA2 to obtain a feature table and a feature sequence. The diversity and diversity were calculated by normalizing to the same random sequence. The feature abundance was then normalized with the relative abundance of each sample according to the SILVA (release 132) classifier. Alpha diversity was used to analyze the complexity of sample species diversity by 5 indices, including Chao1, observedspecies, goodscoverage, shannon, simpson (these indices were calculated by QIIME 2). Beta diversity was calculated by QIIME2, R packet plotted. Sequence alignment was performed using Blast, and each representative sequence was annotated with the feature sequence using the SILVA database. The results were mapped and sequence analyzed by using R-packets (v3.5.2).
2.7 Statistical data processing
The data analysis uses SPSS 22.0 statistical software package, normal distribution continuity data to represent, multiple sample mean comparisons and variance analysis was used by the variance analysis.
3. Results and discussion
3.1 Index of general Condition and disease Activity changes in mice
The mice of each group were analyzed for body mass, food intake, and water intake. The results are shown in FIG. 1, in which daily weight changes are recorded in the control group, the model group, the positive control group and the BE-7-131 treated group, respectively, and the abscissa indicates the number of days and the ordinate indicates the percentage of weight change (WEIGHT CHANGE (%)). The mice in the control group have normal food intake and water intake, and the quality of the mice is in an ascending trend; after the model group mice start moulding, the food intake and water intake are reduced, and the weight has a descending trend from the 4 th day of moulding, and has statistical significance compared with the control group. The mice in the BE-7-131 treated group also had a decreased body mass, but from day 6, the difference was significant compared to the model group, and the effect was comparable to that of the positive drug group.
3.2 Fecal viscosity and hematochezia Condition
The results of fecal viscosity and hematocrit are shown in fig. 2-4, wherein fig. 2 shows fecal trait scores of mice of different groups, fig. 3 shows right graphs of mice of different groups as average fecal blood score (mean stool blood score), and fig. 4 shows DAI values of mice of different groups. The number of times of defecation of the model group mice after the third day is increased, and the conditions of soft stool, watery stool and the like appear; the conditions of occult blood and bloody stool appear after the fourth day; the water sample and blood are aggravated after the fifth day, and the defecation is difficult. After the positive drug group and the BE-7-131 treatment group are given to the mice in a dry mode, the activities of the mice are increased, the hair condition is improved, and on the 8 th day, compared with the model group, the BE-7-131 dry mode is given, so that the fecal viscosity and the hematochezia condition are improved.
3.3 General conditions of the colon and pathological observations
Whole colon tissue was isolated, the colon length of each group of mice was measured with a ruler, and relevant statistical analysis was performed. As shown in FIG. 5, the control group had the longest colon length, the model group had the shortest colon length, and the positive drug group and the BE-7-131 treated group were significantly different from the control group (P < 0.001); the BE-7-131 treated group had a significantly longer colon length than the model group.
Colon lesions were HE stained and AB-PAS stained and scored for histopathology. . The staining result is shown in figure 6, the intestinal glands of the mucous membrane layer of the mice in the control group are closely arranged, the intestinal gland epithelial cells are normal in morphology, and the structure is normal without defects; colon of the model group mice can see the loss of intestinal glands and epithelial cells, has obvious defects, and is accompanied by massive inflammatory cell infiltration, and inflammation invades submucosa and myometrium; after the intervention of the positive medicine group and the BE-7-131 treatment group, inflammatory cell infiltration is reduced, and intestinal mucosa epithelial cell integrity is improved. Pathological tissue scoring results as shown in fig. 7, the model group lesion scores were significantly increased (P < 0.001) compared to the control group. Compared with the model group, the pathological score of mice in the BE-7-131 treatment group is significantly reduced (P < 0.01). The result shows that BE-7-131 can improve DSS-induced colon inflammation of mice and has the effect of relieving local lesion damage of colon of the mice with the diabrosis.
3.4 Detection results of inflammatory factors of colon tissue
Inflammatory factors IL-1 beta, IL-6, TNF-alpha levels were measured in colon tissue from each group of mice. The results are shown in FIG. 8, in which IL-1β, IL-6, TNF- α levels were minimal in colon tissues of control mice; the colon tissue of the model group has the highest IL-1 beta, IL-6 and TNF-alpha levels, and the level is obviously increased (P is less than 0.001) compared with the control group; IL-1 beta, IL-6, TNF-alpha levels in colon tissue were also significantly reduced (P < 0.001) in the positive and BE-7-131 treated groups compared to the model group. The results show that BE-7-131 can inhibit the expression of IL-1 beta, IL-6 and TNF-alpha in the local colon tissue of ulcerative colitis mice.
3.5 Colonic intestinal flora species annotation
Based on the absolute abundance of OUT and the annotation information, statistical analysis was performed on the ratio of the number of sequences to the total number of sequences at the gate and genus levels for each sample, and the species composition differences at the gate and genus levels for each group were determined. FIG. 9 shows a block diagram of intestinal flora of different groups of mice. In the control group, the flora profile reflects the composition of the intestinal flora of normal mice, with Bacteroidetes (79.26%), firmicutes (16.40%), proteobacteria (1.01%), epsilonbacteraeota (0.63%) being the 4 major bacterial phylum. Muribaculaceae-unclassified, alloprevotella, muribaculum, alistipes is a control group mainly belonging to the horizontal constitution. In the model group, the flora spectrum reflects the composition of the intestinal flora of mice in the case of disease, with Firmicutes (60.23%), epsilonbacteraeota (15.55%), bacteroidetes (13.91%), and Proteobacteria (8.44%) being the 4 major bacterial phylum. The ratio of Firmicutes, epsilonbacteraeota to Proteobacteria increased and the ratio of Bacteroidetes decreased compared to the control. Bacteroidetes (56.64%), firmicutes (36.23%), proteobacteria (2.28%) and Epsilonbacteraeota (2.18%) were 4 major bacterial families in the BE-7-131 treated group, with the ratios of both Bacteroidetes and Firmicutes bacteria being similar to the placebo group, with Patescibacteria first appearing in the main species suggesting that this bacteria might BE involved in the action of the BE-7-131 treated group in alleviating ulcerative colitis.
3.6 Analysis of species diversity of colonic intestinal flora
By analyzing the diversity of the individual samples (alpha analysis), the species abundance and diversity of the microbial community can be reflected, and the evaluation is carried out by adopting two indexes, wherein Chao1 reflects the species abundance in the samples, and the ratio condition (uniformity) of each species is not considered; simpson reflects the abundance and uniformity of species, and the results are shown in FIG. 10. The dry prognosis of the BE-7-131 treatment group was found not to improve the species abundance and diversity of the microflora within the intestinal flora. Beta diversity is an index for measuring the similarity of flora compositions among different samples, and the species distance among the samples can be reflected by weighted PCoA analysis, and the analysis result is shown in figure 11. The model group was farther from the control group, while the positive drug group and the BE-7-131 treatment group were closer to the control group than the model group. Thus, after treatment with BE-7-131, the intestinal flora content was altered to more closely resemble the structure of the normal intestinal flora.
3.7 Analysis of colonic intestinal flora species differentiation
The LeFSe analysis was further used to compare the differences in gut flora abundance at the level of each species classification caused by the 3% dss induction treatment. LeFSe analysis is a combination of non-parametric analysis and linear discriminant analysis, is suitable for flora abundance difference analysis, and uses LDA > 4 and P < 0.5 as screening criteria to determine the difference microorganisms in each group. The experimental result shows that p_ Bacteroidetes, f _ Muribaculaceae, g _ Alloprevotella is the main significant difference bacterium of the control group; f_ Helicobacteraceae, p _ Epsilonbacteraeota, c _ Campylobacteria, f _ Ruminococcaceae is the main difference bacterium of the model group; f_ Prevotellaceae, g _ Alloprevotella, g _ Alloprevotella _ unclassified, g _Akkermansia is the main differentiating bacterium of the BE-7-131 treatment group. The results are shown in FIG. 12, and the experimental results show that the ratio of Bacteroidetes is significantly increased, the ratio of Firmicutes and Proteobacteria is significantly reduced, the ratio of probiotics such as Bacteroidetes, alloprevotella is increased, and the change of flora structure and components can play a role in the incidence of ulcerative colitis.
The effect of the invention was evaluated by establishing a DSS-induced acute mouse colitis model. The animal model is commonly used for researching pathological mechanism of ulcerative colitis and evaluating curative effect of medicines. By means of DSS-induced colitis mice model, we examined the general body mass characteristics, DAI score, colon length, colon histopathological score of mice. The experimental results show that the heterocyclic compound can effectively treat and relieve the symptoms of ulcerative colitis: including weight loss, diarrhea, and hematochezia; can inhibit the production of inflammatory mediators: inflammatory molecules including TNF-alpha, IL-6 or IL-1 beta, etc., to alleviate inflammatory symptoms; can regulate intestinal flora composition, promote flora recovery, and regulate intestinal health; and the ability to further protect the mucosal barrier and repair colon lesions. Therefore, the heterocyclic compound can be used as an effective therapeutic drug for ulcerative colitis, and can be prepared into various dosage forms or pharmaceutical compositions for treating ulcerative colitis.
The embodiments of the present invention have been described in detail with reference to the accompanying drawings, but the present invention is not limited to the above embodiments, and various changes can be made within the knowledge of one of ordinary skill in the art without departing from the spirit of the present invention. Furthermore, embodiments of the invention and features of the embodiments may be combined with each other without conflict.
Claims (3)
1. The application of a heterocyclic compound in preparing a medicament for treating ulcerative colitis is characterized in that the structural formula of the heterocyclic compound is shown as a formula (I):
formula (I).
2. The use according to claim 1, wherein the medicament is in the form of a capsule, tablet, pill, granule, oral liquid or injection.
3. The use of claim 1, wherein the medicament further comprises a pharmaceutically acceptable carrier.
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