CN113577063A - Application of compound in preparation of medicine for treating inflammatory bowel disease - Google Patents
Application of compound in preparation of medicine for treating inflammatory bowel disease Download PDFInfo
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- CN113577063A CN113577063A CN202111008120.2A CN202111008120A CN113577063A CN 113577063 A CN113577063 A CN 113577063A CN 202111008120 A CN202111008120 A CN 202111008120A CN 113577063 A CN113577063 A CN 113577063A
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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
- A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
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- 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
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- 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
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- 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]
Abstract
The invention relates to the field of medicines, and particularly discloses application of a compound in preparation of a medicine for treating inflammatory bowel disease, wherein the structural formula of the compound is shown as a formula (I). The invention discovers for the first time that the compound (LH031) has the functions of reducing the release of inflammatory factors and promoting the growth of inflammatory model cells, has obvious therapeutic action on inflammatory bowel diseases (ulcerative colitis and Crohn's disease), has better or no better effect than the prior therapeutic drug-celecoxib, can be used for developing novel drugs for treating inflammatory bowel diseases, can be prepared into dosage forms of oral agents, injection and the like, is simple and convenient to use, and has important medical prospect and economic value.
Description
Technical Field
The invention relates to the field of medicines, in particular to application of a compound in preparing a medicine for treating inflammatory bowel diseases.
Background
Inflammatory Bowel Disease (IBD), an idiopathic inflammatory bowel disease affecting the ileum, rectum, and colon. The clinical manifestations are diarrhea, abdominal pain and even bloody stool. The disease includes Ulcerative Colitis (UC) and Crohn's Disease (CD). Ulcerative colitis is a continuous inflammation of the mucosal layer and submucosa of the colon, the disease usually affects the rectum first and gradually spreads to the whole colon, Crohn's disease can affect the whole digestive tract and is a discontinuous whole-layer inflammation, and the most frequently affected parts are the terminal ileum, colon and perianal.
At present, the medicines for treating the inflammatory bowel diseases comprise an aminosalicylic acid preparation, glucocorticoid and an immunosuppressant, wherein the aminosalicylic acid preparation has a certain curative effect on controlling the enteritis active period of light and medium patients, is suitable for patients with pathological changes limited in colon, and has a narrow application range; glucocorticoids are best suited for active patients, but are prone to glucocorticoid dependence; the immunosuppressant is mainly used for patients with poor glucocorticoid treatment effect; the above-mentioned therapeutic agents are limited to some extent, and therefore, there is a high necessity for a new agent for treating inflammatory bowel disease.
Disclosure of Invention
The present invention aims to overcome the disadvantages of the prior art and to provide the use of a compound for the manufacture of a medicament for the treatment of inflammatory bowel disease.
In order to achieve the purpose, the invention adopts the technical scheme that:
the invention provides application of a compound in preparing a medicament for treating inflammatory bowel disease, wherein the structural formula of the compound is shown as the formula (I):
said compounds are disclosed in patent ZL200780006529 (application No: CN200780006529.2, title of the invention: indolopyridine as Eg5 kinesin modulator), are inhibitors of the kinesin Eg5 and can be used for the treatment of cell proliferative diseases such as tumors. The above compound is named LH 031.
As a preferred embodiment of the use according to the invention, said inflammatory bowel disease comprises ulcerative colitis and Crohn's disease.
As a preferred embodiment of the use according to the invention, the compound reduces the content of inflammatory factors in model cells of inflammation.
More preferably, the inflammatory factor comprises TNF- α or IL-6. Here, the inflammatory factor is not limited thereto, and the inflammatory factor includes inflammatory factors known to those skilled in the art.
Experiments show that the content of TNF-alpha or IL-6 secreted by inflammatory model cells treated by LH031 is remarkably reduced (P is less than 0.05 or 0.01), which indicates that LH031 has the function of reducing the release of inflammatory factors.
As a preferred embodiment of the use according to the invention, the compound promotes the growth of inflammatory model cells.
A CCK-8 method is adopted to detect the influence of LH031 on the growth of inflammatory model cells, and test results show that the cell viability after LH031 treatment is remarkably increased, which shows that LH031 can promote the growth of inflammatory model cells and increase the viability of inflammatory model cells.
As a preferred embodiment of the use of the present invention, the inflammation model cells include an inflammation model cell constructed by LPS-induced macrophage RAW 264.7.
Macrophage RAW264.7 was cultured in high-glucose DMEM medium containing 10% FBS and 1% diabody.
As a preferable embodiment of the application of the invention, the dosage form of the medicament comprises an oral preparation or an injection preparation.
As a preferable embodiment of the application of the invention, the dosage of the oral preparation is 10-40 mg/kg.
As a preferred embodiment of the use according to the invention, the oral dosage is 40 mg/kg.
Compared with the prior art, the invention has the following beneficial effects:
the invention discovers for the first time that the compound (LH031) has the functions of reducing the release of inflammatory factors and promoting the growth of inflammatory model cells, has obvious therapeutic action on inflammatory bowel diseases (ulcerative colitis and Crohn's disease), has better or no better effect than the prior therapeutic drug-celecoxib, can be used for developing novel drugs for treating inflammatory bowel diseases, can be prepared into dosage forms of oral agents, injection and the like, is simple and convenient to use, and has important medical prospect and economic value.
Drawings
FIG. 1 is a graph of the effect of compound (LH031) on the viability of cells in a model of inflammation (P < 0.05;. P < 0.01. in comparison with a model control);
FIG. 2 is a graph of the effect of compound (LH031) on the release of inflammatory factors in inflammatory model cells (P < 0.05;. P < 0.01. in comparison to model control);
FIG. 3 is a graph of the effect of compound (LH031) on DAI scores in a rat model of ulcerative colitis;
FIG. 4 is a graph of the effect of compound (LH031) on CMDI scores in a rat model of ulcerative colitis;
FIG. 5 is a graph of the effect of pathological scoring on the Compound (LH031) rat model of ulcerative colitis.
Detailed Description
To better illustrate the objects, aspects and advantages of the present invention, the present invention will be further described with reference to the accompanying drawings and specific embodiments.
In the following examples, the experimental methods used were all conventional methods unless otherwise specified, and the materials, reagents and the like used were commercially available without otherwise specified.
Example 1 Effect of Compound (LH031) on cell viability in model of inflammation
The test method comprises the following steps:
1. culture of macrophage RAW264.7 cells
Recovering macrophage RAW264.7 by conventional method, standing at 37 deg.C and 5% CO2In the incubator, culture was performed with high-glucose DMEM medium containing 10% FBS and 1% double antibody. After the cells grow to 80-85% confluence, they are digested with 0.25% EDTA-trypsin solution and then passaged.
2. Molding die
The macrophage RAW264.7 cultured above grows to logarithmic phase, is digested with EDTA-trypsin solution containing 0.25%, gently blown, and added with DMEM medium containing 10% fetal calf serum to make into cell suspension, and the cell concentration is adjusted to 2 × 105Perml, inoculated into a 96-well plate at 100. mu.L per well, and then placed at 37 ℃ in 5% CO2Was cultured overnight in an incubator.
The experiment was divided into a normal control group (DMEM medium), a model control group (1. mu.g/mL LPS), an LH031 low dose group (1. mu.g/mL LPS + 1. mu.M LH031), an LH031 high dose group (1. mu.g/mL LPS + 10. mu.M LH031), and a positive control group (1. mu.g/mL LPS + 2.5. mu.M celecoxib). Adding culture medium containing corresponding medicine into each group, adding DMEM into normal control group at a concentration of 150 μ L per well, CO-culturing for 24 hr, removing original culture medium, washing with PBS for 2 times, adding 10% CCK-8-containing DMEM solution at a concentration of 100 μ L, adding 5% CO at 37 deg.C2Incubate in incubator for 2h, use microplate reader at 450nm wavelength determination of each hole OD value, calculated cell activity ═ (OD experimental group/OD control group) × 100%.
As a result: referring to FIG. 1, the cell viability of the model control group was significantly reduced compared to the normal control group (P < 0.01). Compared with the model control group, the cell viability of the low-LH 031 and high-dose groups and the positive control group is remarkably increased (P is less than 0.01), and the cell viability is better along with the increase of the LH031 dose, which indicates that LH031 can promote the growth of inflammatory model cells and increase the cell viability.
Example 2 Effect of Compound (LH031) on the Release of inflammatory factors in model cells of inflammation
The macrophage RAW264.7 cultured above grows to logarithmic phase, is digested with EDTA-trypsin solution containing 0.25%, gently blown, and added with DMEM culture medium containing 10% fetal calf serum to make into cell suspensionLiquid, adjusted to a cell concentration of 2X 105Perml, inoculated into a 96-well plate at 100. mu.L per well, and then placed at 37 ℃ in 5% CO2Was cultured overnight in an incubator. The experiment was divided into a normal control group (DMEM medium), a model control group (1. mu.g/mL LPS), an LH031 low dose group (1. mu.g/mL LPS + 1. mu.M LH031), an LH031 high dose group (1. mu.g/mL LPS + 10. mu.M LH031), and a positive control group (1. mu.g/mL LPS + 2.5. mu.M celecoxib). Adding culture medium containing corresponding medicine into each group, adding DMEM into normal control group, co-culturing 150 μ L per well for 24 hr, collecting cell supernatant of each well, and storing at-80 deg.C. TNF-alpha and IL-6 inflammation index detection is carried out according to the kit instruction.
As a result: referring to FIG. 2, TNF-. alpha.and IL-6 levels were significantly increased in the model control group compared to the normal control group (P < 0.01). Compared with the model control group, the cell secretion content of TNF-alpha and IL-6 in the LH031 low and high dose group and the positive control group is obviously reduced (P is less than 0.05 or 0.01), which indicates that LH031 has the function of reducing the release of inflammatory factors.
EXAMPLE 3 therapeutic Effect of Compound (LH031) on ulcerative colitis in rats
1. Experimental methods
Molding: female SPF-grade SD rats aged 8 weeks were randomly divided into 5 groups of 12 per group according to body weight. SD rats were continuously fed with a composition containing 3% Dextran Sodium Sulfate (DSS) for 5 days, and a rat Ulcerative Colitis (UC) model was established, and disease was monitored daily by measuring body weight.
Treatment: dosing was started on day 2 of molding and continued for 2 weeks. The administration mode, administration dose, etc. are shown in the following table.
TABLE 1
| Group of | Therapeutic agents | Mode of administration | Dosage form | Volume of administration | Frequency of administration |
| Normal control group | Physiological saline | Oral administration for gastric lavage | / | 10mL/kg | Once a day |
| Model control group | Physiological saline | Oral administration for gastric lavage | / | 10mL/kg | Once a day |
| LH031 low dose group | LH031 | Oral administration for gastric lavage | 10mg/kg | 10mL/kg | Once a day |
| LH031 medium dose group | LH031 | Oral administration for gastric lavage | 20mg/kg | 10mL/kg | Once a day |
| LH031 high dose group | LH031 | Oral administration for gastric lavage | 40mg/kg | 10mL/kg | Once a day |
Measurement indexes are as follows:
1) general state observations in rats: general conditions of rats including body mass, stool characteristics, hair gloss, mental state, irritation susceptibility, etc. were recorded, and stool bleeding was measured using a stool occult blood measurement kit (dry chemistry method). Disease activity was assessed on day 14 of molding using the DAI score. The specific scoring criteria are as follows: the body mass is not reduced to 0 minute, 1 minute is reduced by 1-5 percent, 2 minutes is reduced by 6-10 percent, 3 minutes is reduced by 11-15 percent, and 4 minutes is reduced by more than 15 percent; the stool character is normally 0 point, the softness is 2 points, and the diarrhea is 4 points; feces bleeding was negative at 0 point, +1 point, +2 points, + 3 points, and macroscopic stool at 4 points. DAI ═ 3 (body mass loss score + stool trait score + stool occult blood condition score).
2) Colonic mucosal tissue damage score: the damage of the intestinal mucosa is evaluated by adopting a Colon Mucosa Damage Index (CMDI), and the grade standard is 0, namely no damage is caused; 1 is mild hyperemia, edema, smooth surface, no erosion or ulcer; 2, congestion and edema, rough and granular mucous membrane with erosion or intestinal adhesion; 3 is high hyperemia and edema, necrosis and ulcer are formed on the surface of the mucous membrane, the maximum longitudinal diameter of the ulcer is less than 1cm, the intestinal wall is thickened or the surface is necrotic and inflammatory; 4 is ulcer maximum longitudinal diameter >1cm on 3-point basis, or total intestinal wall necrosis.
3) Histopathological examination of the colon: taking out the whole colon of the rat, washing, cutting pathological tissues about 1cm, adding 4% formaldehyde solution for fixation, and making pathological sections. HE staining was performed, and the degree of inflammation, lesion depth, destruction degree of lacuna, and inflammatory range were observed under an optical microscope and scored, respectively.
Degree of inflammation score: the non-inflammation is 0 point, the mild degree is 1 point, the moderate degree is 2 points and the severe degree is 3 points; lesion depth scoring: no lesion is 0 min, lesion involvement mucosa layer is 1 min, involvement submucosa layer is 2 min, involvement muscle layer is 3 min, involvement serous layer is 4 min; degree of crypt destruction score, no crypt destruction was 0 points, basal 1/3 crypts were destroyed to 1 point, basal 2/3 crypts were destroyed to 2 points, only intact surface epithelium was 3 points, all crypts and epithelium were destroyed to 4 points; inflammation range score: the disease is not divided into 0, the range of the disease is 1-25%, 2-26-50%, 3-51% and 4-76-100%. Colon histopathology scores were calculated as four scores.
4) Statistical analysis: experimental data were statistically processed by GraphPad Prism 7.0 biometrics software: the measured data are expressed by Mean + -SD, and analysis of variance is combined with Dunnett's multiple comparison method; pathology scoring was performed using Kruskal-Wallis rank sum test in combination with Dunnett's multiple comparisons.
2. As a result:
1) general state: after DSS treatment, model control animals showed significant symptoms of colitis, manifested as significant weight loss, diarrhea in most animals, and significant bleeding in the feces. The DAI score was significantly higher in the model control group animals compared to the normal group (P < 0.01). After 2 weeks of treatment, the DAI scores of the LH031 low dose group (3.15 + -0.85), the medium dose group (2.37 + -0.63) and the high dose group (1.86 + -0.45) were significantly reduced compared to the model control group (4.23 + -0.96), and the differences were statistically significant (P <0.01), as shown in FIG. 3, indicating that LH031 can improve the general symptoms of colitis animals dose-dependently.
2) Intestinal mucosa damage: after DSS treatment, the intestinal mucosa of the model control group animals showed significant damage, manifested by high hyperemia and edema, necrosis and ulcer on the mucosal surface, thickening of intestinal wall or necrosis and inflammation on the surface. The CMDI score was significantly higher in the model control group animals compared to the normal group (P < 0.01). After 2 days, compared with the model control group (4.27 +/-0.65), the CMDI scores of the LH031 medium dose group (2.34 +/-0.58) and the LH031 high dose group (2.15 +/-0.46) are obviously reduced, and the difference is significant and statistically significant (P is less than 0.01), and the LH031 low dose group (3.59 +/-0.72) can also reduce the CMDI score but has no statistical significance (P is more than 0.05), so that the results are shown in figure 4, which shows that LH031 can improve the damage of the intestinal mucosa of the colitis animal at higher doses.
3) And (3) pathological scoring: taking damaged intestinal tissues of each group, making pathological sections, and performing HE staining. The model group animals have serious inflammation, lesion is affected with submucosa, and crypt is destroyed. Compared with the normal group, the pathological score of the model control group animals is obviously increased (P < 0.01). Compared with the model control group (12.45 +/-3.67), the pathological scores of the LH031 low-dose group (8.34 +/-1.39), the medium-dose group (6.73 +/-0.96) and the high-dose group (5.29 +/-1.21) are obviously reduced, and the difference has obvious statistical significance (P is less than 0.01), which is shown in figure 5 and indicates that the LH031 can improve the pathological score of the colitis.
In conclusion, LH031 has significant improvement in DAI score, CMDI score and histopathological score of rat ulcerative colitis model, and can be used for treatment of ulcerative colitis.
Finally, it should be noted that the above embodiments are only used for illustrating the technical solutions of the present invention and not for limiting the protection scope of the present invention, and although the present invention is described in detail with reference to the preferred embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made on the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention.
Claims (9)
1. Use of a compound for the manufacture of a medicament for the treatment of inflammatory bowel disease, wherein the compound has the structural formula shown in formula (I):
2. the use of claim 1, wherein the inflammatory bowel disease comprises ulcerative colitis and Crohn's disease.
3. The use of claim 1, wherein the compound reduces the level of inflammatory factors in model cells of inflammation.
4. The use of claim 3, wherein said inflammatory factor comprises TNF-a or IL-6.
5. The use of claim 1, wherein the compound promotes the growth of model cells of inflammation.
6. The use according to claim 3 or 5, wherein the model cells of inflammation comprise model cells of inflammation constructed from LPS induced macrophage RAW 264.7.
7. The use of claim 1, wherein the pharmaceutical dosage form comprises an oral dosage form or an injectable dosage form.
8. The use according to claim 7, wherein the oral dosage is 10 to 40 mg/kg.
9. The use of claim 8, wherein the oral dosage is 40 mg/kg.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389628A (en) * | 2006-02-22 | 2009-03-18 | 4Sc股份公司 | Indolopyridines as EG5 kinesin modulators |
| WO2009109620A1 (en) * | 2008-03-05 | 2009-09-11 | 4Sc Ag | Process for preparing enantiomerically pure indolopyridines |
| CN111514137A (en) * | 2020-04-14 | 2020-08-11 | 广州领晟医疗科技有限公司 | Application of compound in preparation of medicine for treating acute lung injury |
| CN111529526A (en) * | 2020-04-14 | 2020-08-14 | 广州领晟医疗科技有限公司 | Application of compound in preparation of medicine for treating acute pancreatitis |
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- 2021-08-30 CN CN202111008120.2A patent/CN113577063B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101389628A (en) * | 2006-02-22 | 2009-03-18 | 4Sc股份公司 | Indolopyridines as EG5 kinesin modulators |
| WO2009109620A1 (en) * | 2008-03-05 | 2009-09-11 | 4Sc Ag | Process for preparing enantiomerically pure indolopyridines |
| CN111514137A (en) * | 2020-04-14 | 2020-08-11 | 广州领晟医疗科技有限公司 | Application of compound in preparation of medicine for treating acute lung injury |
| CN111529526A (en) * | 2020-04-14 | 2020-08-14 | 广州领晟医疗科技有限公司 | Application of compound in preparation of medicine for treating acute pancreatitis |
Non-Patent Citations (1)
| Title |
|---|
| ZHONGJUN XIA等: "A Phase 1 Dose-Escalation Study of LH031, a Kinesin Spindle Protein Inhibitor, in Patients with Refractory/Resistance Multiple Myeloma", 《BLOOD》 * |
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