CN111658651B - Application of CQMU151 in preparing medicament for treating Th17 cell-mediated autoimmune disease - Google Patents
Application of CQMU151 in preparing medicament for treating Th17 cell-mediated autoimmune disease Download PDFInfo
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- CN111658651B CN111658651B CN202010513993.8A CN202010513993A CN111658651B CN 111658651 B CN111658651 B CN 111658651B CN 202010513993 A CN202010513993 A CN 202010513993A CN 111658651 B CN111658651 B CN 111658651B
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- 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
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
The invention relates to application of 1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholinosulfonyl) benzamide in preparation of a medicament for treating Th17 cell-mediated autoimmune disease. The invention obtains the compound by screening from the Chembridge compound library, and experiments show that: the compound has the function of inhibiting the differentiation of Th17 cells in vitro; can inhibit the differentiation of Th17 cells and the generation of IL-17 in vivo, and relieve the clinical symptoms of autoimmune diseases such as Th17 cell-mediated Experimental Autoimmune Uveitis (EAU), Experimental Autoimmune Encephalomyelitis (EAE), type 1 diabetes and the like, and has good application prospect.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to application of N- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholine sulfonyl) benzamide (named as CQMU151 for short) in preparation of a medicine for treating Th17 cell-mediated autoimmune disease.
Background
As a third subset of Th cell discovery, Th17 cells are potent tissue inflammation-inducing cells, involved in the pathogenesis of many inflammatory and autoimmune diseases. Th17 cells play an important role not only in host defense against bacterial and fungal infections, but also in many immune-related diseases, including uveitis, psoriasis, rheumatoid arthritis, multiple sclerosis, inflammatory bowel disease, and asthma/airway inflammatory diseases, among others. anti-IL-17 has been shown to have a good therapeutic effect on a variety of human diseases.
In Th17 cells, IL-17 transcription is regulated by the Th17 specific transcriptional regulator ROR γ t. ROR γ t is a ligand-dependent transcription factor belonging to the nuclear hormone receptor superfamily. The discovery of the non-steroidal small molecule ROR gamma t inverse agonist is one of the hot research fields for treating Th17 mediated autoimmune diseases at present. Wherein digoxin and ursolic acid, as two natural products, inhibit IL-17 production by selectively inhibiting ROR gamma t. However, digoxin has carcinogenic and toxic side effects; ursolic acid can also act on other targets except ROR gamma t, such as glucocorticoid receptor, etc. Therefore, further studies are needed to find more specific ROR γ t inverse agonists.
Disclosure of Invention
The invention aims to provide application of N- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholine sulfonyl) benzamide in preparing a medicine for treating autoimmune diseases mediated by Th17 cells. Experiments show that: the compound has the function of inhibiting the differentiation of Th17 cells in vitro; can inhibit the differentiation of Th17 cells and the generation of IL-17 in vivo, and relieve the clinical symptoms of autoimmune diseases such as Th17 cell-mediated Experimental Autoimmune Uveitis (EAU), Experimental Autoimmune Encephalomyelitis (EAE), type 1 diabetes and the like, and has good application prospect.
The Th17 cell mediated autoimmune disease is uveitis, or the Th17 cell mediated autoimmune disease is type 1 diabetes, or the Th17 cell mediated autoimmune disease is encephalomyelitis.
The drug prepared from N- ((1H-benzo [ d ] imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide is administered as an injection or infusion solution.
The amount of the drug prepared from N- ((1H-benzo [ d ] imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide used is 20-50mg per kilogram body weight per day.
The N- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholine sulfonyl) benzamide provided by the invention has the following English name:
N-((1H-benzo[d]imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide, the molecular formula is: c19H20N4O4S, molecular weight is 400.45, and structural formula is:
the analogues and derivatives thereof also have similar properties.
The invention takes ROR gamma t as a target spot and uses N- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholine sulfonyl) benzamide to carry out in vitro and in vivo verification.
The applicant experiments prove that the N- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholine sulfonyl) benzamide has the effect of inhibiting Th17 cell differentiation in vitro; can inhibit the differentiation of Th17 cells and the generation of IL-17 in vivo, and relieve the clinical symptoms of Th17 cell mediated autoimmune diseases such as Experimental Autoimmune Uveitis (EAU), Experimental Autoimmune Encephalomyelitis (EAE) and type 1 diabetes, has definite target and small toxic and side effects, and can be used for preparing medicaments for treating Th17 cell mediated autoimmune diseases.
Drawings
FIG. 1 is a chart of the Th17 cell flow scale results, wherein the Control group indicates no intervention and CQMU151 indicates the flow results of compound dry prognosis;
FIG. 2 is a dual luciferase calculation of compounds, in which the solid black bars represent blank groups, the horizontal bars represent DMSO control groups, and the vertical bars represent compound intervention groups;
FIG. 3 shows the clinical and pathological scoring results of EAU mice after in vivo intervention with the dots indicating blank groups, squares indicating placebo groups and triangles indicating compound intervention groups.
FIG. 4 shows the results of the compound-dried EAU mice spleen Th17 cell ratio, wherein the dots represent the blank group, the squares represent the placebo group, and the triangles represent the compound-dried group.
FIG. 5 shows the clinical and pathological scoring results of EAE mice after compound intervention, wherein the circles indicate the blank group, the squares indicate the placebo group, and the triangles indicate the compound intervention group.
FIG. 6 shows the food intake, water intake and incidence of diabetes on day 7 after model creation for type 1 diabetic mice after two compound intervention, wherein the circles represent blank groups, the squares represent placebo groups, and the triangles represent compound intervention groups; the solid black bars represent the blank group, the horizontal bars represent the placebo group, and the vertical bars represent the compound intervention group.
Detailed Description
Reagents, cells, instruments of the described embodiments of the invention:
example 1N- ((1H-benzo [ d)]Imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide inhibits primary CD4 in vitro+Differentiation of T cells into Th17 cells
1. The experimental method comprises the following steps:
1) after the mice are killed, the mice are soaked in 75% ethanol, and spleens are dissected and separated out in an ultra-clean bench to a filter screen.
2) After trituration with a 5ml syringe rubber head, filtration was rinsed with PBS. The filtrate was collected into a 15ml centrifuge tube.
3) Centrifuging at 4 deg.C for 10 min with a centrifugal force of 350 × g, discarding the supernatant, adding erythrocyte lysate in an amount 5 times the cell volume, gently blowing off, standing for 2 min, centrifuging at 4 deg.C for 5 min with a centrifugal force of 350 × g, and discarding the supernatant.
4) The same amount of cold PBS as the red blood cell lysate was added, gently blown up, centrifuged at 350 × g for 2 minutes at 4 deg.C, the supernatant was discarded, counted, and washed once more.
5) Light-protected operation, mouse naive CD4 according to Miltenyi+Description of the T cell isolation kit procedures initial T cell counts were isolated and plated at 0.5 x 10 x 6 cells per well in 24-well plates coated with mouse anti-CD 3 and mouse anti-CD 28 and IL-1 β (20ng/ml), IL-6(25ng/ml), IL-23(20 ng/ml), were addedng/ml), TGF-. beta.s (3ng/ml) induced differentiation of Th17 cells with concurrent compound intervention. Cells were harvested after 3 days of culture for Th17 cell flow assay.
2. The experimental results are as follows: CQMU151 can stably inhibit primary CD4 in vitro+The inhibition rate of the differentiation of T cells to Th17 cells is over 50%. The results are shown in FIG. 1.
Example 2 binding assay results for N- ((1H-benzo [ d ] imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide to target ROR γ t
1. The experimental method comprises the following steps:
a dual-luciferase method (Yang X O, et al. T helper 17 linkage differentiation is programmed by means of organ receptors ROR alpha and ROR gamma. immunity 28,29-39(2008)) is adopted to construct a ROR gamma t overexpression plasmid and an IL-17 promoter reporter plasmid. Dividing into an empty load group without a reporter gene, a control group of reporter gene + ROR gamma T over-expression plasmid + DMSO and an experimental group of reporter gene + ROR gamma T over-expression plasmid + compound interference, and transducing the plasmids into 293T engineering cells. DMSO/compound interference was added at 16 h post-drain. Expression was carried out for 2 days.
And (3) cracking cells after 48 hours according to the steps of a dual-luciferase detection kit of the promega, detecting fluorescence values of the firefly and the renilla, and performing calculation statistics.
2. The experimental results are as follows: the compounds all proved to target ROR γ t. The results are shown in FIG. 2.
Example 3 the Effect of N- ((1H-benzo [ d ] imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide in vivo on the severity of disease in mouse EAU
1. The experimental method comprises the following steps:
antigen preparation: weighing 5mg of IRBP by using a microbalance651-670The powder is placed in an EP tube, 1ml of sterile PBS containing 2% DMSO is added into the EP tube containing the IRBP by a pipette, the solution is accelerated to dissolve by shaking on an oscillator, and then the solution is centrifuged for 30s at 3000r/min on a rotating speed centrifuge so as to discharge bubbles in the tube, so that an IRBP solution with the concentration of 5mg/ml is prepared, and the solution is stored at 4 ℃ for standby.
20 mice were anesthetized with pentobarbital sodium, 100ul (i.e., 500ng) of IRBP solution (5mg/ml) and 100ul of complete Freund's adjuvant containing 5mg/ml M.tuberculosis were connected via a three-way sterile tube and mixed well to form a white emulsion, and then the mixed solution with the total volume of 200ul was injected subcutaneously into the nape, axilla, thigh and caudal root of each mouse. Followed by intraperitoneal injection of 1ug pertussis toxin dissolved in 200ul sterile PBS.
On the 9 th day after molding, the anterior chamber condition of the mice was observed under a slit lamp, and the mice observed to have early symptoms of the anterior chamber (ciliary hemorrhage, conjunctival congestion, etc.) were marked as the mice successfully molded, and the mice not exhibiting symptoms were eliminated. The mice successfully molded were randomly divided into a blank group (5), a placebo group (6), and a compound-treated group (6). The compound-treated groups of mice were then each injected intraperitoneally with 25mg/kg of compound (dissolved in DMSO, with 30% PEG300+ 1% Tween-80+ ddH)2Diluted with O for use). Placebo mice were injected i.p. with the same amount of liquid in the same proportion of diluent solvent without compound. Injections were continued for 5 days.
2. The experimental results are as follows: CQMU151 reduces clinical and pathological scores in EAU mice and acts to reduce disease severity. The results are shown in FIG. 3.
EXAMPLE 4 Effect of N- ((1H-benzo [ d ] imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide on Th17 cell differentiation in vivo results
1. The experimental method comprises the following steps:
the 15 mice were sacrificed 14 days after molding, soaked in 75% ethanol, and the spleen was dissected and separated to a filter screen in a super clean bench.
After trituration with a 5ml syringe rubber head, filtration was rinsed with PBS. The filtrate was collected into a 15ml centrifuge tube.
Centrifuging at 4 deg.C for 10 min with a centrifugal force of 350 × g, discarding the supernatant, adding erythrocyte lysate in an amount 5 times the cell volume, gently blowing off, standing for 2 min, centrifuging at 4 deg.C for 5 min with a centrifugal force of 350 × g, and discarding the supernatant.
The same amount of cold PBS as the red blood cell lysate was added, gently blown up, centrifuged at 350 × g for 2 minutes at 4 deg.C, the supernatant was discarded, counted, and washed once more.
Each mouse was assayed for Th17 flow using 1 x 10^6 cells.
2. The experimental results are as follows: after the administration of CQMU151 in vivo, spleen Th17 cell flow assay results showed that the differentiation of Th17 cells in vivo was also inhibited, as was the case with the in vitro results. The results are shown in FIG. 4.
Example 5 the Effect of N- ((1H-benzo [ d ] imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide in vivo on the severity of disease in mouse EAE
1. The experimental method comprises the following steps:
antigen preparation: 2mg of MOG was weighed using a microbalance35-55The powder is placed in an EP tube, 1ml of sterile PBS containing 2% DMSO is added into the EP tube containing MOG by a pipette, the mixture is shaken on an oscillator to accelerate dissolution, and then the mixture is centrifuged for 30s at 3000r/min on a rotating speed centrifuge to discharge bubbles in the tube, so that IRBP solution with the concentration of 2mg/ml is prepared, and the IRBP solution is stored at 4 ℃ for standby.
20 mice were anesthetized with pentobarbital sodium, 100. mu.l (i.e., 200ng) of MOG solution (2mg/ml) and 100ul of complete Freund's adjuvant containing 5mg/ml M.tuberculosis were connected via a sterile three-way tube and then sufficiently mixed to form a white emulsion, and then the above mixed solution with a total volume of 200ul was used to perform subcutaneous injection on the bilateral neck and back of each mouse and the bilateral groin. 200ng of pertussis toxin in 200ul sterile PBS was then injected intraperitoneally.
On day 13 after molding, the condition of the tail and four limbs of the mouse was observed, and the mouse observed to have early symptoms (tail weakness, hind limb paralysis, etc.) was marked as a successfully molded mouse, and the mouse not having symptoms was eliminated. The mice successfully molded were randomly divided into a blank group (4), a placebo group (4), and a compound-treated group (4). The compound-treated groups of mice were then each injected intraperitoneally with 25mg/kg of compound (dissolved in DMSO, with 30% PEG300+ 1% Tween-80+ ddH)2Diluted with O for use). Placebo mice were injected i.p. with the same amount of liquid in the same proportion of diluent solvent without compound. Injections were continued for 5 days.
2. The experimental results are as follows: CQMU151 can reduce clinical and pathological scores of EAE mice and reduce disease severity. The results are shown in FIG. 5.
Example 6N- ((1H-benzo [ d ] imidazol-2-yl) methyl) -3- (morpholinosulfonyl) benzamide reduces disease severity in mice in vivo in type 1 diabetes
1. The experimental method comprises the following steps:
after fasting for 12 hours, 18 mice were molded with STZ solution (protected from light, stored on ice). 0.1mol/L sodium citrate buffer solution is prepared, STZ powder is dissolved in the buffer solution to prepare 10mg/ml STZ solution, and sterile filtration is carried out.
After the mice were weighed, the STZ solution was pushed in 200 mg/kg. After 2 hours of observation, the stomach was perfused with 5% dextrose in water at 1 g/kg. The observation was carried out for 7 days.
Mice were randomly divided into a blank group (6), a placebo group (6), and a compound-treated group (6), and the compound-treated mice were intraperitoneally injected with 25mg/kg of a compound (dissolved in DMSO, with 30% PEG300+ 1% Tween-80+ ddH) on days 1 before and 2-4 after molding, respectively2Diluted with O for use). Placebo mice were injected i.p. with the same amount of liquid in the same proportion of diluent solvent without compound.
2. The experimental results are as follows: CQMU151 relieves clinical symptoms such as polydipsia and polyphagia of type 1 diabetic mice.
And (4) conclusion: n- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholinosulfonyl) benzamide can inhibit the differentiation of Th17 cells in vitro and in vivo, and can reduce the severity of Th17 cell-mediated autoimmune diseases.
The above description is only for the preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. It is intended that the following claims be interpreted as including all such alterations, modifications, and equivalents as fall within the true spirit and scope of the invention.
Claims (5)
1. An application of N- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholine sulfonyl) benzamide in preparing a medicament for treating Th17 cell-mediated autoimmune disease, wherein the Th17 cell-mediated autoimmune disease is uveitis.
2. Application of N- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholine sulfonyl) benzamide in preparation of medicines for treating Th17 cell mediated autoimmune disease type 1 diabetes.
3. Application of N- ((1H-benzo [ d ] imidazole-2-yl) methyl) -3- (morpholine sulfonyl) benzamide in preparation of drugs for treating Th17 cell-mediated autoimmune diseases, namely encephalomyelitis.
4. Use according to any one of claims 1 to 3, characterized in that: the medicine is administered in injection or infusion solution.
5. The use of claim 4, wherein: the dosage of the medicine is 20-50mg per kilogram of body weight per day.
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