CN111450101B - Application of imidazole pyridine derivative in preparation of medicines - Google Patents
Application of imidazole pyridine derivative in preparation of medicines Download PDFInfo
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- CN111450101B CN111450101B CN202010059361.9A CN202010059361A CN111450101B CN 111450101 B CN111450101 B CN 111450101B CN 202010059361 A CN202010059361 A CN 202010059361A CN 111450101 B CN111450101 B CN 111450101B
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- 239000003814 drug Substances 0.000 title claims abstract description 15
- SBPIDKODQVLBGV-UHFFFAOYSA-N 1h-imidazole;pyridine Chemical class C1=CNC=N1.C1=CC=NC=C1 SBPIDKODQVLBGV-UHFFFAOYSA-N 0.000 title claims abstract description 4
- 238000002360 preparation method Methods 0.000 title abstract description 5
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- 238000011282 treatment Methods 0.000 claims description 12
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- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 2
- 206010055171 Hypertensive nephropathy Diseases 0.000 claims description 2
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 2
- 125000001041 indolyl group Chemical group 0.000 claims description 2
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- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Natural products C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims 1
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Substances C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 claims 1
- 125000004857 imidazopyridinyl group Chemical class N1C(=NC2=C1C=CC=N2)* 0.000 claims 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims 1
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Classifications
-
- 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
- A61K31/535—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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
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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)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Urology & Nephrology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses an application of an imidazole pyridine derivative or a salt thereof in preparation of a medicament, wherein the compound is used for treating or preventing chronic kidney diseases, preferably kidney diseases caused by hyperglycemia or hypertension, but is not limited to the two inducers, and particularly, the medicament can inhibit or improve various kidney injuries.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to application of a compound (code number X22) of a formula (I) or pharmaceutically acceptable salt thereof in preparation of a medicine for treating or preventing chronic kidney disease.
Background
Chronic kidney disease is one of the most common complications of basal diseases such as hyperglycemia or hypertension. Upon stimulation by these risk factors, glomerular basement membrane thickens and tubular interstitium expands to progressive fibrosis. As the disease progresses, it eventually progresses to end-stage renal disease, severely affecting the quality of life of the patient and even endangering life.
Based on pharmacological and pathological mechanism researches for many years, the inventor discovers that the compound with the X22 structure can effectively treat chronic kidney disease induced by multifactorial factors such as hyperglycemia, hypertension and the like, and the pathology related to the kidney disease can be obviously improved.
Disclosure of Invention
The invention aims at providing a novel application of 4- {5' - [3' -propyl-2 ' - [3' - (1 ' -methyl) indolyl ] -imidazo [4,5-b ] pyridine ] yl } morpholin (a compound of formula (I), with a code X22).
In particular, the invention provides the use of a compound (X22) of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment or prophylaxis of chronic kidney disease.
Preferably the use of the invention is in the manufacture of a medicament for the treatment or prophylaxis of chronic kidney disease.
The invention also provides the use of a compound (X22) of formula (I) or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for ameliorating chronic kidney disease.
Preferably the use of the invention is in the manufacture of a medicament for ameliorating chronic kidney disease.
Kidney disease occurs in a variety of etiologies including urinary system obstruction, hyperlipidemia, hypertension, autoimmunity, drug toxicity reactions, and the like. The treatment modes of the different etiologies are different, and the invention is mainly aimed at diabetic nephropathy or hypertensive nephropathy, but is not limited to the two causative factors; most preferably, for the treatment of kidney injury and altered renal tissue function.
Preferably, in the use of the present invention, the main pathological feature of kidney disease is glomerulosclerosis and tubular dilation.
The renal tissue function alterations include proteinuria, reduced renal function, tubular fibrosis, and thickening of the basement membrane.
Preferably, in the use of the present invention, the effect of the compound (X22) of formula (I) or a salt thereof on blood glucose or blood pressure is not statistically significant.
The medicament for use in the present invention contains an effective dose of the compound (X22) of formula (I). The effective dose may be the amount of drug in a unit dosage form (e.g., a tablet, a needle, a pill, or a dose), or may be a unit dose (e.g., a unit body weight dose) of a patient in need of treatment/prophylaxis. In the present invention, an effective dose (in terms of content) may be 10. Mu.g to 1g, preferably 0.1mg to 500mg, more preferably 1mg to 100mg.
The medicament for use in the present invention will generally also contain a pharmaceutically acceptable carrier. The pharmaceutically acceptable carrier used refers to nontoxic fillers, stabilizers, diluents, adjuvants or other formulation adjuvants. For example, diluents, excipients, such as water, physiological saline, and the like; fillers such as starch, sucrose, etc.; binders, such as cellulose derivatives, alginates, gelatin and/or polyvinylpyrrolidone; humectants, such as glycerol; disintegrants, such as agar-agar, calcium carbonate and/or sodium bicarbonate; absorption promoters, such as quaternary ammonium compounds; surfactants such as cetyl alcohol; adsorption carriers such as kaolin and/or saponite clay; lubricants such as talc, calcium/magnesium stearate, polyethylene glycol, and the like. In addition, the pharmaceutical composition of the present invention may further contain other auxiliary materials such as flavoring agents, sweeteners, etc. The pharmaceutical composition may be formulated into various dosage forms according to the purpose of treatment and the need of the administration route, preferably the composition is in the form of unit administration dosage such as lyophilized preparation, tablet, capsule, powder, emulsion, water injection or spray, more preferably the pharmaceutical composition is in the form of injection (e.g., lyophilized powder injection) or oral dosage form (e.g., tablet, capsule). The medicament may be administered by conventional routes, in particular enterally, e.g. orally, e.g. in the form of tablets or capsules, or parenterally, e.g. in the form of injectable solutions or suspensions, topically, e.g. in the form of lotions or gels, or in the form of nasal or test agents.
The present invention will be described in detail below with reference to specific examples and drawings. It should be particularly pointed out that these descriptions are only a few exemplary descriptions and are not intended to limit the scope of the invention. Many variations and modifications of the invention will be apparent to those skilled in the art in light of the teachings of this specification.
Description of the drawings:
FIG. 1 shows the effect of compound (X22) of formula (I) on blood glucose and body weight of diabetic rats and the improvement of model urine proteins and kidney function.
FIG. 2 shows the inhibitory effect of compound (X22) of formula (I) on kidney fibrosis in diabetic mice.
FIG. 3 shows the inhibitory effect of the compound (X22) of formula (I) on in vitro tubular epithelial cell fibrosis caused by high concentration glucose.
FIG. 4 shows the therapeutic effect of compound (X22) of formula (I) on AngII-induced hypertensive glomerular fibrosis and enlargement.
The specific embodiment is as follows:
the invention is further illustrated in the following examples. These examples are for the purpose of illustrating the invention only and are not intended to limit the scope of the invention.
Example 1 the compounds of the invention do not affect blood glucose and body weight in mice.
The C57L/B6 mice were randomly divided into 3 groups (6 per group) of:
control group (Control group): healthy C57L/B6 mice;
model type 1 diabetes mice (STZ): constructing a model of type 1 diabetes mice using Streptozotocin (STZ);
compound treatment group (stz+x22 10 mg/kg): after completion of the construction of type 1 diabetic model mice, the mice were given the compound of formula (I) (X22), 1% CMC-Na suspension, starting at the 9 th week at a dose of 10mg/kg/day, by intragastric administration for 8 consecutive weeks.
Blood glucose (Blood glucose) and body weight (weight) were recorded weekly for each group during 16 weeks after molding. The results are shown in fig. 1A, with no difference in blood glucose levels between the treated mice and STZ mice. Meanwhile, the application of compound (X22) did not affect the body weight of the diabetic mouse model.
Mice were sacrificed after the end of the dosing period, kidney weights of the mice were individually weighed, compared to body weight and plotted. The results show that the increase in renal tissue weight ratio due to hyperglycemia can be significantly reduced by X22, see fig. 1B. Meanwhile, urine samples are collected, and urine proteins and urine creatinine are detected by biochemical analysis. Figures 1C-D show that compound (X22) of formula (I) significantly alleviates high sugar-induced urinary protein and renal dysfunction.
EXAMPLE 2 the compounds of the invention significantly inhibit hyperglycemia-induced renal fibrosis
Animals were grouped as in example 1, mice were sacrificed and kidney tissue was obtained 8 weeks after dosing. 4% formalin fixation, paraffin embedding, 5 μm thickness sections were followed by hematoxylin & eosin (H & E) staining, sirius Red (Sirus Red) staining and microscopy. Fig. 2A shows that hyperglycemia causes glomerular hypertrophy, glomerular basement membrane thickening, tubular dilation; at the same time, tubular interstitial fibrosis is caused, but the pathological features are significantly relieved after X22 treatment.
In addition, collagen 4 (COL-4) and a fibrosis marker TGF-beta were detected by Western immunoblotting. FIG. 2B shows that COL-4 and TGF-beta were significantly increased in the STZ group, while X22 significantly inhibited the expression of these proteins (p < 0.05).
After the tissues are crushed and RNA is extracted, the real-time quantitative PCR method is utilized to respectively detect fibrosis related markers COL-4 and TGF-beta; cell adhesion factors VCAM and ICAM. As shown in FIGS. 2C-D, X22 significantly inhibited COL-4, TGF-. Beta., VCAM, ICAM expression in the kidney caused by hyperglycemia.
Example 3 the compounds of the invention significantly improve fibrosis of tubular epithelial cells in vitro caused by hyperglycemia.
NRK-52E cells were stimulated with high concentration of glucose (HG, 33 mM) for 24 hours, followed by lysis of the cells to obtain total protein and detection of fibrosis-associated proteins COL-4, TGF-beta using Western blotting, with GAPDH as an internal reference. As shown in FIG. 3A, the increase in COL-4 and TGF-beta expression induced by HG can be significantly inhibited by X22. In addition, NRK-52E cells were stimulated with HG for 10 hours, total RNA from the cells was extracted with TRIzol, and the RNA expression levels of COL-4, TGF-. Beta., VCAM, ICAM were detected by using a real-time quantitative PCR method. The results are shown in FIGS. 3B-E, X22 also significantly inhibited HG-induced fibrosis and increased levels of cell adhesion factor RNA in vitro.
EXAMPLE 4 Compounds of the invention do not affect mouse blood pressure but significantly improve hypertension-induced glomerular fibrosis, enlargement
The C57BL/6 mice are divided into 3 groups, and 6 mice in each group are respectively:
blank control (Ctrl): healthy mice;
renal hypertension model group (AngII): subcutaneous micropump injection (1000 ng/kg/min) using AngII was performed for 4 weeks;
treatment group (Ang II+X22 10 mg/kg): subcutaneous micropump injection (1000 ng/kg/min) using Ang II for 2 weeks; mice were given a gastric administration of the compound of formula (I) at a dose of 10mg/kg/day on day 15 for 2 consecutive weeks.
As shown in fig. 4A and 4B, the blood pressure of the mice in the treatment group was not significantly different from that of AngII, indicating that the formula (I) did not affect the blood pressure of the mice in the model, and the pharmacological effect was not achieved by lowering blood pressure. After administration, mice are sacrificed, kidney tissues are taken, 4% formalin is used for fixation, paraffin embedding is carried out, hematoxylin & eosin (H & E) staining is carried out after 5 mu m thickness of sections are cut, sirius Red (Sirus Red) staining is carried out, and microscopic examination is carried out; simultaneously, the level of TNF-alpha is detected by an immunohistochemical method. FIG. 4B shows that AngII causes glomerular hypertrophy and tubular dilation; at the same time, tubular interstitial fibrosis is caused, and the pathological characteristics of the X22 after treatment are obviously improved.
Claims (1)
1. The use of an imidazopyridine derivative or a salt thereof in the manufacture of a medicament for the treatment of diabetic nephropathy or hypertensive nephropathy;
the imidazole pyridine derivative is 4- {5' - [3' -propyl-2 ' - [3' ' - (1 ' ' -methyl) indolyl ] -imidazole [4,5-b ] pyridine ] yl } morpholine.
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Non-Patent Citations (3)
| Title |
|---|
| Inhibition of ROS and inflammation by an imidazopyridine derivative X22 attenuate high fat diet-induced arterial injuries;Li W等;《Vascular Pharmacology》;第72卷;第153-162页 * |
| Synthesis and anti-inflammatory evaluation of novel benzimidazole and imidazopyridine derivatives;Chen G等;《ACS Medicinal Chemistry Letters》;第04卷(第01期);第69-74页 * |
| The imidazopyridine derivative X22 prevents diabetic kidney dysfunction through inactivating NF-κB signaling;Jiang Y等;《Biochemical and Biophysical Research Communications》;第525卷(第04期);第877-882页 * |
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