CN114560817B - Small molecule drug for inhibiting fibrosis and application thereof - Google Patents
Small molecule drug for inhibiting fibrosis and application thereof Download PDFInfo
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D249/10—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- A—HUMAN NECESSITIES
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Abstract
According to the invention, a cell model and an animal model are constructed, PAX4 is used as a target spot for drug screening for the first time, and a small molecule drug gfr-960v _5which can effectively inhibit PAX4 and further inhibit organ fibrosis is obtained. Experiments prove that the PAX4 inhibitor gfr-960v \u5 can reverse the increase of the content of transcription factor PAX4 caused by AngII and the common markers of fibronectin, alpha SMA and Col I when cardiac fibrosis occurs; in the tissue where the heart is fibrotic, the PAX4 inhibitor gfr-960v \u5 can reduce the area of cardiac fibrosis caused by AngII and can improve the diastolic dysfunction (E/E' rise) caused by angiotensin II, which is much lower than a possible toxicological dose, with a relatively wide safety dose window. The results show that the PAX4 inhibitor gfr-960v _5can play the roles of relieving the increase of extracellular matrix, inhibiting the occurrence of fibrosis and improving the cardiac function by inhibiting PAX4, and provides a new medicine approach and a theoretical basis for treating the fibrosis diseases.
Description
Technical Field
The invention relates to the field of biological medicines, and in particular relates to a small-molecule PAX4 inhibitor and application thereof in preparation of a medicine for inhibiting fibrosis.
Background
Cardiac fibrosis is an important pathological change in most heart diseases. Cardiac fibrosis is manifested by excessive deposition of extracellular matrix in cardiac tissue, resulting in destruction of physiological cardiac tissue structures, ultimately leading to heart failure, a serious threat to human health and life. Alterations in gene expression in fibroblasts are central to the initiation and maintenance of the cardiac fibrosis response. Myofibroblasts are mainly differentiated from fibroblasts. Myofibroblasts have important contraction and secretion functions and are characterized by expressing α -smooth actin (α SMA), fibronectin (fibronectin) and Collagen type I (Collagen I, col I) in a large amount. Angiotensin II is a polypeptide preparation recognized in present research to regulate vasoconstriction, affect cardiac function, and induce cardiac fibrosis, and is commonly used to treat mice or fibroblasts to mimic the state of cardiac fibrosis. To date, cardiac fibrosis remains an important target and difficulty in the clinical treatment of heart disease today. Because the treatment of cardiac fibrosis can delay the occurrence and development of heart failure, the search for targets and drugs for treating cardiac fibrosis is an important problem to be solved.
The transcription factor PAX4 is a member of the IV subfamily of the Paired box (PAX) family. Current research suggests that members of the PAX family perform important functions in many stages of embryonic development and organogenesis, and also in all aspects of the body after adulthood. The evolution of the sequence of members of the PAX family, from insects, amphibians, birds, mammals, is well conserved. The protein structure of PAX4 comprises a 128-amino acid bioparate Paired Domain (PD) and a Homeodomain Domain (HD), and the C-terminal of the PAX protein structure not only has a common transcription activation domain of PAX family, but also has a unique negative regulation domain. Current research suggests that members of the PAX family are important regulators of tissue development and cell differentiation. The study of PAX4 was mainly focused on pancreatic islets, cancer and retina-related studies. In previous studies in our team, PAX4 was found to be an important target for organ fibrosis (CN 111214660B), and based on this, the development of drugs for treating fibrosis is the focus of further research.
Disclosure of Invention
The invention aims to provide a small molecule drug for inhibiting fibrosis and application thereof. More specifically, the invention provides the following technical scheme:
in a first aspect of the invention, there is provided a small molecule compound gfr-960v \5, the structure of which is as follows:
in a second aspect of the present invention, there is provided a pharmaceutical composition for inhibiting fibrosis, wherein the active ingredient of the pharmaceutical composition is a small molecule compound gfr-960v _5.
In one embodiment, the pharmaceutical composition further comprises pharmaceutically acceptable auxiliary ingredients.
In one embodiment, the above pharmaceutical composition is selected from a solution, a suspension, a paste, a powder, a granule, a tablet or a tincture.
In a third aspect of the present invention, there is provided a use of the above-mentioned small molecule compound gfr-960v \u5 in the preparation of a medicament for inhibiting fibrosis.
In a preferred embodiment, the fibrosis is pulmonary fibrosis, cardiac fibrosis or pancreatic fibrosis.
Compared with the prior art, the invention obtains the following technical effects：
According to the invention, a cell model and an animal model are constructed, PAX4 is used as a target spot for drug screening for the first time, and a small molecule drug gfr-960v _5which can effectively inhibit PAX4 and further inhibit organ fibrosis is obtained. Experiments prove that the PAX4 inhibitor gfr-960v _5 (100 mu g/kg) can reverse the increase of the content of transcription factor PAX4 caused by AngII and the common markers of fibrinectin, alpha SMA and Col I when cardiac fibrosis occurs; in the tissue where fibrosis occurs in the heart, the PAX4 inhibitor gfr-960v _5may reduce the area of cardiac fibrosis caused by AngII, and may have the effect of improving the diastolic function (E/E' elevation) caused by angiotensin II. At this dose gfr-960v _5, there was no significant impairment of cardiac and hepatic renal function in mice, while well below the possible toxicological dose. The results show that the PAX4 inhibitor gfr-960v _5can play the roles of relieving the increase of extracellular matrix, inhibiting the occurrence of fibrosis and improving the cardiac function by inhibiting PAX4, and provides a new medicine approach and a theoretical basis for treating the fibrosis diseases.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the principles of the invention and not to limit the invention. In the drawings:
FIG. 1A: the intensities of the transcription factor PAX4 and fibrosis markers fibronectin, α SMA, col I after administration of gfr-960v \u5 stimulation.
FIG. 1B: relative quantification of brightness and statistical analysis results.
FIG. 2: real-time fluorescence quantitative PCR (polymerase chain reaction) is used for detecting the change of transcription levels of a transcription factor PAX4 and fibrosis markers fibrinectin, alpha SMA and Col I after a cardiac fibroblast is pretreated for half an hour by being given with a PAX4 inhibitor gfr-960v \ 5 and is stimulated by 1 mu M angiotensin II for 2 days.
FIG. 3: after injecting PAX4 inhibitor gfr-960v _5into the abdominal cavity of the mouse, the detection results of the biochemical indexes AST, CR, GLU and CKMB of the blood of the mouse are obtained.
FIG. 4A: after administration of PAX4 inhibitor gfr-960v _5, sirius heart stained red, scale: 500 μm.
FIG. 4B: and (5) carrying out statistical analysis on the area of the cardiac fibrosis.
FIG. 5: after a fibrosis model is constructed by injecting AngII into a mouse by a micro-osmotic pump, and then injecting PAX4 inhibitor gfr-960v \u5 into the abdominal cavity, the ultrasonic cardiac detection finds that the use of the PAX4 inhibitor gfr-960v \u5 can improve the diastolic dysfunction (E/E' rise) caused by angiotensin II.
FIG. 6: injecting AngII into a mouse embedded micro-osmotic pump to construct a fibrosis model, then injecting PAX4 inhibitor gfr-960v _5into the abdominal cavity, and detecting the transcription level changes of transcription factors PAX4 and fibrosis markers fibrinectin, alpha SMA and Col I of heart tissues by real-time fluorescence quantitative PCR.
Detailed Description
The invention is further illustrated with reference to specific examples. It should be understood that the specific embodiments described herein are illustrative only and are not limiting upon the scope of the invention.
The examples do not show the specific techniques or conditions, according to the technical or conditions described in the literature in the field, or according to the product specifications. The reagents or instruments used are conventional products which are not known to manufacturers and are available from normal sources.
The experimental procedures in the following examples are all conventional ones unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.
Example 1 detection of expression levels of respective markers in mouse cardiac fibroblasts
1. Isolation and culture of mouse cardiac fibroblasts:
male C57/BL6 mice of about 8 weeks old were sacrificed by cervical dislocation, rapidly soaked in 75% alcohol for about half a minute, immediately placed on a clean bench to open the chest and remove the heart, placed in PBS buffer at 4 degrees celsius to wash twice, the blood vessels at the atria and the bottom of the heart were cut off, then the ventricles were cut into small pieces and washed once with PBS to wash off part of the residual blood. Digestion was performed by adding 0.1% collagenase type II (330U, worthington, columbia, NJ, USA/Sigma, st. Louis, MO, USA) in PBS balanced salt solution. The whole digestion process is carried out under the condition of constant-temperature stirring at 36-37 ℃, supernatant digestive juice is taken out after digestion is carried out for 8 minutes, and the supernatant digestive juice is added into the DMEM culture solution containing 10% FBS in equal amount and is uniformly mixed. Repeating the process for about 7 to 8 times until the tissue block is completely digested, centrifuging collected tubes of cells at room temperature and 1000 rpm for 5 minutes, discarding supernatant, resuspending cells in DMEM (DMEM) culture solution containing 10% FBS (FBS), combining the obtained myocardial cell suspensions, and inoculating the myocardial cell suspensions in a culture dish with the diameter of 100 mm5% CO at 37 deg.C 2 The culture box is placed for 2 hours to ensure that the fibroblasts are basically adhered to the wall. The culture solution in the culture dish is removed by suction, and a new DMEM culture solution containing 10% FBS is added for continuous culture. After 3 days the cells were confluent, passaged and subjected to subsequent experiments.
2. The experimental method comprises the following steps:
2.1 Immunofluorescence staining experiment:
fixing the mouse heart fibroblast obtained in the step 1 by using 37 ℃ warm 4% paraformaldehyde for 15 minutes at 37 ℃, washing the fixed mouse heart fibroblast for 3 times by using warm PBS (phosphate buffered saline), and then breaking a membrane by using 0.2% Triton X-100 for 20-30 minutes. After 3 washes with warm PBS, blocking solution (5% BSA) was added for 30 min. Thereafter, primary anti- α SMA (ab 32575, abcam, cambridge, MA, USA), fibrinectin (ab 2413, abcam, cambridge, MA, USA), PAX4 (ab 101721, abcam, cambridge, MA, USA) were used for overnight incubation at 4 degrees celsius. After recovering the primary antibody for storage, the PBS was washed 3 times, and then the secondary antibody Alexa Fluor was incubated at room temperature for 488 hours. Nuclei were stained with Hoechst (Invitrogen, carlsbad, calif., USA) for 8 minutes at room temperature. Fluorescence intensity was counted and analyzed using the morpholinology Explorer BioApplication module of the high content screening imaging system Cellomics array Scan VTI HCS Reader (Thermo Fisher Scientific, rockford, IL, USA).
2.2 Extraction of cellular RNA:
RNA in cells was extracted with Trizol reagent, and qPCR (1. Mu. GRNA) detection was performed using Bio-Rad CFX 96Touch after reverse transcription using a promega kit.
3. Detection of markers in mouse cardiac fibroblast fibrosis model:
the mouse cardiac fibroblasts obtained in step 1 were cultured for P1 generation in a 96-well plate, and the cells were stimulated with angiotensin II at a concentration of 1 μ M for 2 days to construct a cell fibrosis model. Cell samples were collected after 2 days and fixed for detection of endogenous PAX4 and fibrosis marker fibrinectin, α SMA and Col I protein levels using immunofluorescence. The intensity in FIG. 1A indicates the localization and content of PAX4, fibrinectin, α SMA and Col I, respectively, recognized by a particular antibody. The experimental result shows that the transcription factor PAX4 is mainly expressed in the cell nucleus. The experimental results suggest that under the stimulation of angiotensin II, the fluorescence intensities of PAX4, fibronectin, alpha SMA and Col I are enhanced to different degrees, and the fluorescence intensities of PAX4, fibronectin, alpha SMA and Col I in cells are obviously reduced after the PAX4 inhibitor gfr-960v \u5 is used. The quantitative results in fig. 1B and fig. 2 show that the increase in the content of transcription factor PAX4 and the markers fibrauctin, α SMA and Col I, which are common in the occurrence of cardiac fibrosis, is significantly increased after 2 days of angiotensin II stimulation, whereas the increase in the content of transcription factor PAX4 and the markers fibrauctin, α SMA and Col I, which are common in the occurrence of cardiac fibrosis, caused by AngII, can be reversed by pre-treating with PAX4 inhibitor gfr-960v 5 for half an hour and then administering angiotensin II stimulation for 2 days.
Example 2 therapeutic Effect of PAX4 inhibitors on pathological models of mouse cardiac fibrosis
Animal pathology model experiment, constructing mouse heart fibrosis model, taking heart tissue, and detecting the size of heart fibrosis area by using a Tianlang scarlet dyeing experiment method.
1. Preparation of angiotensin II-induced cardiac fibrosis model in mice:
male C57BL/6 mice at 10 weeks of age were randomly divided into two groups, a model group and a treatment group:
model group: the mouse uses angiotensin (3 mg. Kg-1. Day-1) micro-osmotic pump embedded pump (Alzet MODEL 1007D, DURECT, cupertino, CA) for 7 days to construct a fibrosis MODEL. Preparation of micro osmotic pressure pump: 1 day before surgery, angiotensin II (dissolved in sterile PBS buffer) was injected into the micro osmotic pump with a 1mL syringe, the micro osmotic pump was soaked in sterile PBS buffer and equilibrated at 37 degrees celsius overnight. During operation, 2% -3% isoflurane is used for anaesthetizing a mouse, a transverse incision with the length of about 0.7 cm is cut at the back neck of the mouse, a forceps is used for extending into the subcutaneous part, subcutaneous tissues are separated in a blunt mode, a micro-osmotic pump is buried, a wound is sutured, and neomycin ointment is coated to prevent infection. The operative group was continuously infused with angiotensin II at a concentration of 3 mg/kg/d for 7 days.
Treatment groups: 1 day after the pump is buried by using an angiotensin II micro-osmotic pump, a mouse heart fibrosis model is constructed by selecting 10-week male C57BL/6 mice and injecting a PAX4 inhibitor gfr-960v _5 (50 mu g/kg/d and 100 mu g/kg/d for seven days) into the abdominal cavity, and the fibrosis degree in the heart is detected.
Seven days after intraperitoneal injection of PAX4 inhibitor gfr-960v _5into mice, the results of detection of mouse blood biochemical indicators AST, CR, GLU and CKMB (FIG. 3) indicate that gfr-960v _5has no damage to the heart, liver and kidney of the mice.
2. Tissue sectioning and staining:
after the mice in the two groups are sacrificed, the horizontal cross section of the cardiac papillary muscle is fixed in 4% paraformaldehyde solution (W/V% prepared by PBS) for 6-8 hours, the paraformaldehyde is discarded, and 20% sucrose solution (W/V% prepared by PBS) is added for dehydration. Then the mixture is put into 70 percent (3 hours) ethanol solution and 80 percent (3 hours) ethanol solution in turn for gradient dehydration, and finally the mixture is put into 90 percent ethanol and n-butanol solution (volume ratio is 1. The next day, 95% ethanol plus n-butanol solution (45 min 2 times), n-butanol (30 min), butanol (20 min) were sequentially added, the surface liquid was blotted with filter paper, and the tissue mass was embedded with paraffin. Then, a heart section is made by a microtome, the thickness of the paraffin section is 5 mu m, the horizontal transverse cutting is carried out on papillary muscles, and sirius red staining is carried out to detect the collagen deposition condition. Dewaxing was first carried out with xylene for 3 min, 3 min for 2 min with 100% ethanol, 3 min for 2 min with 95% ethanol, 3 min for 1 min with 80% ethanol, and 3 min for 1 min with 70% ethanol. Finally, washing with distilled water 3 times. Then, sirius red dyeing is carried out, water is dipped to be dry firstly, the solution is placed into the sirius red solution for dyeing for 1 minute, the loose color is washed off in distilled water (3 times), the solution is quickly washed with 95% ethanol for 1 time, then the solution is placed into 100% ethanol for 1 minute and 2 times (the yellow-dyed color is not washed off), finally, 80% dimethylbenzene is used for carrying out transparent treatment (10 minutes and 2 times), the surface of the slice is covered with neutral resin, and the slice is sealed and stored by a cover glass. And finally, observing and quantitatively analyzing the tissue section. Quantitative collagen fiber area (sirius red stain) was analyzed using a nanoboomer-SQ (Hamamatsu, japan) image analysis system. The sirius red stained sections were observed, and the collagen fibrosis area (red stained portion) was measured for each specimen, and the total heart cross sectional area was measured by dividing the fibrosis area by the total heart area, i.e., the percentage of fibrosis.
The staining results are shown in fig. 4A, and the PAX4 inhibitor gfr-960v _5can reduce the area of cardiac fibrosis caused by AngII in the tissues with cardiac fibrosis, and the statistical results are shown in fig. 4B and fig. 6.
3. Performing ultrasonic cardiac detection:
two groups of mice are respectively placed in an anesthesia box and are anesthetized by isoflurane (2.5 percent of isoflurane, 0.8L/min), after the anesthesia is finished, the mice are taken out of the anesthesia box, are rapidly placed on a heating plate in a supine position, a nose mask connected with anesthetic is worn, the four limbs of the mice are fixed by rubber strips, and the concentration of the isoflurane is adjusted to 1 percent for maintaining the anesthesia. The breast was depilated with depilatory cream (Nail, canada). Echocardiography examination of mice was performed using a Vevo 2100 sonicator (Fujifilm Visual sonic, canada).
The echocardiogram results are shown in fig. 5, and the use of the PAX4 inhibitor gfr-960v _5improved the diastolic dysfunction (E/E' elevation) caused by angiotensin II (fig. 5). The results of the echocardiography suggest that inhibition of PAX4 protects the diastolic function of mice.
The experimental results show that the PAX4 inhibitor gfr-960v _5can play the roles of relieving the increase of extracellular matrix, inhibiting the occurrence of fibrosis and improving the cardiac function by inhibiting PAX 4.
Example 3 PAX4 inhibitor drug safety testing
In order to estimate the safety of the small molecular compound, safety indexes such as the highest dosage, the liver and kidney Toxicity and the like of the compound are estimated by using a drug Toxicity prediction algorithm Lazar (https:// lazar.in-silico.ch/predict), a sensitivity Predictor (my-pharm.ac.jp) and an eMLTox (http:// xundrug.cn/moltox). The results are shown in the following table 1, which shows that the highest dosage of PAX4 inhibitor gfr-960v \u5 is 100 times higher than that of the antifibrosis acting dosage shown by animal experiments, and the dosage has no toxic or side effect on high-toxicity sensitive organs such as heart, respiratory system, nervous system and the like.
TABLE 1 gfr-960v _5safety dose analysis
| Index (I) | As a result, the | Algorithm |
| Highest dose (human) | ~ 2.0 mg/kg_bw/day | Lazar |
| Highest dose (mouse) | ~ 18.0 mg/kg_bw/day | Lazar |
| Highest dose (rat) | ~ 12.5 mg/kg_bw/day | Lazar |
| Cardiotoxicity | Is composed of | eMolTox |
| Pulmonary toxicity | Is composed of | Toxicity Predictor |
| Toxicity of central nervous system | Is composed of | eMolTox |
| Hepatotoxicity | Is provided with | eMolTox |
| Nephrotoxicity | Is composed of | eMolTox |
| Carcinogenicity causing method | Is free of | eMolTox |
| Reproductive toxicity | Is free of | eMolTox |
| Cytotoxicity | Is free of | eMolTox |
| Skin allergy | Is free of | eMolTox |
| Mitochondrial toxicity | Is free of | eMolTox |
| Endocrine toxicity | Is provided with | eMolTox |
| Mutant genotoxicity | Is free of | eMolTox |
| Acute oral toxicity | Is free of | eMolTox |
| P450 drug metabolic toxicity | Is free of | eMolTox |
It will be apparent to those skilled in the art that various changes and modifications may be made in the present invention without departing from the spirit and scope of the invention. Thus, if such modifications and variations of the present invention fall within the scope of the claims of the present invention and their equivalents, the present invention is also intended to include such modifications and variations.
Claims (4)
1. Use of a small molecule compound gfr-960v _5in the preparation of a pharmaceutical composition for inhibiting cardiac fibrosis, wherein the structure of the small molecule compound gfr-960v _5is as follows:
2. the use of claim 1, wherein the medicament further comprises pharmaceutically acceptable auxiliary ingredients.
3. Use according to claim 1 or 2, wherein the pharmaceutical composition is selected from the group consisting of a solution, a suspension, a paste, a powder, a granule, a tablet or a tincture.
4. The use of claim 1, wherein the medicament is administered at a dose of less than 2.0 mg/kg bw/day.
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| GB0127923D0 (en) * | 2001-11-21 | 2002-01-16 | Sterix Ltd | Compound |
| CN1738615A (en) * | 2002-11-15 | 2006-02-22 | 沃泰克斯药物股份有限公司 | Diaminotriazoles useful as inhibitors of protein kinases |
| WO2005000309A2 (en) * | 2003-06-27 | 2005-01-06 | Ionix Pharmaceuticals Limited | Chemical compounds |
| US10118903B2 (en) * | 2014-02-07 | 2018-11-06 | Musc Foundation For Research Development | Aminotriazole-based KDM1A inhibitors as epigenetic modulators |
| GB201705263D0 (en) * | 2017-03-31 | 2017-05-17 | Probiodrug Ag | Novel inhibitors |
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| Title |
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| 羧胺***抗博莱霉素诱导小鼠肺纤维化的作用及初步机制研究;王聪慧;《中国博士学位论文全文数据库 医药卫生科技辑》;20121115(第11期);E079-3 * |
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