CN115350191B - New application of reagent BX-471 - Google Patents
New application of reagent BX-471 Download PDFInfo
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- CN115350191B CN115350191B CN202211170592.2A CN202211170592A CN115350191B CN 115350191 B CN115350191 B CN 115350191B CN 202211170592 A CN202211170592 A CN 202211170592A CN 115350191 B CN115350191 B CN 115350191B
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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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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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
- A61P3/04—Anorexiants; Antiobesity agents
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to the field of medical application, in particular to a novel application of a reagent BX-471, and specifically relates to a function of the reagent BX-471 in inhibiting a chemokine receptor 1 (CCR 1), which has the functions of treating and preventing obesity. The invention adopts the following technical scheme: a new use of reagent BX-471, its molecular formula is: c (C) 21 H 24 N 4 O 3 FC l Which has the effect of inhibiting chemokine receptor 1 (CCR 1), characterized in that: it also has effects in treating and preventing obesity. By adopting the scheme, the aim of the invention is as follows: the new application of the reagent BX-471 is expanded, and a theoretical basis is provided for the reagent BX-471 to have the functions of treating and preventing obesity.
Description
Technical Field
The invention relates to the field of medical application, in particular to a novel application of a reagent BX-471, and specifically relates to the effect of the reagent BX-471 in treating and preventing obesity.
Background
Obesity refers to a state in which excessive accumulation of body fat is caused by excessive intake of energy or metabolic change of the body, thereby causing weight gain, and a certain physical pathology and physiological abnormality are accompanied. The prevalence of obesity in the global area is on an increasing trend year by year, and in china, the obesity problem is becoming more prominent with the improvement of the living standard of people. The occurrence of obesity increases the risk of metabolic diseases, cardiovascular diseases, alzheimer's disease, musculoskeletal diseases, cancer and the like. The prior weight-losing means comprise diet, exercise, weight-losing medicines, even weight-losing operations and the like. However, due to factors such as high-pressure social environment, sedentary working mode, individual variability and the like, weight losing difficulty and weight losing are realized by means of diet or exercise. In addition, bariatric surgery is temporarily not popular due to its high cost and high risk. In the masses, the weight-losing medicine is easier to lose weight than diet and exercise and is more acceptable to patients than surgery, but the weight-losing medicine in the current market is mixed with the fish bone, so that the serious side effect is likely to occur. In view of the above, the research and development of a safe and nontoxic weight-losing medicine which can be applied to clinic is significant.
Obesity is considered a chronic low inflammatory response characterized by elevated levels of pro-inflammatory factors and endotoxins (LPS) in the local and circulatory system. In the case of obesity, adipocytes produce pro-inflammatory cytokines and chemokines which infiltrate macrophages into Adipose Tissue (AT), thereby releasing a large amount of inflammatory factors such as Interleukin-6 (il-6), tumor necrosis factor α (Tumor necrosis factor- α, tnfα) and the like, resulting in continuous progression of inflammation.
Disclosure of Invention
The purpose of the invention is that: the new application of the reagent BX-471 is expanded, and a theoretical basis is provided for the reagent BX-471 to have the functions of treating and preventing obesity.
The invention adopts the following technical scheme: a new use of reagent BX-471, its molecular formula is: c (C) 21 H 24 N 4 O 3 FC l The structure is as follows:which has the effect of inhibiting chemokine receptor 1 (CCR 1), characterized in that: it also has effects in treating and preventing obesity.
The concrete steps are as follows: chemokine receptor 1 (CCR 1) has been demonstrated to be highly expressed under obese conditions. The reagent BX-471 as a chemokine receptor 1 (CCR 1) specific inhibitor can significantly inhibit the function of chemokine receptor 1 (CCR 1) production. It was found that the chemokine receptor 1 (CCR 1) was highly expressed in white adipose tissue and brown adipose in obese mice, the function of inhibiting chemokine receptor 1 (CCR 1) by the reagent BX-471 was significantly down-regulated by intraperitoneal injection of the reagent BX-471, the weight of the mice, the liver and adipose tissue, and the expression level of specific brown genes (such as UCP1, uncoupling protein 1) in adipose tissue was significantly increased, and the inflammatory level and liver injury level were significantly improved. The mouse proves that the reagent BX-471 plays an important role in the regulation and control of the treatment and prevention of the obesity, and has great significance for clinically treating the obesity.
The invention is further described below with reference to the accompanying drawings.
Drawings
FIG. 1 shows the expression levels of CCR1 in obese mice according to examples of the present invention;
FIG. 2 is a schematic diagram of the construction of a BX471 mouse model by intraperitoneal injection according to an embodiment of the present invention;
FIG. 3A, B, C shows weight loss in mice with inhibition of CCR1 function by BX-471 of examples of the present invention;
FIG. 4A, B, C shows that BX-471 inhibits CCR1 function of the present invention to improve lipid accumulation in brown adipose tissue and increase expression of heat-generating related genes;
FIG. 5A, B shows that BX-471 inhibits CCR1 function increasing brown coloration of white adipose tissue according to an embodiment of the invention;
FIG. 6 is a schematic representation of BX-471 inhibiting TG and TC in liver and plasma according to an embodiment of the present invention.
Detailed Description
The present invention will be described in detail below.
The material extraction method comprises the following steps:
fat and/or liver tissue sections H & E staining,
baking slices: placing the cut paraffin slice in a 65 ℃ oven to bake the slice for 1.5hr;
dewaxing: xylene I5 min→xylene II 5min→xylene III 5min;
and (3) rehydrating: 100% ethanol I for 5min, 100% ethanol II for 5min, 90% ethanol for 5min, 70% ethanol for 5min, and running water washing for 1min;
dyeing: hematoxylin staining for 5min, running water washing for 10min, eosin staining for 2min;
dehydration and transparency: 10sec of 70% ethanol, 10sec of 90% ethanol, 10sec of 100% ethanol, 5min of xylene, and 5min of xylene II;
and (5) performing lens sealing microscopy: the slices were naturally dried in a fume hood until the xylene had completely volatilized, and then manually sealed with neutral gum. When observed under a microscope, the cell nucleus appears blue, and the cell plasma appears (pink).
Immunohistochemistry:
1. baking slices: placing the slices into an oven at 65-68 ℃, and baking the slices for 1.5 hours until paraffin on the slices is fully removed; 2. dewaxing and rehydrating: xylene I5 min, xylene II 5min, xylene III 5min, 100% ethanol I3 s, 100% ethanol II 5min, 100% ethanol III 5min, 90% ethanol 5min, 70% ethanol 5min, and running water washing 1min;3. citrate buffer (ph=6.0) antigen retrieval: 2L of 0.01mol/L citrate buffer was added to the autoclave, and the mixture was placed into the reconstituted slices. Heating to boiling, timing for 10min, slowly cooling to room temperature, taking out slices, washing with distilled water for 3 times, and spin-drying; 4. tissue contours were drawn using immunohistochemical oil strokes, taking care to remain approximately 0.5 cm distance from the tissue edges. Soaking and washing in PBST for 3 times, each time for 5min; 5. 50 μl of endogenous peroxidase blocker was added to each slice, and the slices were blocked from light at room temperature for 10 min. Soaking and washing in PBST for 3 times after the sealing is finished, and 5min each time; 6. about 50 mu L of 5% goat blocking serum is added to each slice, the slices are blocked for 30min at room temperature, and finally the serum is thrown away; 7. mu.L of UCP1 primary antibody was added to each slice. The sections were placed in a wet box at 4 degrees overnight; 8. discarding the primary antibody, and soaking and washing with PBST for 3 times and 5min each time; 9. adding about 50 mu L of secondary antibody (Dako, K5007) into each slice to obtain solution A in DAB color developing agent, and incubating at room temperature for 30 min;10. discarding the secondary antibody, and soaking and washing with PBST for 3 times, each time for 5min; 11. preparing DAB color developing agent, wherein the proportion of the solution B to the solution C is 50:1, storing in a dark place. Adding about 50 mu L of DAB color developing agent into each slice under a microscope, immediately immersing and washing in distilled water when light brown color appears, stopping color development, and depending on the amount of different proteins expressed in tissues and the dilution concentration of primary antibodies, the dyeing time can be different, but generally does not exceed 5min, and generally is about 3-4 min;12. washing with running water for 2min to remove residual color reagent; 13. counterstaining in hematoxylin staining solution for 2min, and washing with running water for 10min; 14.70% ethanol 5min, 90% ethanol 5min, 100% ethanol 5min, xylene I5 min, xylene II 5min;15. the sections were placed in a fume hood, after about 5min the sections were essentially volatilized clean from the xylenes, centered on the tissue with a neutral gum, covered with a glass slide, and observed under a microscope.
Detection of expression levels of genes in adipose and/or liver tissue:
extracting total RNA of fat and/or liver tissue by using a Trizol method; taking 60-80mg of adipose tissue and/or 15-20-mg liver tissue, adding 600 mu L of Trizol, and homogenizing on ice; adding 150 μl of chloroform, vortex shaking for 15s to fully mix the components, standing on ice for 10min, and centrifuging at 14000 rpm for 15 min; sucking the upper water sample layer, adding isopropyl alcohol precooled in equal volume, gently reversing and uniformly mixing for several times, standing on ice for 10min, and centrifuging at 14000 rpm for 10min; removing supernatant, adding 600 μl of ice 75% ethanol, bouncing off the precipitate, centrifuging 12000g for 5min; removing the supernatant, opening a tube cover, drying until no residual ethanol exists, adding enzyme-removed water to dissolve and precipitate, incubating for 5min, flicking, mixing, and centrifuging instantaneously; nanodrop 2000 detects RNA concentration, identifies RNA yield and purity, notes: the samples were run at 4 ℃ throughout.
Reverse transcription of RNA into cDNA:
removal of genomic DNA: preparing the following reaction system on ice; reaction conditions: 42 ℃ for 2min, 4 ℃ forever.
Reverse transcription reaction:
preparing the following reaction system on ice; the reaction procedure: 37 ℃ for 15 min- > 85 ℃ for 5 s- > 4 ℃ for forever.
RT-PCR
qPCR was performed using the SYBR Select Master Mix kit to relatively quantitatively analyze the mRNA levels of the relevant genes.
The following system is prepared on ice:
the reaction procedure was as follows:
relative quantitative analysis: after the RT-qPCR is completed, ct value data of each sample is obtained by taking the expression quantity of 18S or beta-actin as an internal reference, and a qPCR relative quantitative method is adopted, and the following formula is adopted: delta ct=ct to-be-measured-Ct internal reference, delta ct=delta Ct experimental group-delta Ct control group, mRNA relative level =2- ΔΔct, the relative level of experimental mRNA expression compared to control was calculated.
RT-qPCR related primer:
primers were all assigned to Invitrogen.
Plasma Triglyceride (TG) level determination:
the measuring method comprises the following steps: taking out a Fasting orbital blood plasma sample of the mouse, and dissolving and mixing the Fasting orbital blood plasma sample on ice. The samples were incubated at 37℃for 10min after mixing in 96-well plates as shown in the following table, and absorbance at 510nm was measured by a microplate reader.
And (3) calculating and analyzing: TG content= (OD sample-OD blank)/(OD calibration-OD blank) calibrator concentration and statistical analysis was performed.
Liver TG level assay:
(1) Tissue sample treatment: the liver tissue of the mice (recording the specific tissue weight) was excised in 20-30mg and homogenized on ice in 500. Mu.L of isopropanol. Placing on ice for 5min, vortex shaking for 5min, centrifuging at 25deg.C and 3000rpm for 10min, collecting supernatant, and preserving at 4deg.C.
(2) Extraction of liver tissue protein: 10. Mu.L of the above supernatant was taken and evaporated to dryness at 37 ℃. 50. Mu.L of 0.1mol/L NaOH was added and vortexed and mixed, centrifuged at 12000rpm at 4℃for 10min, and the supernatant was taken and the protein concentration was detected by BCA.
(3) Liver TG, TC, NEFA level assay: and (2) taking the homogenized supernatant in the step 7.1 (1) for TG, TC, NEFA content measurement, wherein the step is the same as the measurement method in blood plasma.
(4) And (3) calculating and analyzing: the measured TG, TC, NEFA content was calculated by normalizing the liver protein level and statistically analyzed.
Plasma Total Cholesterol (TC) level determination:
the measuring method comprises the following steps: taking out a Fasting orbital blood plasma sample of the mouse, and dissolving and mixing the Fasting orbital blood plasma sample on ice. The samples were incubated at 37℃for 10min after mixing in 96-well plates as shown in the following table, and absorbance at 510nm was measured by a microplate reader.
And (3) calculating and analyzing: TC content= (OD sample-OD blank)/(OD calibration-OD blank) ×calibrator concentration, and statistical analysis was performed.
Statistical method
Group comparisons were performed by statistical methods such as t-test, one-way ANOVA, etc. using software such as Excel, SPSS21.0, graphPad Prism, etc., p < 0.05 indicates a statistical difference. All experimental data are expressed as mean ± standard error (mean ± SEM). * p < 0.05, < p < 0.01, < p < 0.001 vs. NC; #p < 0.05, #p < 0.01, #p < 0.001 vs. WT mice.
Expression of chemokine receptor 1 (CCR 1) in adipose tissue in diet-induced obese mice:
the experimental results of this subject revealed that the expression level of chemokine receptor 1 (CCR 1) gene in adipose tissue of High Fat Diet (HFD) mice was significantly increased compared to normal diet (NC) mice (fig. 1). Therefore, we infer that chemokine receptor 1 (CCR 1) is involved in regulating the occurrence and progression of obesity.
The construction and experimental verification of the intraperitoneal injection reagent BX-471 mouse model: the intraperitoneal injection of the reagent BX-471 mice model and 8-week-old C57BL/6 male mice were all kept in SPF-grade negative pressure laminar flow racks in animal houses of university of Winzhong medical science. The 12/12 hour lighting/darkness cycle is alternately carried out, the indoor temperature is 22+/-2 ℃, the humidity is 40% -60%, and sufficient food and drinking water are provided during the feeding period. Mice were divided into control groups and intraperitoneal injection BX471 (20 mg/kg) experimental groups according to 8 mice/cage and labeled, as detailed in the following figure (FIG. 2). After 1 week of acclimatization to NC diet (Normal chow,10% fat), the diet was changed to HFD diet (High-fat diet,60% fat) in the experimental group, and fed for 8 weeks. All animal procedures were performed according to the standards of the university of medical science, university of wenzhou, guidelines for care and use of laboratory animals.
Agent BX-471 inhibits chemokine receptor 1 (CCR 1) function inhibiting weight gain in mice; after 8 weeks of HFD diet feeding, the body weight of the mice in the reagent BX-471 treated group was significantly reduced compared to the body weight of the mice in the control group (fig. 3A). And the increase in the ratio of eWAT, iWAT, mWAT to pWAT caused by HFD diet can be significantly inhibited after treatment with BX-471 as shown in FIG. 3B. And the positive reaction is realized on the premise that the food intake of the two groups of mice is unchanged (figure 3C). It is demonstrated that agent BX-471 can significantly reduce the systemic fat content of obese mice.
Agent BX-471 inhibits chemokine receptor 1 (CCR 1) function improving brown adipose tissue function: h & E staining results showed that the fat cells of BAT were significantly increased in mice of the Vehicle group and that agent BX-471 significantly reduced HFD diet-induced BAT fat accumulation (FIG. 4A). The results of immunohistochemical UCP1 showed that UCP1 (uncoupling protein 1) expression levels were significantly increased in BAT in the Vehicle group mice compared to those in the Vehicle group mice (FIG. 4B), and that the expression of heat-generating related genes (Ucp 1, prdm16, pgc. Alpha.) (FIG. 4C). In conclusion, the reagent BX-471 can remarkably promote the expression of genes related to heat generation of BAT and inhibit lipid accumulation.
The agent BX-471 inhibited chemokine receptor 1 (CCR 1) function and increased brown color of white adipose tissue, and the results of UCP1 immunohistochemistry showed that UCP1 expression levels were significantly reduced in Vehicle group mice iWAT (inguinal fat) and eWAT (epididymal fat) compared with BX-471 group (FIG. 5A), and heat-generating related genes (Ucp 1, prdm16, pgc. Alpha.) were reduced in both adipose tissues compared with BX-471 group mice (FIG. 5B). This suggests that agent BX-471 is capable of modulating HFD diet-induced obesity by promoting the expression of thermogenesis-related genes in white adipose tissue. In conclusion, the reagent BX-471 can promote the expression of genes related to heat generation in white adipose tissues and inhibit lipid accumulation.
Inhibition of chemokine receptor 1 (CCR 1) function by reagent BX-471 significantly prevented the diet-induced increase in TG and TC levels in liver and plasma in mice of the veccle group (see fig. 6), demonstrating that reagent BX-471 significantly reduced lipid levels in liver and plasma in obese mice.
The information for the reagent BX-471 used in this example is as follows: reagent production company: DC Chemicals; reagent name: (ZK 811752); reagent cargo number: DC7675; chemical name: piperazine,1- [ [2- [ (aminocarbonyl) amino ] -4-chlorophenyloxy ] acetyl ] -4- [ (4-fluorophenyl) methyl ] -2-methyl-, (2R) -.
Claims (1)
1. An application of a reagent BX-471 in preparing a medicament for treating and preventing obesity, which is characterized in that: the molecular formula is as follows: C21H24N4O3FCl, the structure is:
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| CN202211170592.2A CN115350191B (en) | 2022-09-23 | 2022-09-23 | New application of reagent BX-471 |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101257897A (en) * | 2005-07-07 | 2008-09-03 | 西特里斯药业公司 | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
| CN106999593A (en) * | 2014-09-12 | 2017-08-01 | 妥必徕疗治公司 | Sai Nikeweiluo combination treatments for treatment of fibrosis |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040092529A1 (en) * | 2002-10-30 | 2004-05-13 | Pfizer Inc | Methods of using piperazine derivatives |
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- 2022-09-23 CN CN202211170592.2A patent/CN115350191B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101257897A (en) * | 2005-07-07 | 2008-09-03 | 西特里斯药业公司 | Methods and related compositions for treating or preventing obesity, insulin resistance disorders, and mitochondrial-associated disorders |
| CN106999593A (en) * | 2014-09-12 | 2017-08-01 | 妥必徕疗治公司 | Sai Nikeweiluo combination treatments for treatment of fibrosis |
Non-Patent Citations (1)
| Title |
|---|
| BX471: A CCR1 Antagonist with Anti-Inflammatory Activity in Man;Richard Horuk;Mini-Reviews in Medicinal Chemistry;第5卷;791-804 * |
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