Application of prodrug for supplementing NAD < + > in prevention and treatment of abdominal aortic aneurysm

Abstract

The invention belongs to the technical field of medicines, and particularly relates to a prodrug for supplementing NAD < + >, which is an NAMPT agonist YB8, and an application of the prodrug in prevention and treatment of abdominal aortic aneurysm. The invention discloses a prodrug YB8 capable of specifically activating nicotinamide phosphoribosyltransferase (NAMPT), and the prodrug YB8 can effectively improve the level of NAD + (nicotinamide adenine dinucleotide) in cells, so that the degenerative change of a vascular structure is slowed down, the purposes of protecting blood vessels and treating abdominal aortic aneurysm are achieved, and the YB8 is proved to be used as a specific activator of NAMPT for the first time. The multi-target treatment effect is achieved by improving the blood vessel NAD + level; the discovery provides a brand new strategy for the drug treatment of abdominal aortic aneurysm, and the treatment advantages are as follows: ultrasonic imaging proves that the tumor progress can be obviously inhibited; the discovery lays an important foundation for developing clinical treatment of abdominal aortic aneurysm based on NAD + metabolism regulation.

Description

TECHNICAL FIELD

[0001] The application relates to the technical field of medicines, in particular to application of a medicine precursor for supplementing NAD+ in prevention and treatment of abdominal aortic aneurysm. BACKGROUND

[0002] Abdominal aortic aneurysm is a high-risk cardiovascular disease caused by compensatory expansion of aortic blood vessels due to vascular structure damage. Existing research shows that vascular abnormal aging caused by multiple factors such as heredity, smoking, alcohol abuse and obesity is an important cause of abdominal aortic aneurysm. On a micro level, the continuous existence of chronic aseptic inflammation causes the vascular smooth muscle cells in the blood vessel wall to transform into an aging-related secretory phenotype; the continuous accumulation of abnormally aged cells causes the aging of aortic blood vessels on a macro level; the blood vessel wall becomes thin, the elasticity decreases, and inflammatory cells infiltrate. At present, there is no medicine for the clinical treatment of abdominal aortic aneurysm.

[0003] NAD+ (nicotinamide adenine dinucleotide) is a core molecule of cell energy metabolism and oxidation-reduction reaction, participates in energy metabolism, DNA damage repair, enhances immunity and has a wide range of biological functions, and is an indispensable coenzyme in cells. Research shows that chronic inflammation and unhealthy lifestyle consume more NAD+, and the level of NAD+ gradually decreases, leading to cell dysfunction related to aging, so maintaining the level of NAD+ is of great significance for delaying aging and preventing aging-related diseases. Since NAD+ has a large molecular weight and cannot be directly absorbed by the human body, it is a feasible way to supplement tryptophan, nicotinic acid, nicotinamide and other NAD+ precursor substances.

[0004] At present, there is no related report on using a compound capable of activating nicotinamide phosphoribosyltransferase for abdominal aortic aneurysm. SUMMARY

[0005] 1. Technical problem to be solved The purpose of the application is to solve the problem that there is no compound capable of activating nicotinamide phosphoribosyltransferase for abdominal aortic aneurysm in the prior art, and propose an application of a medicine precursor for supplementing NAD+ in prevention and treatment of abdominal aortic aneurysm.

[0006] 2. Technical scheme In order to achieve the above-mentioned purpose, the application adopts the following technical scheme: A medicine precursor for supplementing NAD+, the medicine precursor is NAMPT agonist YB8, and the NAMPT agonist YB8 has the structure shown in formula I:

[0007] Formula 1.

[0008] The present application also provides the prodrug, which is a pharmaceutically acceptable salt of NAMPT agonist YB8.

[0009] The present application also provides the use of the prodrug in multi-target therapy for increasing the NAD+ level of blood vessels.

[0010] The present application also provides the use of the prodrug in delaying the progression of abdominal aortic aneurysm.

[0011] The present application also provides the use of the prodrug in preventing and treating abdominal aortic aneurysm.

[0012] The present application also provides the use of the prodrug in preparing a drug for abdominal aortic aneurysm.

[0013] The present application also provides an abdominal aortic aneurysm model for evaluating the therapeutic effect of the prodrug, wherein the abdominal aortic aneurysm model is prepared by applying a certain concentration of elastase to the infrarenal aorta of a mouse, and feeding 0.5% 3-aminopropionitrile fumarate BAPN in the daily drinking water of the mouse for 4 weeks, and then dynamically monitoring the diameter change of the aneurysm by live ultrasound imaging technology to evaluate the therapeutic effect of YB8.

[0014] Preferably, the concentration of the elastase is 35 mg / ml.

[0015] Preferably, the dilation of the artery is slowed down or retracted, which is therapeutically effective.

[0016] 3. Beneficial effects Compared with the prior art, the present application has the following advantages: (1) In the present application, a prodrug YB8 capable of specifically activating nicotinamide phosphoribosyltransferase (NAMPT) is found, which can effectively increase the intracellular NAD+ (nicotinamide adenine dinucleotide) level, thereby slowing down the degenerative changes of the vascular structure, achieving vascular protection, and treating abdominal aortic aneurysm.

[0017] (2) In the present application, it is first confirmed that YB8 as a specific activator of NAMPT exerts a multi-target therapy effect by increasing the NAD+ level of blood vessels; the discovery provides a new strategy for the drug treatment of abdominal aortic aneurysm, and the treatment advantage is that the progression of the aneurysm can be significantly inhibited by ultrasound imaging; the discovery lays an important foundation for the development of clinical treatment of abdominal aortic aneurysm based on the regulation of NAD+ metabolism. BRIEF DESCRIPTION OF DRAWINGS

[0018] Figure 1 The present application provides that YB8 is administered to increase the NAD+ content in the artery; Figure 2 The present application provides a representative ultrasound image of the aorta of the control group; Figure 3 Representative ultrasound image of the aorta of the administration group proposed in the present application; Figure 4 Measurement of the maximum diameter of the infrarenal abdominal aorta of each group of mice proposed in the present application; Figure 5 Representative gross photograph of the aorta of the control group proposed in the present application; Figure 6 Representative gross photograph of the aorta of the administration group proposed in the present application; Figure 7 Relative content of elastic fibers in the aortic blood vessels proposed in the present application. DETAILED DESCRIPTION

[0019] The technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application. Obviously, the described embodiments are only some of the embodiments of the present application, but not all the embodiments of the present application.

[0020] Embodiment 1 A drug precursor for supplementing NAD+, the drug precursor is NAMPT agonist YB8, the NAMPT agonist YB8 has the structure shown in formula I:

[0021] Formula 1.

[0022] The drug precursor is a pharmaceutically acceptable salt of NAMPT agonist YB8.

[0023] In this embodiment, an abdominal aortic aneurysm model for evaluating the therapeutic effect of the drug precursor is also proposed, the abdominal aortic aneurysm model refers to applying a certain concentration of elastase locally on the infrarenal aorta of a mouse, and feeding 0.5% 3-aminopropionitrile fumarate BAPN in its daily drinking water for 4 weeks, and dynamically monitoring the diameter change of the aneurysm by live ultrasound imaging technology, so as to evaluate the therapeutic effect of YB8, the concentration of elastase is 35 mg / ml, and the slowing down or retraction of the artery expansion is effective treatment.

[0024] In this embodiment, a drug precursor YB8 capable of specifically activating nicotinamide phosphoribosyltransferase (NAMPT) is found, which can effectively improve the intracellular NAD+ (nicotinamide adenine dinucleotide) level, thereby slowing down the degenerative changes of the vascular structure, achieving vascular protection, and achieving the purpose of treating abdominal aortic aneurysm.

[0025] In this embodiment, it is first confirmed that YB8 acts as a specific activator of NAMPT, and plays a multi-target treatment role by increasing the vascular NAD+ level; the discovery provides a new strategy for the drug treatment of abdominal aortic aneurysm, and the treatment advantages are as follows: it can significantly inhibit the aneurysm progression through ultrasonic imaging; the discoveries lay an important foundation for the development of clinical treatment of abdominal aortic aneurysm based on NAD+ metabolic regulation.

[0026] Embodiment 2: It has the implementation content of the above-mentioned embodiment, wherein, for the specific implementation of the above-mentioned embodiment, please refer to the above description, and the embodiment here is not repeated in detail; and in the embodiment of the present application, the difference from the above-mentioned embodiment is that: In this embodiment, the mice used are C57BL / 6J mice (hereinafter referred to as C57 mice), purchased from Shanghai Slek Experimental Animal Co., Ltd., and all animal operations involved in the experiment process are humanized for the mice.

[0027] In this embodiment, the experiment is carried out by using a vascular peripheral elastase-induced abdominal aortic aneurysm model: 35 mg / ml of elastase is applied locally to the infrarenal aorta of the mouse, and 0.5 % of 3-aminopropionitrile fumarate (BAPN) is fed in its daily drinking water for 1 month. Two weeks after the operation, the mice in the administration group are administered by intraperitoneal injection for two weeks.

[0028] In this embodiment, the specific implementation steps of the vascular peripheral elastase-induced abdominal aortic aneurysm model are as follows: a. Dissolve and prepare the PPE solution with the required concentration in physiological saline under a sterile environment; b. After the C57 mice are weighed, they are anesthetized with 1% sodium pentobarbital solution (40 mg / kg); c. The mouse is fixed with its abdomen upwards, and after the surgical area is disinfected, the inner muscle layer is cut along the white line of the abdomen, and gauze dipped in physiological saline is placed on one side of the surgical opening. Gently squeeze the mouse's abdomen with a cotton swab, and place the abdominal organs on the wet gauze. Under a biological microscope, carefully separate the abdominal aorta segment downstream of the renal artery branch using tweezers; d. Dip the pre-cut cotton strip in 10 μL of PPE solution to cover the surface of the abdominal aorta. After 10 min, add 3 μL of PPE solution to the cotton strip, repeat 3 times, and after the third time, wait for 10 min, then remove the cotton strip and suture. After the operation, place the mouse on a heating pad for warming, and wait for it to fully recover; e. After the mouse has completed the operation, replace its drinking water with aminopropionitrile solution, and send it back to the animal house for feeding. The modeling period is 28 days.

[0029] In this embodiment, the specific administration regimen is: using a mixed solvent of 9% DMSO (dimethyl sulfoxide) + 10% Tween-80 (polysorbate 80) + 81% normal saline as a solvent, the administration dose is 10 mg / kg, the administration cycle is 14 days, and the administration is performed twice a day, and the body weight is recorded every two days during the period.

[0030] In this embodiment, after 28 days of modeling, the abdominal aorta of the mouse is imaged in vivo using an ultrasonic Doppler instrument to obtain the maximum diameter of the abdominal aorta of the mouse. The specific operation is: a. After weighing the mouse, 1% sodium pentobarbital solution (40 mg / kg) is used for anesthesia; b. The mouse is fixed supine on a heating plate (maintaining body temperature at 37°C), the limbs are gently fixed with adhesive tape, and the head is slightly raised to reduce airway compression; c. Shave the abdominal hair and apply ultrasonic coupling agent to reduce acoustic impedance; d. Scan longitudinally along the abdominal white line from below the xiphoid, identify the abdominal aorta, rotate the probe to the transverse section, and confirm that the abdominal aorta is located in front of the spine and left of the inferior vena cava.

[0031] In this embodiment, as shown in Figure 1 : The control group without any treatment after modeling has a significantly enlarged abdominal aorta in the form of a tumor, with a maximum diameter of about 3.0 mm; Figure 2 : After 14 days of modeling, YB8 is given to the mouse, and the enlargement of the abdominal aorta is improved, with a maximum diameter of about 1.7 mm; Figure 3 : YB8 can inhibit the enlargement of the abdominal aortic aneurysm. These results show that the compound YB8 can effectively delay the progression of the abdominal aortic aneurysm.

[0032] Example 3: It has the implementation content of the above-mentioned embodiments, wherein for the specific implementation of the above-mentioned embodiments, reference can be made to the above description, and the embodiments herein are not repeated in detail; and in the embodiments of the present application, the difference from the above-mentioned embodiments is that: In this embodiment, the mice used are C57BL / 6J mice (hereinafter referred to as C57 mice), purchased from Shanghai Slek Experimental Animal Co., Ltd., and all animal operations involved in the experimental process are humanized for the mice.

[0033] In this embodiment, the peripheral elastase-induced abdominal aortic aneurysm model is used to carry out the experiment: 35 mg / ml of elastase is applied locally to the infrarenal aorta of the mouse, and 0.5% 3-aminopropionitrile fumarate (BAPN) is fed in its daily drinking water for 1 month. Two weeks after the operation, the mice in the administration group are administered by intraperitoneal injection for two weeks.

[0034] In this embodiment, after the modeling is completed, the aorta of the mouse is obtained after being perfused with physiological saline under anesthesia; the tissue adhered around the aorta is removed by using a biological microscope, and the level of arterial injury is evaluated by using photographing, pathological section staining and other means.

[0035] In this embodiment, (1) the relative content level of NAD+ / NADH in the artery is detected by using a detection kit, the NAD+ / NADH detection kit is purchased from Shanghai Blue Sky Biotech Co., Ltd., and the operation is performed according to the instruction; (2) the relative content of elastic fibers is determined by realizing EVG staining; the higher the content of vascular elastic fibers, the stronger the anti-injury ability of the blood vessel.

[0036] The above merely describes a preferred specific embodiment of the present application, but the protection scope of the present application is not limited to this. Any person skilled in the art, according to the technical solution and the inventive concept of the present application, can make equivalent replacement or change within the technical range disclosed by the present application, which should be covered within the protection scope of the present application.

Claims

1. A prodrug for supplementing NAD+, characterized in that, The prodrug is NAMPT agonist YB8 having the structure shown in Formula I: Formula 1.

2. The NAD+ supplementing prodrug of claim 1, wherein, The prodrug is a pharmaceutically acceptable salt of NAMPT agonist YB8.

3. The NAD+ supplementing prodrug of claim 1, wherein, The prodrug is used in multi-target therapy for improving blood vessel NAD+ level.

4. The NAD+ supplementing prodrug of claim 1, wherein, The prodrug is used in delaying the progression of abdominal aortic aneurysm.

5. The NAD+ supplementing prodrug of claim 1, wherein, The prodrug is used in preventing and treating abdominal aortic aneurysm.

6. The NAD+ supplementing prodrug of claim 1, wherein, The prodrug is used in preparing a drug for abdominal aortic aneurysm.

7. An abdominal aortic aneurysm model for evaluating the therapeutic effect of the prodrug according to claim 1, characterized by, The abdominal aortic aneurysm model refers to applying a certain concentration of elastase locally to the infrarenal aorta of a mouse, feeding 0.5% 3-aminopropionitrile fumarate BAPN in its daily drinking water for 4 weeks, dynamically monitoring the diameter change of the aneurysm by live ultrasound imaging technology, and evaluating the treatment effect of YB8.

8. The abdominal aortic aneurysm model of claim 7, wherein, The concentration of the elastase is 35 mg / ml.

9. The abdominal aortic aneurysm model of claim 7, wherein, The slowing down or retraction of the artery expansion is therapeutically effective.

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