New use of sulfonylurea drugs for anti-aging

Abstract

The present invention provides a new use of sulfonylurea drugs for anti-aging. Specifically, the present invention discovers the use of sulfonylurea drugs or their optical isomers, or their pharmaceutically acceptable salts in the preparation of anti-aging compositions or preparations. The experiments of the present invention show that sulfonylurea drugs, preferably glimepiride, chlorpropamide, glibenclamide, tolbutamide, significantly prolong the lifespan of nematodes, and thus have an effective anti-aging effect.

Description

Technical Field

[0001] The present invention relates to the field of medicine, and particularly to the anti-aging uses of sulfonylurea drugs such as glimepiride, chlorpropamide, glibenclamide, and tolbutamide. Background Art

[0002] Aging is a physiological degradation process that occurs after the body matures. Specifically, it is manifested as a decline in its own functions, stress ability, and the stability of the internal environment, as well as irreversible processes such as degenerative changes in organs and functions. In addition, aging is also the main inducement of most chronic diseases, such as coronary heart disease, malignant tumors, diabetes, and degenerative diseases of the brain and internal organs. With the development of society, the aging problem is becoming increasingly serious in more developed regions. It is estimated that by 2050, more than 20% of the world's population will be elderly. Although aging is an irreversible process, research shows that it has great plasticity, so it is possible to delay aging through some intervention means. Delaying aging and improving the health status of the elderly population through anti-aging drugs is one of the effective intervention countermeasures. Under the current situation of "population aging" and the background of "implementing the Healthy China Strategy", the development of anti-aging drugs is of great significance.

[0003] Sulfonylurea drugs are generally considered to be the earliest, most diverse, and most widely clinically used oral hypoglycemic drugs. Currently, there is no literature reporting that sulfonylurea drugs such as glimepiride, chlorpropamide, glibenclamide, and tolbutamide can be used for anti-aging. Summary of the Invention

[0004] The object of the present invention is to provide a new use of sulfonylurea drugs in anti-aging.

[0005] In a first aspect of the present invention, there is provided a use of a sulfonylurea drug, or its optical isomer, or its pharmaceutically acceptable salt, for preparing a composition or preparation for anti-aging.

[0006] In another preferred embodiment, the sulfonylurea drug is selected from: glimepiride, chlorpropamide, glibenclamide, tolbutamide, or a combination thereof.

[0007] In another preferred embodiment, the use of the composition or preparation is to extend lifespan; and / or delay aging.

[0008] In another preferred embodiment, the composition is a pharmaceutical composition, a cosmetic composition, a dietary supplement, a food composition, a health product composition.

[0009] In another preferred embodiment, the pharmaceutical composition contains:

[0010] (a) A sulfonylurea drug, or its optical isomer, or its pharmaceutically acceptable salt as an active ingredient;

[0011] (b) A pharmaceutically acceptable carrier or excipient.

[0012] In another preferred embodiment, the pharmaceutical composition further comprises an additional anti-aging active ingredient.

[0013] In another preferred embodiment, the sulfonylurea drug is selected from: glimepiride, chlorpropamide, glibenclamide, tolbutamide, or a combination thereof.

[0014] In another preferred embodiment, the pharmaceutical composition is an injectable or oral drug.

[0015] In another preferred embodiment, the form of the pharmaceutical composition is selected from the group consisting of: tablets, capsules, granules, suspensions, pills, solutions, syrups, or injections.

[0016] In another preferred embodiment, the composition or formulation is administered to a mammal or a nematode.

[0017] In another preferred embodiment, the mammal includes: a primate; more preferably, the mammal is a human.

[0018] In a second aspect of the present invention, there is provided a cosmetic composition or product, the cosmetic composition or product containing a sulfonylurea drug as an anti-aging active ingredient.

[0019] In another preferred embodiment, the sulfonylurea drug is selected from: glimepiride, chlorpropamide, glibenclamide, tolbutamide, or a combination thereof.

[0020] In a third aspect of the present invention, there is provided an in vitro, non-therapeutic and non-diagnostic anti-aging method, comprising the step of: administering to a subject in need a sulfonylurea drug, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an anti-aging active ingredient.

[0021] In another preferred embodiment, the subject is a mammal or a nematode.

[0022] In another preferred embodiment, the mammal includes: a primate; more preferably, the mammal is a human.

[0023] In a fourth aspect of the present invention, there is provided a pharmaceutical composition for anti-aging, the pharmaceutical composition containing:

[0024] (a1) A sulfonylurea drug, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;

[0025] (a2) An additional anti-aging active ingredient, said additional anti-aging active ingredient being selected from the group consisting of metformin, resveratrol, rapamycin, quercetin, etanercept, curcumin, arbutin, or a combination thereof;

[0026] (b) A pharmaceutically acceptable carrier or excipient.

[0027] It should be understood that within the scope of the present invention, each of the above technical features of the present invention and the technical features specifically described hereinafter (such as in the examples) can be combined with each other to form new or preferred technical solutions. Due to space limitations, they will not be elaborated one by one here. BRIEF DESCRIPTION OF THE DRAWINGS

[0028] Figure 1 It shows the situation where the sulfonylurea glimepiride (400 / 100 / 25 μM) prolongs the lifespan of nematodes (>10%) during live bacteria feeding.

[0029] Figure 2 It shows the situation where the sulfonylurea chlorpropamide (400 / 100 / 25 μM) prolongs the lifespan of nematodes (>10%) during live bacteria feeding.

[0030] Figure 3 It shows the situation where the sulfonylurea glibenclamide (400 / 100 / 25 μM) prolongs the lifespan of nematodes (>10%) during live bacteria feeding.

[0031] Figure 4 It shows the situation where the sulfonylurea tolbutamide (400 / 100 / 25 μM) prolongs the lifespan of nematodes (>10%) during live bacteria feeding. DETAILED DESCRIPTION OF THE INVENTION

[0032] Through extensive and in-depth research, the inventors of the present invention unexpectedly discovered for the first time that sulfonylurea drugs have anti-aging uses, and on this basis, the present invention was completed.

[0033] Specifically, the present invention provides that sulfonylurea drugs, preferably glimepiride, chlorpropamide, glibenclamide, tolbutamide have anti-aging uses. Using nematodes as model animals in the present invention, experiments show that at a concentration of 25 μm, glimepiride can extend the lifespan of nematodes by 25.34%; at a concentration of 100 μm, chlorpropamide can extend the lifespan of nematodes by 26.21%; at a concentration of 25 μm, glibenclamide can extend the lifespan of nematodes by 29.61%; at a concentration of 400 μm, tolbutamide can extend the lifespan of nematodes by 29.61%.

[0034] TERMS

[0035] As used herein, the term "active ingredient of the present invention", "anti-aging active ingredient of the present invention", "compound of the present invention", "anti-aging compound of the present invention" refers to sulfonylurea drugs, or pharmaceutically acceptable salts thereof, or solvates thereof, or optical isomers thereof, or racemates thereof, or crystals thereof, or hydrates thereof, or deuterated compounds thereof, or combinations thereof.

[0036] Aging and anti-aging

[0037] As used herein, "aging" refers to the process of loss and degradation that occurs in an organism in terms of its constituent substances, tissue structure, physiological functions, etc. over time. In the present invention, aging refers to biological aging.

[0038] As used herein, "anti-aging" means delaying, retarding, reducing, halting, and / or reversing the aging effect or process.

[0039] Cellular senescence is a phenomenon that causes individual cells to be unable to divide continuously and become arrested after several divisions. To detect cellular senescence, a cell staining test is generally used, which detects senescence-related markers (such as β-galactosidase activity). Senescent cells can interfere with the important functions of the entire organism and thus cause certain disorders. The aging of the entire organism is accompanied by an increased risk of certain disorders (such as diseases, complications, and symptoms).

[0040] Caenorhabditis elegans

[0041] Caenorhabditis elegans has achieved many excellent research results as a classic aging model. It has the characteristics of small size, short life cycle, easy cultivation and operation, and clear genetic background. And C. elegans is the first model animal to complete whole-genome sequencing. Its genome is very small and has a high homology with humans. These characteristics give it great advantages in the high-throughput screening of anti-aging drugs.

[0042] Sulfonylurea drugs

[0043] Sulfonylurea drugs are the earliest, most diverse, and most widely used oral hypoglycemic drugs in clinical practice. It is now known that sulfonylurea drugs act on the sulfonylurea receptor on the surface of pancreatic islet β cells, causing the ATP-sensitive potassium channels on the surface of pancreatic islet β cells to close, depolarizing the cell membrane, and thus releasing insulin to produce a hypoglycemic effect.

[0044] Glimepiride

[0045] Glimepiride is a third-generation long-acting anti-diabetic sulfonylurea drug. It has the same efficacy and fewer side effects at a smaller dose compared to glibenclamide. Its mechanism of action is to bind to the sulfonylurea receptor on the surface of pancreatic islet β cells, promoting the ATP-sensitive K +(K-ATP) channels close, causing depolarization of the cell membrane, opening voltage-dependent calcium channels, allowing Ca2+ influx, promoting insulin release, and inhibiting hepatic glucose synthesis, thereby reducing blood glucose. In addition, glimepiride can also increase cardiac glucose uptake through an insulin-independent pathway, which may be due to increased expression of two proteins, glucose transporter 1 and 4. Since glimepiride has a weak effect on cardiovascular K-ATP channels, cardiovascular adverse reactions are also rare. Glimepiride reaches its maximum serum concentration approximately 2.5 hours after oral administration and has a very high protein binding rate (>99%). It is the optimal sulfonylurea hypoglycemic drug in current clinical evaluations and is particularly suitable for type 2 diabetes patients who cannot be controlled by general sulfonylureas. It is the first sulfonylurea drug that can be used simultaneously with insulin. Since the drug has a short action time with the receptor, shortening the insulin secretion time, it has a strong insulin-sparing effect and can overcome secondary failure of pancreatic islet cells to a certain extent. Chemical formula: C 24 H 34 N4O5S, molecular weight: 490.62, CAS number: 93479-97-1. The structural formula is shown in Formula (Ⅰ):

[0046]

[0047] Chlorpropamide

[0048] Chlorpropamide is the first-generation sulfonylurea hypoglycemic drug. It selectively acts on the sulfonylurea receptor on the surface of pancreatic islet β cell membranes, causing the K-ATP channels to close, resulting in depolarization of the cell membrane, opening voltage-dependent calcium channels, allowing Ca2+ influx, promoting insulin release, and reducing blood glucose. Chlorpropamide is mainly used clinically to treat mild to moderate adult-onset diabetes. Due to its relatively large side effects, its clinical use has shown a decreasing trend year by year. Chemical formula: C 10 H 13 ClN2O3S, molecular weight: 276.74, CAS number: 94-20-2. The structural formula is shown in Formula (Ⅱ):

[0049]

[0050] Glibenclamide

[0051] Glibenclamide is a second-generation sulfonylurea hypoglycemic agent, and its potency is 200 times that of tolbutamide. Glibenclamide acts on the sulfonylurea receptor on the surface of pancreatic islet β cell membranes, causing the K-ATP channels to close, resulting in depolarization of the cell membrane, opening of voltage-dependent calcium channels, influx of Ca2+ and subsequent release of insulin, thereby reducing blood glucose levels. Glibenclamide can increase the insulin level in the portal vein or act directly on the liver, inhibiting hepatic glycogenolysis and gluconeogenesis, and reducing the production and output of glucose by the liver. Glibenclamide is rapidly absorbed orally, has a very high protein binding rate of 95%, reaches its peak plasma concentration 2 - 5 hours after oral administration, and has a duration of action of 24 hours. Glibenclamide is suitable for mild to moderate non-insulin-dependent (adult type, obese type) diabetic patients whose efficacy of single dietary control is not satisfactory. The patient's pancreatic islet β cells should have a certain insulin-secreting function and no serious complications. Due to its long clearance rate and the highest susceptibility to hypoglycemic reactions, it should be used with caution clinically and can be used for patients with ineffective hypoglycemic effects of certain gliclazide and glipizide hypoglycemic agents. Chemical formula: C 23 H 28 ClN3O5S, molecular weight: 494, CAS number: 10238-21-8. The structural formula is shown in Formula (Ⅲ):

[0052]

[0053] Tolbutamide

[0054] Tolbutamide is a first-generation sulfonylurea hypoglycemic agent. Its main mechanism of action is to act on the sulfonylurea receptor on the surface of pancreatic islet β cell membranes, causing the K-ATP channels to close, resulting in depolarization of the cell membrane, opening of voltage-dependent calcium channels, influx of Ca2+ and subsequent release of insulin, thereby reducing blood glucose levels. Tolbutamide is rapidly absorbed orally, generally appearing in the blood within 30 minutes after oral administration, reaching its peak plasma concentration 3 - 4 hours after oral administration, distributed in the extracellular fluid, with a protein binding rate of 90%, and a duration of action of 6 - 12 hours. Clinically, as a hypoglycemic agent, it is suitable for stable mild to moderate adult diabetic patients. Chemical formula: C 12 H 18 N2O3S, molecular weight: 270.35, CAS number: 64-77-7. The structural formula is shown in Formula (Ⅳ):

[0055]

[0056] The main side effects of sulfonylurea drugs are hypoglycemic reactions, which mostly occur in cases of excessive dosage, failure to reduce the dosage after blood sugar drops, not eating after taking the drug, combined use of hypoglycemic drugs, excessive alcohol consumption, as well as in the elderly, the weak, and those with impaired liver and kidney functions. Other adverse reactions include: digestive tract reactions such as loss of appetite, nausea, vomiting, abdominal distension, abdominal pain, and diarrhea; hematological system reactions such as leukopenia, neutropenia, thrombocytopenia, or pancytopenia, and hemolytic anemia; allergic reactions such as dermatitis and urticaria; and neurological reactions such as headache, dizziness, paresthesia, drowsiness, tinnitus, visual impairment, tremor, and ataxia in cases of excessive dosage.

[0057] Most sulfonylurea drugs are metabolized by the liver into inactive products and then excreted via the kidneys. Therefore, elderly patients and diabetic patients with impaired liver and kidney functions should use them with caution. Prolonged exposure of sulfonylurea receptors to the drug can cause receptor desensitization and apoptosis of pancreatic islet β cells, which suggests that intermittent exposure of sulfonylurea receptors can better exert the hypoglycemic effect of sulfonylurea drugs, and rapid-acting and short-acting sulfonylurea drugs can reduce this desensitization effect.

[0058] Drug Compositions and Administration Methods

[0059] The present invention also provides a composition, preparation, or product containing the active ingredient of the present invention, which can be used for anti-aging. Representative compositions, preparations, or products include anti-aging drugs, health products, and cosmetics.

[0060] A preferred composition is a pharmaceutical composition, which contains an effective amount of verapamil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

[0061] As used herein, the term "effective amount" or "effective dose" refers to an amount that can produce a function or activity (i.e., anti-aging function) in humans and / or animals and is acceptable to humans and / or animals.

[0062] As used herein, the components of the term "pharmaceutically acceptable" are suitable for humans and / or mammals without excessive adverse side effects (such as toxicity, irritation, and allergic reactions), that is, substances with a reasonable benefit / risk ratio. The term "pharmaceutically acceptable carrier" refers to a carrier used for administering therapeutic agents, including various excipients and diluents.

[0063] The pharmaceutical composition of the present invention contains a safe and effective amount of the active ingredient of the present invention and a pharmaceutically acceptable carrier. Such carriers include (but are not limited to): saline, buffer solution, glucose, water, glycerol, ethanol, and combinations thereof. Generally, the pharmaceutical preparation should be matched with the administration method, and the dosage forms of the pharmaceutical composition of the present invention are injection, oral preparation (tablet, capsule, oral liquid), transdermal agent, sustained-release agent. For example, it is prepared by a conventional method with physiological saline or an aqueous solution containing glucose and other adjuvants. The said pharmaceutical composition should be manufactured under aseptic conditions.

[0064] The effective amount of the active ingredient described in the present invention may vary with the mode of administration, the severity of the disease to be treated, etc. The selection of the preferred effective amount can be determined by those of ordinary skill in the art according to various factors (such as through clinical trials). The said factors include but are not limited to: the pharmacokinetic parameters of the said active ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated in the patient, the patient's body weight, the patient's immune status, the route of administration, etc. Generally, when the active ingredient of the present invention is administered at a dose of about 0.00001 mg - 50 mg / kg of animal body weight per day (preferably 0.0001 mg - 10 mg / kg of animal body weight), satisfactory effects can be obtained. For example, due to the urgent requirements of the treatment condition, several separate doses can be administered per day, or the dose can be proportionally reduced.

[0065] The main advantages of the present invention:

[0066] (a) It is first confirmed that sulfonylurea drugs can effectively anti-aging and extend lifespan.

[0067] (b) Sulfonylurea drugs at a lower concentration, preferably glibenclamide at a concentration of 25 μm, can extend the lifespan of nematodes by up to 29.61%.

[0068] The present invention will be further described below in conjunction with specific embodiments. It should be understood that these embodiments are only used to illustrate the present invention and not to limit the scope of the present invention. The experimental methods without specific conditions noted in the following embodiments are usually according to conventional conditions, such as the conditions described in Sambrook et al., Molecular Cloning: A Laboratory Manual (New York: Cold Spring Harbor Laboratory Press, 1989), or according to the conditions recommended by the manufacturer. Unless otherwise stated, percentages and parts are calculated by weight.

[0069] Example 1. Lifespan experiment of sulfonylurea drugs glimepiride, chlorpropamide, glibenclamide and tolbutamide on nematodes in live bacteria

[0070] Glimepiride (CAS: 93479-97-1), Chlorpropamide (CAS: 94-20-2), Glibenclamide (CAS: 10238-21-8), Tolbutamide (CAS: 64-77-7) were all purchased from Shanghai Titan Scientific Co., Ltd.; Wild-type Caenorhabditis elegans (N2) was purchased from the CAENORHABDITIS GENETICS CENTER (CGC). Synchronized nematodes were transferred to nematode growth medium (NGM) of the blank control group and the sulfonylurea drug administration groups (400 / 100 / 25 μM) at the L4 stage. There were about 60 nematodes in each group, and the medium was changed every 3 days. The culture was carried out at 20 °C. The number of surviving nematodes was recorded every day, and the dead nematodes were removed from the culture dish until all nematodes died. The data were summarized, and the survival curve was plotted using Graph Pad, and the significant difference was calculated (Log-rank test).

[0071] The data of the lifespan experiment are shown in Table 1, and the survival curve is as Figures 1-4 shown. The sulfonylurea drugs at a dosing concentration of 100 μM all extended the lifespan of nematodes on live bacteria by more than 10%. Compared with the control group, at the concentrations of 400 / 100 / 25 μM, Glimepiride extended the lifespan of nematodes by 16.5% / 10.68% / 25.34% respectively, Chlorpropamide extended the lifespan of nematodes by 24.85% / 26.21% / 20.58%, Glibenclamide extended the lifespan of nematodes by 24.37% / 27.77% / 29.61%, and Tolbutamide extended the lifespan of nematodes by 29.61% / 19.51% / 24.08%. The significant difference relative to the control group: * indicates P < 0.05.

[0072] Table 1. Data of lifespan experiment

[0073]

[0074]

[0075] In summary, through the nematode lifespan experiment of the present invention, the results show that the sulfonylurea drugs Glimepiride, Chlorpropamide, Glibenclamide and Tolbutamide of the present invention can extend the lifespan of nematodes and have high utilization value in the field of anti-aging.

[0076] All the documents mentioned in the present invention are cited in this application as references, just as if each document was cited separately as a reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of this application.

Claims

1. Use of a sulfonylurea drug or a pharmaceutically acceptable salt thereof, characterized in that, For preparing a pharmaceutical composition or preparation, the pharmaceutical composition or preparation is used for anti-aging; wherein, the anti-aging refers to extending lifespan; and the aging is a physiological degradation process that occurs after the body matures; Wherein, the sulfonylurea drugs are selected from: chlorpropamide, tolbutamide, or a combination thereof.

2. The use according to claim 1, characterized in that, The sulfonylurea drug is selected from tolbutamide.

3. The use according to claim 1, characterized in that, The pharmaceutical composition contains: (a) A sulfonylurea drug or a pharmaceutically acceptable salt thereof as an active ingredient; wherein, the sulfonylurea drugs are selected from: chlorpropamide, tolbutamide, or a combination thereof; (b) A pharmaceutically acceptable carrier.

4. The use according to claim 1, characterized in that, The pharmaceutical composition is an injectable drug or an oral drug.

5. The use according to claim 1, characterized in that, The form of the pharmaceutical composition is selected from the group consisting of: tablets, capsules, granules, suspensions, pills, solutions, syrups, or injections.

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