CN112022862A - New anti-aging application of sulfonylurea medicine - Google Patents

Abstract

The invention provides a new anti-aging application of sulfonylurea drugs. Specifically, the invention finds the application of the sulfonylurea medicament or the optical isomer thereof or the pharmaceutically acceptable salt thereof in preparing the anti-aging composition or preparation. Experiments show that sulfonylurea medicines, preferably glimepiride, chlorpropamide, glibenclamide and tolbutamide, remarkably prolong the service life of nematodes, so that the compound has an effective anti-aging effect.

Description

New anti-aging application of sulfonylurea medicine

Technical Field

The invention relates to the field of medicines, in particular to anti-aging application of sulfonylurea drugs of glimepiride, chlorpropamide, glibenclamide and tolbutamide.

Background

Aging is a physiological degenerative process that occurs after the body has matured. It is characterized by irreversible processes such as self hypofunction, reduced stress ability and stability of internal environment, and degenerative change of organs and functions. In addition, aging is also a major cause 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 increasingly serious in more developed areas. It is expected that by 2050, more than 20% of the population will be aged worldwide. Although senescence is an irreversible process, studies have shown that it is highly plastic, and thus it is possible to delay senescence by some intervention means. Delaying aging and improving the health status of the elderly population through anti-aging drugs is one of the effective intervention strategies. Under the current situation of 'population aging' and 'implementation of healthy Chinese strategy', the development of anti-aging drugs has important significance.

Sulfonylureas are generally considered the first, most varied, and most widely used oral hypoglycemic agents. At present, no literature reports that sulfonylurea drugs, namely glimepiride, chlorpropamide, glibenclamide and tolbutamide, can be used for resisting aging.

Disclosure of Invention

The invention aims to provide a new application of sulfonylurea medicaments in anti-aging.

In a first aspect of the invention there is provided the use of a sulfonylurea drug, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a composition or formulation for anti-ageing.

In another preferred embodiment, the sulfonylurea drug is selected from the group consisting of: glimepiride, chlorpropamide, glyburide, tolbutamide, or combinations thereof.

In another preferred embodiment, the use of the composition or formulation is to extend longevity; and/or delay aging.

In another preferred embodiment, the composition is a pharmaceutical composition, a cosmetic composition, a dietary supplement, a food composition, a nutraceutical composition.

In another preferred embodiment, the pharmaceutical composition comprises:

(a) a sulfonylurea drug, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;

(b) a pharmaceutically acceptable carrier or excipient.

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

In another preferred embodiment, the sulfonylurea agent is selected from: glimepiride, chlorpropamide, glyburide, tolbutamide, or combinations thereof.

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

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

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

In another preferred embodiment, the mammal comprises: a primate; more preferably the mammal is a human.

In a second aspect of the present invention, a cosmetic composition or product is provided, which contains a sulfonylurea drug as an anti-aging active ingredient.

In another preferred embodiment, the sulfonylurea agent is selected from: glimepiride, chlorpropamide, glyburide, tolbutamide, or combinations thereof.

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

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

In another preferred embodiment, the mammal comprises: a primate; more preferably the mammal is a human.

In a fourth aspect of the present invention, there is provided a pharmaceutical composition for anti-aging, comprising:

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

(a2) an additional anti-aging active selected from the group consisting of: metformin, resveratrol, rapamycin, quercetin, etanercept, curcumin, arbutin, or combinations thereof;

(b) a pharmaceutically acceptable carrier or excipient.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows that the sulfonylurea drug Glimepiride (400/100/25 μ M) extended nematode longevity (> 10%) when live fed.

FIG. 2 shows that sulfonylurea drug chlorpropamide (400/100/25 μ M) prolongs nematode longevity (> 10%) when live fed.

FIG. 3 shows that the sulfonylurea drug glibenclamide (400/100/25 μ M) extended nematode longevity (> 10%) when live fed.

FIG. 4 shows that the sulfonylurea drug tolbutamide (400/100/25 μ M) extends nematode longevity (> 10%) when live fed.

Detailed Description

The inventor of the invention has made extensive and intensive studies, and has surprisingly found that sulfonylurea drugs have an anti-aging effect for the first time, and has completed the invention on the basis of the discovery.

Specifically, the invention provides a sulfonylurea medicament, preferably application of glimepiride, chlorpropamide, glibenclamide and tolbutamide to anti-aging. The invention takes the nematode as a model animal, and experiments show that the life of the nematode can be prolonged to 25.34 percent under the concentration of 25 mu m of the glimepiride; the chlorpropamide can prolong the life of the nematode to 26.21 percent under the concentration of 100 mu m; the life of the nematodes can be prolonged by 29.61% under the concentration of 25 μm of the glibenclamide; the life of the nematode can be prolonged to 29.61% under the concentration of 400 mu m.

Term(s) for

As used herein, the terms "active ingredient of the present invention", "antiaging active ingredient of the present invention", "compound of the present invention", "antiaging compound of the present invention" sulfonylurea drug, or pharmaceutically acceptable salt thereof, or solvate thereof, or optical isomer thereof, or racemate thereof, or crystal thereof, or hydrate thereof, or deuterated compound thereof, or combination thereof.

Aging and anti-aging

As used herein, "aging" refers to the process of loss and degeneration of an organism in terms of constituent substances, tissue structure, physiological functions, etc., which occurs with time. In the present invention, aging refers to biological aging.

As used herein, "anti-aging" refers to delaying, retarding, reducing, stopping and/or reversing an aging effect or process.

Cell aging is a phenomenon that results in the inability of individual cells to divide continuously, arresting them after several divisions. To detect cellular senescence, a cell staining assay is typically used which detects senescence-associated markers (e.g., β -galactosidase activity). Senescent cells can interfere with important functions of the whole organism and thereby cause certain disorders. Aging of the whole organism is accompanied by an increased risk of certain disorders, such as diseases, complications and symptoms.

Caenorhabditis elegans

Caenorhabditis elegans has obtained a plurality of excellent research results as a classical aging model, and has the characteristics of small size, short life cycle, easy culture and operation, clear genetic background and the like. And the nematode is the first model animal to complete the whole genome sequencing, and the genome is very small and has high homology with human. These characteristics make it a great advantage in high throughput screening of anti-aging drugs.

Sulfonylurea medicine

The sulfonylurea medicine is the oral hypoglycemic medicine with the earliest application, the most varieties and the most extensive clinical application. Sulfonylureas drug acts on sulphonylurea receptor on surface of islet beta cell, to close ATP sensitive potassium channel on surface of islet beta cell, depolarize cell membrane, release insulin, and reduce blood sugar.

Glimepiride

Glimepiride (glimepiride) is a third-generation sulfonylurea long-acting antidiabetic agent, and has the same drug effect and smaller side effect at a smaller dose compared with glibenclamide. The action mechanism is that through the combination with sulfonylurea receptor on the surface of islet beta cell, ATP sensitive K is promoted⁺(K-ATP) channels close, causing depolarization of cell membranes, opening voltage-dependent calcium channels, influx of Ca2+, facilitating release of insulin, and inhibiting hepatic glucose synthesis, thereby lowering blood glucose. In addition, glimepiride may also increase cardiac glucose uptake through a non-insulin dependent pathway, which may be the result of increased expression of both glucose transport factor 1,4 proteins. Because the glimepiride has weak effect on cardiovascular K-ATP channels, the adverse reaction of the cardiovascular system is also little. The maximum serum concentration of the glimepiride is reached after about 2.5 hours of oral administration, and the protein binding rate is very high (>99 percent) is the optimal sulfonylurea hypoglycemic agent in the current clinical evaluation, and is particularly suitable forType 2 diabetes patients who cannot be controlled by sulfonylureas in general. It is the first sulfonylurea drug to be used with insulin. The action time of the medicine and a receptor is short, so that the insulin secretion time is shortened, the medicine has a strong insulin-saving effect, and the secondary failure of islet cells can be overcome to a certain extent. The chemical formula is as follows: c₂₄H₃₄N₄O₅S, molecular weight: 490.62, CAS number: 93479-97-1. The structural formula is shown as the formula (I):

chlorosulfonylpropylurea

Chloropropionuride (chlorpapamide) is the first generation of sulfonylurea hypoglycemic agent, which selectively acts on sulfonylurea receptor on the surface of pancreatic islet beta cell membrane to close K-ATP channel, cause depolarization of cell membrane, open voltage-dependent calcium channel, and cause release of insulin by Ca2+ influx, so as to reduce blood sugar. Chlorpropamide is mainly used for clinically treating light and moderate adult-type diabetes, and clinical use tends to be reduced year by year due to large side effects. The chemical formula is as follows: c₁₀H₁₃ClN₂O₃S, molecular weight: 276.74, CAS number: 94-20-2. The structural formula is shown as a formula (II):

glibenclamide

Glibenclamide (glibenclamide) is the second generation sulfonylurea hypoglycemic agent, and its action strength is 200 times of tolbutamide. The glibenclamide promotes the K-ATP channel to be closed through a sulfonylurea receptor on the surface of an islet beta cell membrane, causes depolarization of the cell membrane, opens a voltage-dependent calcium channel, and promotes release of insulin through Ca2+ inflow, so that blood sugar is reduced. Glibenclamide can increase portal insulin level or act directly on liver, inhibit hepatic glycogenolysis and gluconeogenesis, and reduce hepatic production and output of glucose. Grid notebookThe urea is fast to absorb by oral administration, the protein binding rate is high and is 95%, the blood concentration reaches the peak value 2-5 hours after the urea is taken orally, and the urea continues to act for 24 hours. The glibenclamide is suitable for light and medium non-insulin dependent diabetes mellitus patients (adult type and obesity type) with unsatisfactory diet control curative effect, and islet beta cells of the patients should have a certain insulin secretion function and have no serious complications. Because of its long clearance rate and the most easy hypoglycemic reaction, it is used cautiously in clinic and may be used in some patients with unobvious gliclazide and glipizide hypoglycemic medicine effect. The chemical formula is as follows: c₂₃H₂₈ClN₃O₅S, molecular weight: 494, CAS No.: 10238-21-8. The structural formula is shown as the formula (III):

tolbutamide

Tolbutamide (tolbutamide) is the first generation of sulfonylurea hypoglycemic agent, and its main action mechanism is acting on sulfonylurea receptor on the surface of pancreatic islet beta cell membrane to make K-ATP channel close, and make depolarization of cell membrane, and make voltage-dependent calcium channel open, and make Ca2+ flow in to make release of insulin and reduce blood sugar. The tolbutamide is fast to absorb by oral administration, generally appears in blood within 30 minutes of oral administration, the blood concentration reaches the peak value 3-4 hours after oral administration, the tolbutamide is distributed in extracellular fluid, the protein binding rate is 90%, and the action lasts for 6-12 hours. The compound is clinically used as a hypoglycemic agent and is suitable for stable light and medium adult diabetes patients. The chemical formula is as follows: c₁₂H₁₈N₂O₃S, molecular weight: 270.35, CAS number: 64-77-7. The structural formula is shown as a formula (IV):

the main side effect of sulfonylurea drugs is hypoglycemia reaction which mostly occurs in overdose or non-decrement after blood sugar reduction, non-eating after taking medicine, combined application of hypoglycemic drugs, large amount of drinking, and the elderly and the patients with weak liver and kidney function impairment. Other adverse reactions include: anorexia, nausea, emesis, abdominal distention, abdominal pain, diarrhea, etc.; leukopenia, neutropenia, thrombocytopenia or pancytopenia, hemolytic anemia and other blood system reactions; allergic reactions such as dermatitis and urticaria, and nervous system reactions such as headache, dizziness, paresthesia, lethargy, tinnitus, hypopsia, tremor and ataxia caused by overdose.

Most sulfonylureas are metabolized into inactive products by the liver and then excreted through the kidney, so it should be used with cautions for the elderly and diabetic patients with liver and kidney insufficiency. The long-time exposure of the sulfonylurea receptor to the drug can cause receptor desensitization and islet beta cell apoptosis, which indicates that the intermittent exposure of the sulfonylurea receptor can better exert the hypoglycemic effect of the sulfonylurea drug, and the fast and short-acting sulfonylurea drug can relieve the desensitization effect.

Pharmaceutical compositions and methods of administration

The invention also provides a composition or a preparation or a product containing the active ingredients of the invention, and the composition or the preparation or the product can be used for resisting aging. Representative compositions or formulations or products include anti-aging drugs, nutraceuticals, and cosmetics.

One preferred composition is a pharmaceutical composition comprising an effective amount of verapamil or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

As used herein, the term "effective amount" or "effective dose" refers to an amount that produces a function or activity (i.e., anti-aging function) in a human and/or animal and is acceptable to the human and/or animal.

As used herein, an ingredient of the term "pharmaceutically acceptable" is one that is suitable for use in humans and/or mammals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., at a reasonable benefit/risk ratio. The term "pharmaceutically acceptable carrier" refers to a carrier for administration of a therapeutic agent, including various excipients and diluents.

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 vectors include (but are not limited to): saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof. The pharmaceutical composition of the invention can be prepared into injections, oral preparations (tablets, capsules, oral liquids), transdermal agents and sustained-release agents. For example, by a conventional method using physiological saline or an aqueous solution containing glucose and other adjuvants. The pharmaceutical composition is preferably manufactured under sterile conditions.

The effective amount of the active ingredient of the present invention may vary depending on the mode of administration and the severity of the disease to be treated, etc. The selection of a preferred effective amount can be determined by one of ordinary skill in the art based on a variety of factors (e.g., by clinical trials). Such factors include, but are not limited to: pharmacokinetic parameters of the active ingredient such as bioavailability, metabolism, half-life, etc.; the severity of the disease to be treated by the patient, the weight of the patient, the immune status of the patient, the route of administration, and the like. In general, satisfactory results are obtained when the active ingredient of the invention is administered at a daily dose of about 0.00001mg to 50mg per kg of animal body weight (preferably 0.0001mg to 10mg per kg of animal body weight). For example, divided doses may be administered several times per day, or the dose may be proportionally reduced, as may be required by the urgency of the condition being treated.

The invention has the main advantages that:

(a) the sulfonylurea medicine is proved to be effective in resisting aging and prolonging the life for the first time.

(b) Sulfonylureas can extend nematode longevity by 29.61% at lower concentrations, preferably at a concentration of 25 μm.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. Experimental procedures without specific conditions noted in the following examples, generally followed by conventional conditions, such as Sambrook et al, molecular cloning: the conditions described in the Laboratory Manual (New York: Cold Spring Harbor Laboratory Press,1989), or according to the manufacturer's recommendations. Unless otherwise indicated, percentages and parts are by weight.

Example 1 nematode longevity experiments on live bacteria with sulfonylurea drugs Glimepiride, chlorpropamide, Glibenclamide and tolbutamide

Glimepiride (CAS: 93479-97-1), chlorpropamide (CAS: 94-20-2), glyburide (CAS: 10238-21-8), tolbutamide (CAS: 64-77-7), all available from Shanghai Tantake technology, Inc.; wild type C.elegans (N2) was purchased from CAENORHABDITIS GENETICS CENTER (CGC). The synchronized nematodes were transferred to the Nematode Growth Medium (NGM) of the placebo group and the sulfonylurea drug administration group (400/100/25. mu.M) at L4, and about 60 nematodes were added to each group, and the medium was changed every 3 days and cultured at 20 ℃. The number of surviving nematodes was recorded daily and the dead nematodes were removed from the plates until all were dead. The data were summarized, survival curves were plotted using Graph Pad, and significance differences (Log-rank test) were calculated.

The life test data are shown in table 1, the survival curve is shown in figure 1, and the life of the nematode prolonged by sulfonylurea drugs on live bacteria is more than 10% under the administration concentration of 100 mu M. Compared with the control group, at the concentration of 400/100/25 mu M, the life of the Glimepiride extended nematode is 16.5%/10.68%/25.34%, the life of the chlorpropamide extended nematode is 24.85%/26.21%/20.58%, the life of the Glibenclamide extended nematode is 24.37%/27.77%/29.61%, and the life of the tolbutamide extended nematode is 29.61%/19.51%/24.08%. Significant differences relative to control: denotes P < 0.05.

TABLE 1 Life test data

In conclusion, the results of the life test of the nematodes show that the sulfonylurea drugs glimepiride, chlorpropamide, glibenclamide and tolbutamide can prolong the life of the nematodes and have high utilization value in the anti-aging field.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

Claims (10)

1. Use of a sulfonylurea drug, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, for the preparation of a composition or formulation for anti-aging.

2. The sulfonylurea agent of claim 1 selected from the group consisting of: glimepiride, chlorpropamide, glyburide, tolbutamide, or combinations thereof.

3. Use according to claim 1, wherein the use of the composition or formulation is for prolonging life; and/or delay aging.

4. The use according to claim 1, wherein the composition is a pharmaceutical composition, a cosmetic composition, a dietary supplement, a food composition, a nutraceutical composition.

5. The use of claim 1, wherein the pharmaceutical composition comprises:

(a) a sulfonylurea drug, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient;

(b) a pharmaceutically acceptable carrier or excipient.

6. The use of claim 1, wherein the pharmaceutical composition is an injectable or oral medicament.

7. The use of claim 1, wherein the pharmaceutical composition is in a form selected from the group consisting of: tablets, capsules, granules, suspensions, pills, solutions, syrups, or injections.

8. A cosmetic composition or product comprising a sulfonylurea drug as an anti-aging active ingredient.

9. An in vitro, non-therapeutic, non-diagnostic anti-aging method comprising the steps of: administering a sulfonylurea drug, or an optical isomer thereof, or a pharmaceutically acceptable salt thereof, as an anti-aging active ingredient to a subject in need thereof.

10. A pharmaceutical composition for anti-aging, comprising:

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

(a2) an additional anti-aging active selected from the group consisting of: metformin, resveratrol, rapamycin, quercetin, etanercept, curcumin, arbutin, or combinations thereof;

(b) a pharmaceutically acceptable carrier or excipient.

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