JP2008162931A - Agent for prevention or treatment of osteoporosis - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide an agent for the prevention and treatment of osteoporosis capable of surely preventing or treating the bone loss without excessively lowering the blood pressure. <P>SOLUTION: The agent for the prevention or treatment of osteoporosis comprises a substance having an angiotensin converting enzyme inhibiting action. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to an agent for preventing or treating osteoporosis.

The renin-angiotensin system is known as a regulatory system for increasing blood pressure, which is an important system for life activity. Renin, which is an enzyme produced in the kidney, acts on angiotensinogen in blood to produce angiotensin I, which is a peptide consisting of 10 amino acids, and angiotensin-converting enzyme is converted into dipeptide His from the C-terminus of this angiotensin I. -Leu is liberated to produce angiotensin II consisting of 8 amino acids. Angiotensin II then contracts vascular smooth muscles to increase blood pressure, secretes aldosterone from the adrenal cortex, and raises blood pressure by reabsorbing sodium in the kidney.

The present inventors pay attention to the fact that hypertension and osteoporosis are two major diseases that develop with aging, and many osteoporosis patients also have hypertension, and there are factors common to these. I thought that it might be, so I did intensive research.

As a result, the inventors have found that the renin-angiotensin system related to an increase in blood pressure is deeply involved in the development of osteoporosis.

On the other hand, administration of angiotensin II to rats caused hypertension, osteoclast proliferation / activation, and decreased bone density. In addition, it was originally a type of antagonist for angiotensin II receptor in hypertensive rats. There has been a report that when certain “olmesartan” is administered, proliferation and activation of osteoclasts are suppressed, and a decrease in bone density is prevented (Non-patent Document 1).

Angiotensin II receptors include “AT1 receptor” and “AT2 receptor”, and olmesartan is a kind of “AT1 receptor” antagonist.

However, as a result of different approaches using the Tsukuba hypertensive mouse with “Losartan”, which is one of the same “AT1 receptor” antagonists as “Olmesartan”, the present inventors found that the bone mass is further reduced. did.

This suggests that the AT2 receptor may perform an alternative function even if the signal transduction via the AT1 receptor is inhibited. With an antagonist of the AT1 receptor, prevention / treatment of osteoporosis is not always sufficient. It means no. In addition, the AT2 receptor fulfills an alternative function, and even though the target signal through the AT1 receptor can be inhibited, it leads to the activation of the signal through the AT2 receptor and conversely worsens hypertension. There is also a risk of causing unwanted effects.

On the other hand, by inhibiting the production stage of angiotensin I by renin, for example, upstream of the renin-angiotensin system, it is considered that osteoporosis can be prevented as well as an increase in blood pressure. There is a concern that inhibiting upstream may increase the possibility of causing other diseases.

Accordingly, the present inventors have an inhibitor of angiotensin converting enzyme (hereinafter sometimes referred to as “ACE”) that catalyzes the conversion of angiotensin I to angiotensin II (hereinafter sometimes referred to as “ACEI”). Therefore, the present inventors have come to consider that the renin-angiotensin system can be suppressed more reliably (inhibiting signal transduction via the angiotensin II receptor) and osteoporosis can be prevented and treated without side effects.

Sankei Shimbun 08/09 Tokyo morning edition 1 page

Accordingly, an object of the present invention is to provide an agent for preventing and treating osteoporosis that can reliably prevent or treat a decrease in bone mass without worrying about extremely lowering blood pressure.

The above object is achieved by the following invention.

(First invention)
An agent for preventing or treating osteoporosis, comprising a substance having an angiotensin converting enzyme inhibitory action or a precursor thereof.

(Second invention)
The agent for preventing or treating osteoporosis according to the first invention, wherein the substance having an angiotensin converting enzyme inhibitory action is at least one selected from the following (A) to (C).
(A) Low molecular weight compound (B) Peptides (C) Polynucleotide that suppresses expression of angiotensin converting enzyme gene

(Third invention)
The preventive or therapeutic agent for osteoporosis according to the second invention, wherein the low molecular compound is a compound having a cyclic structure.

(Fourth invention)
The preventive or therapeutic agent for osteoporosis according to the third invention, wherein the substance having an angiotensin converting enzyme inhibitory action is enalapril or a derivative thereof.

The agent for preventing or treating osteoporosis of the present invention is a revolutionary agent that can prevent or treat both hypertension and osteoporosis as a single agent.

Hereinafter, the present invention will be described in detail.

<Preventive or therapeutic agent for osteoporosis of the present invention>
(1) Kind of active ingredient As the substance having an angiotensin converting enzyme inhibitory action (hereinafter sometimes referred to as “ACEI”) used in the present invention, any substance having an angiotensin converting enzyme inhibitory action can be used. Examples thereof include (A) low molecular weight compounds, (B) peptides, and (C) polynucleotides that suppress the expression of angiotensin converting enzyme gene.

In the present invention, the “precursor of a substance having an angiotensin converting enzyme inhibitory activity” is a derivative or a pharmaceutically acceptable salt that can be converted into a substance having an angiotensin converting enzyme action in vivo. .

(A) Low molecular compound In the present invention, the ACEI that is a low molecular compound is not particularly limited as long as it has an angiotensin converting enzyme action. For example, a compound having one or more cyclic structures in the molecule is preferable. It is illustrated as. Examples of the cyclic structure include a monocyclic ring, a condensed polycyclic ring, and a ring assembly structure. In addition, the cyclic structure may be a heterocyclic ring in addition to a carbon alone structure.
Moreover, the precursor etc. which can be converted into the said compound by a human body, such as derivatives, such as a pharmacologically acceptable salt of this said compound, may be sufficient.

Specifically, the following known angiotensin converting enzyme inhibitors (including precursors) and the like can be used.

Illustrative examples include alasepril (such as “Cetapril” manufactured by Dainippon Sumitomo Pharma Co., Ltd.), deacetyl alacepril, ano-alacepril, imidapril hydrochloride (such as “Tanatril” manufactured by Tanabe Seiyaku Co., Ltd.), imidapril, imidaprilat, Indalapril, indolapril, enalapril maleate (manufactured by “Lenibase”, etc.), enalapril, enalapril, captopril, “Captopril” manufactured by Daiichi Sankyo Co., Ltd. ), Quinapril hydrochloride (“Conan” manufactured by Mitsubishi Pharma Corporation), quinapril, quinaprilate, clear zapril (cliazapril), cilazapril, spirapril, zefenopril, temocapril hydrochloride (Daiichi Sankyo Co., Ltd., “ACECOL”) Etc.), temocapril, temocapril , Delapril hydrochloride (“Adecut” manufactured by Takeda Pharmaceutical Co., Ltd.), trandolapril (“prelan” manufactured by Chugai Pharmaceutical Co., Ltd.), trandolaprilate, pivalpril, fentiapril , Fosinopril, Fusinopril, Perindopril Erbumine, Perindopril, Perindopril, Benazapril, Benazepril hydrochloride (“Cibasen” manufactured by Novartis Pharma Co., Ltd.), Benazepril, Benazeprilate, Benzapril, benzepril, pentepril ), Moexipril, ramipril, lisinopril (“Longes” manufactured by Shionogi & Co., Ltd.), and (R) -3-[(S) -1-carboxy-5- (4-piperidyl) -pentyl] -Amino-4-oxo-2,3,4,5-teto Hydro-1,5-benzothiazepine-5-acetic acid, described in JP-A 09-067252, trans-10-hydroxy isolated from royal jelly - like decenoic acid.

(B) Peptides In addition, as the ACEI that is a peptide, for example, angiotensin converting enzyme, which is a protein-derived peptide, can be used. However, these are chemically or well-known biotechnology techniques. It may be used and artificially synthesized.

Specifically, for example, a peptide derived from corn protein described in JP-A-2-240027,
An α-zein or gluten meal described in JP-A-2-240028, which is a bovine-derived casein peptide described in Japanese Patent Publication No. 61-51564, which is described in JP-A-3-81291. A peptide mixture obtained by enzymatic decomposition and a fraction having a molecular weight of 10,000 or less obtained by gel filtration or ultrafiltration. A liquid containing a fig-derived substance having a molecular weight of 10,000 or less as described in JP-A-2-282394. Fraction obtained by hydrolyzing fish protein described in the publication and molecular weight fractionation Peptide described in JP-A-6-107686 Peptide described in JP-A-2-240027 JP-A-3-81291 No. 61-5, a peptide derived from the Antarctic krill tissue A peptide derived from bovine casein described in Japanese Patent No. 564 was obtained by degrading fish meat or soybean with Bacillus serine protease, Bacillus endoprotease, or plant-derived thiol protease described in JP-A-62-169732 Peptide mixture Degradation product derived from koji and koji koji by neutral protease of Bacillus subtilis described in JP-A-4-304896, acidic protease of Aspergillus niger, acidic protease of Rhizopus deremer described in JP-A-8-269088 And peptides corresponding to amino acid sequences 20 to 25 residues of kappa casein glycomacropeptide.

(C) Polynucleotide that suppresses expression of angiotensin converting enzyme gene As a polynucleotide that suppresses expression of angiotensin converting enzyme gene, antisense DNA against angiotensin converting enzyme DNA or double strand having RNA interference action against mRNA of angiotensin converting enzyme Alternatively, single-stranded RNA (dsRNA, shRNA, microRNA, etc.) and the like can be mentioned.
The polynucleotide may be a hybrid of DNA and RNA.

Furthermore, the polynucleotide that suppresses the expression of the angiotensin converting enzyme gene includes, in addition to the above-mentioned polynucleotide, one or several of these polynucleotide sequences within a range that does not affect the expression inhibitory action of the angiotensin converting enzyme gene. Those in which a single nucleotide is deleted, substituted, added or inserted are also included.
These polynucleotides can be used as DNA, RNA, or as plasmids, viral vectors, and the like.

(2) Other components The preventive or therapeutic agent for osteoporosis of the present invention can contain other components within a range not inhibiting the inhibitory effect or preventive or therapeutic effect thereof, for example, a pharmaceutically acceptable carrier. As excipients, lubricants, binders, disintegrants, stabilizers, flavoring agents, diluents, surfactants, emulsifiers, solubilizers, absorption promoters, moisturizers, adsorbents, fillers, increasing amounts It can be formulated by a well-known method using additives such as humectants, moisturizers and preservatives.
Here, examples of the excipient include organic excipients and inorganic excipients.

The preventive or therapeutic agent for osteoporosis of the present invention may be a combination with conventionally known preventive or therapeutic components for osteoporosis.

(3) Dosage Form Examples of the osteoporosis preventive or therapeutic agent form of the present invention include forms such as tablets, capsules, granules, powders, pills, troches, syrups, and injections.

(4) Administration method The administration method of the preventive or therapeutic agent for osteoporosis of the present invention includes oral administration, intravenous administration such as intravenous injection, intramuscular administration, transdermal administration, nasal administration, intradermal administration, subcutaneous administration, abdominal cavity Examples include internal administration, rectal administration, mucosal administration, and inhalation.
When the active ingredient angiotensin converting enzyme inhibitory substance is a low molecular weight compound or peptide, oral administration is preferable from the viewpoint of simplicity and the like, and it is safe and keeps the blood concentration constant. From the standpoint, intravenous administration such as intravenous injection is preferable, and intramuscular administration such as intramuscular injection is preferable from the viewpoint of reliably reaching the affected area.

In addition, when the substance having an angiotensin converting enzyme inhibitory action which is an active ingredient is a polynucleotide, a method in which an expression plasmid is directly administered into muscle (DNA vaccine method), a liposome method, a lipofectin method, a microinjection method, a calcium phosphate method, Examples include electroporation, and the DNA vaccine method and the liposome method are particularly preferable.

When using a viral vector (Nikkei Science, April 1994, 20-45, Monthly Pharmaceutical Affairs, 36 (1), 23-48 (1994), Experimental Medicine Extra Number, 12 (15), (1994), and As described in these cited references and the like, it can be carried out by incorporating a gene of interest into a virus.

Examples of the virus used for the viral vector include retrovirus, adenovirus, adeno-associated virus, herpes virus, vaccinia virus, poxvirus, poliovirus, and simbis virus.
Among viruses, retroviruses, adenoviruses, adeno-associated viruses, vaccinia viruses and the like are preferable, and adenoviruses are particularly preferable.

In order to actually make a gene act as a medicine, in addition to the “in vivo method” in which the gene is directly introduced into the body, the gene is introduced into a cell collected from a human, and then the gene-introduced cell is returned to the body. [Nikkei Science, April 1994 issue, pp. 20-45, Monthly Pharmaceutical Affairs, 36 (1), 23-48 (1994), Experimental Medicine Extra Number, 12 (15), (1994 ), And their cited references, etc.] are preferable in that the in vivo method is simple and inexpensive, and the ex vivo method is preferable in that the gene is efficiently introduced into the cell.

In the case of administration by “in vivo method”, an appropriate administration route can be selected according to the disease, symptom and the like for the purpose of treatment. Examples of the administration route include vein, artery, subcutaneous, intradermal, intramuscular and the like.

In the case of administering by “in vivo method”, for example, it can take a form of preparation such as a liquid. In general, a form such as an injection containing a gene is preferable, and various components commonly used in injections and the like can be added as necessary.

In addition, in a liposome containing a gene or a membrane-fused liposome (such as Sendai virus (HVJ) -liposome), it can be used in the form of a liposome preparation such as a suspension, a freezing agent, and a centrifugal concentrated freezing agent.

(5) Content of active ingredient The content of the active ingredient angiotensin converting enzyme inhibitory substance or its precursor in the preventive or therapeutic agent for osteoporosis of the present invention varies depending on the dosage form. Although it is not limited, it may be appropriately selected in relation to the dosage within a range in which various dosage forms are possible. For example, in the case of a liquid preparation, it is preferably 0.0001 to 10 (w / v%), more preferably 0. 0.001 to 5 (w / v%), particularly in the case of an injection, preferably 0.0002 to 0.2 (w / v%), more preferably 0.001 to 0.1 (w / v%), In the case of a solid agent, it can be preferably prepared as 0.01 to 50 (w / w%), more preferably 0.02 to 20 (w / w%), but it is not necessarily limited to this range.

(6) Dosage of osteoporosis prevention or treatment agent (in terms of active ingredient)
The dose of the prophylactic or therapeutic agent for osteoporosis of the present invention varies depending on the administration route, symptoms, target tissues and organs, age, weight, form of the prophylactic or therapeutic agent, etc., for example, an angiotensin converting enzyme which is an active ingredient When the substance having an inhibitory action is a low molecular weight compound, a peptide or the like, the amount of the active ingredient in the prophylactic or therapeutic agent is preferably 0.005 to 500 mg, more preferably 1 kg of the subject body weight requiring treatment. 0.1 to 100 mg, provided that the lower limit is preferably 0.01 mg (more preferably 0.1 mg) per day for adults, and the upper limit is preferably 20 g (more preferably 2000 mg, more preferably 500 mg, It is desirable to administer according to the symptom in one or several divided doses so that it is particularly preferably 100 mg).

The dose when the active ingredient angiotensin converting enzyme inhibitory substance is a polynucleotide should also be adjusted as appropriate depending on the symptom, target tissue or organ, age, weight, etc. Preferably, 0.0001 to 100 mg, more preferably 0.001 to 10 mg is administered at a rate of once every several days or months.

Hereinafter, the present invention will be described in detail in Examples, but prior to that, a hypertensive mouse used for confirming the effect of the osteoporosis preventive / therapeutic agent of Examples will be described.
As the hypertension model mouse, a known “Tsukuba hypertension mouse” was used.
This "Tsukuba hypertensive mouse" is a human renin-angiotensin system-dependent, obtained by crossing a transgenic mouse introduced with a human renin gene and a transgenic mouse introduced with a human angiotensinogen gene. It is a double transgenic hypertensive mouse.

In order to confirm the effect of the preventive or therapeutic agent, BV / TV (bone volume / tissue volume) × 100, that is, the bone mass fraction (three-dimensional bone mass (%)) obtained by dividing the bone mass by the total tissue mass. Evaluated by value.
The bone mass was measured by micro CT (manufactured by Scanco Medical AG, micro CT-40).

Example 1
(ACEI: enalapril maleate)
A group of 2-month-old male hypertensive mice was bred with drinking water (33 mg / L) containing enalapril maleate, a known ACEI (ACE inhibitor) for 1 month, and then microtied CT scans were performed. The bone mass of the cancellous bone was measured. As control examples, a group of mice with normal blood pressure and a group of hypertensive mice bred without administration of enalapril maleate were used (1-5 mice per group).

The results are shown in FIG. The data in FIG. 1 represents the average of the three-dimensional bone mass of each group.

As can be seen from FIG. 1, osteoporosis was clearly corrected in the group administered with enalapril maleate.

Comparative Example 1
(AT1 receptor antagonist: losartan)
FIG. 2 shows the results of a test conducted in the same manner as in Example 1 using drinking water (170 mg / L) containing losartan, which is an AT1 receptor antagonist.

As can be seen from FIG. 2, the group administered with losartan rather worsened osteoporosis.

The agent for preventing or treating osteoporosis of the present invention is a revolutionary agent that can prevent or treat both hypertension and osteoporosis as a single agent.

It is a figure showing the change of the bone mass by enalapril maleate (ACE inhibitor) administration. It is a figure showing the change of the bone mass by losartan (AT1 receptor antagonist) administration.

Claims (4)

An agent for preventing or treating osteoporosis, comprising a substance having an angiotensin converting enzyme inhibitory action or a precursor thereof. The agent for preventing or treating osteoporosis according to claim 1, wherein the substance having an angiotensin converting enzyme inhibitory action is at least one selected from the following (A) to (C).
(A) Low molecular weight compound (B) Peptides (C) Polynucleotide that suppresses expression of angiotensin converting enzyme gene The preventive or therapeutic agent for osteoporosis according to claim 2, wherein the low molecular compound is a compound having a cyclic structure. The preventive or therapeutic agent for osteoporosis according to claim 3, wherein the substance having an angiotensin converting enzyme inhibitory action is enalapril or a derivative thereof.

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