Inhibition of aortic valve calcification

Abstract

The present invention relates to compounds useful for inhibiting aortic valve calcification and for treating diseases including aortic sclerosis and stenosis, and in particular to the use of proton pump inhibitors, including prazole compounds, for said treatment.

Description

Detailed Description of the Invention

[0001] [Technical field] The present invention relates to compounds useful for inhibiting aortic valve calcification and for the treatment of diseases involving aortic sclerosis and stenosis, and in particular to the use of the proton pump inhibitor rabeprazole for said treatment.

[0002] [Background technology] Calcific aortic valve disease is a slowly progressive condition ranging from thickening of the aortic valve cusps (aortic sclerosis) to severe calcification with impaired blood flow (aortic stenosis).

[0003] Aortic stenosis is the third leading cardiovascular disease and the most common form of valvular heart disease. Data from Norway indicates that many patients undergoing cardiac surgery have early, asymptomatic aortic stenosis. The incidence of aortic stenosis increases exponentially after age 60. In Western Europe and North America, approximately 20% of the male population begins to show early changes at age 50, increasing to 50% by age 75.

[0004] Currently, aortic stenosis (narrowing of the aorta) is treated with valve replacement, either with a biological or mechanical valve. Biological valves are placed via catheter, last 8 to 15 years, and do not require anticoagulation. Mechanical valves require open-heart surgery and lifelong anticoagulation therapy, last approximately 20 years. After symptoms appear, 50% of patients die within two years unless they undergo valve replacement.

[0005] What is needed in the art is a drug therapy to prevent the progression of aortic valve calcification.

[0006] [Summary of the Invention] The present invention relates to compounds useful for inhibiting aortic valve calcification and for treating diseases including aortic sclerosis and stenosis, and in particular to the repurposing of proton pump inhibitors, particularly prazole compounds, for such treatments.

[0007] In some preferred embodiments, the present invention provides a prazole compound for use in suppressing or preventing a disease associated with aortic calcification in a subject. In some preferred embodiments, the present invention provides a method for treating, preventing, or suppressing a disease associated with aortic calcification in a subject in need thereof, comprising administering an effective amount of a prazole compound to the subject.

[0008] In some preferred embodiments, the prazole compound is a racemic mixture of the S- and R-enantiomers of the prazole compound. In some preferred embodiments, the prazole compound is the S-enantiomer. In some preferred embodiments, the prazole compound is the R-enantiomer. In some preferred embodiments, the prazole compound is selected from the group consisting of rabeprazole, omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. In some preferred embodiments, the prazole compound is a rabeprazole compound. In some preferred embodiments, the prazole compound is an omeprazole compound. In some preferred embodiments, the prazole compound is a lansoprazole compound. In some preferred embodiments, the prazole compound is a pantoprazole compound. In some preferred embodiments, the prazole compound is an esomeprazole compound.

[0009] In some preferred embodiments, the disease associated with aortic calcification is aortic sclerosis.

[0010] In some preferred embodiments, the disease associated with aortic calcification is aortic stenosis (aortic stenosis).

[0011] In some preferred embodiments, the subject is at risk of developing a disease associated with aortic calcification.

[0012] In some preferred embodiments, the subject has asymptomatic changes in the aortic valve.

[0013] In some preferred embodiments, the subject has a biological valve prosthesis.

[0014] In some preferred embodiments, the subject has been diagnosed with rheumatic heart disease.

[0015] In some preferred embodiments, the subject has been diagnosed with peripheral vascular calcification.

[0016] In some preferred embodiments, the disease is congenital calcification.

[0017] In some preferred embodiments, the subject has been diagnosed with a pathological calcification disease in an area of ​​the body other than the aorta.

[0018] In some preferred embodiments, administration of an effective amount of a prazole compound reduces the amount of aortic calcification in a subject.

[0019] In some preferred embodiments, the prazole compound has the following structure:

[0020] [ka]

[0021] where: R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, optionally fluorinated alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl; R2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl; R3 and R5 are the same or different and each is hydrogen, alkyl, C1-4 lower alkyl (e.g., methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy; R4 is hydrogen, alkyl, C1-4 lower alkyl (e.g., methyl, ethyl, etc.), optionally fluorinated alkoxy, or alkoxyalkoxy; Q is nitrogen, CH or CR; W is nitrogen, CH or CR; y is an integer from 0 to 4; Z is nitrogen, CH or CR1; or a free base, salt, ester, hydrate, hydrate salt, amide, enantiomer, isomer, tautomer, prodrug, polymorph or derivative thereof.

[0022] In some preferred embodiments, the prazole compound is provided as a pharmaceutical composition comprising an effective amount of the prazole compound and a pharmaceutically acceptable carrier or diluent.

[0023] In some preferred embodiments, the subject is at least 60 years old. In some preferred embodiments, the subject is at least 75 years old.

[0024] [Brief description of the drawing] Figure 1: Micrographs of control cells (no induction of calcification, left panel), cells induced to calcify (center panel), and cells calcified in the presence of inhibitors (right panel).

[0025] FIG. 2: Provides results showing the inhibition of calcification by the rabeprazole (referred to as Rab in the figure) compound of the present invention.

[0026] Figure 3: Results showing the inhibition of calcification by three other FDA-approved proton pump inhibitors (prazoles), designated Class 1 (omeprazole), Class 2 (pantoprazole), and Class 3 (lansoprazole), compared to rabeprazole.

[0027] Figure 4: Western blotting detection of proton pump alpha subunit (ATP4a) protein in human valves.

[0028] [Detailed Description of the Invention] Aortic sclerosis and stenosis are serious diseases that can lead to death if left untreated. The present invention provides a treatment that can be used to prevent calcification before it begins or as soon as calcification begins (e.g., in asymptomatic patients).

[0029] In some preferred embodiments, the present invention provides prazole compounds for use in inhibiting or preventing a disease associated with aortic calcification in a subject.

[0030] The prazole compounds of the present invention are H+,K+-ATPase proton pump inhibitors (PPIs). The term proton pump inhibitor or PPI refers to any pharmaceutical agent that has pharmacological activity as an inhibitor of H+,K+-ATPase. Classes of PPIs include, but are not limited to, substituted arylimidazoles, substituted bicyclic arylimidazoles, substituted benzimidazole compounds, and substituted imidazopyridines. PPIs useful in the present invention may be in any form, such as free bases, free acids, salts, esters, hydrates, anhydrides, hydrated salts, amides, enantiomers, isomers, tautomers, prodrugs, polymorphs, or derivatives, as desired, provided that the free bases, free acids, salts, esters, hydrates, anhydrides, hydrated salts, amides, enantiomers, isomers, tautomers, prodrugs, polymorphs, or other pharmacologically suitable derivatives thereof are therapeutically active or can be converted to therapeutically active forms in vivo or in vitro.

[0031] In a preferred embodiment, the prazole compounds used in the present invention are chemical entities having the following core structure:

[0032] [ka]

[0033] where: R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, optionally fluorinated alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl; R2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl; R3 and R5 are the same or different and each is hydrogen, alkyl, C1-4 lower alkyl (e.g., methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy; R4 is hydrogen, alkyl, C1-4 lower alkyl (e.g., methyl, ethyl, etc.), optionally fluorinated alkoxy, or alkoxyalkoxy; Q is nitrogen, CH or CR; W is nitrogen, CH or CR; y is an integer from 0 to 4; Z is nitrogen, CH or CR1; or a free base, salt, ester, hydrate, hydrate salt, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof. The "prazole compound" can be in any form, such as a free base, free acid, salt, ester, hydrate, anhydride, hydrate salt, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or derivative thereof, as desired, provided that the free base, free acid, salt, ester, hydrate, anhydride, hydrate salt, amide, enantiomer, isomer, tautomer, prodrug, polymorph, or other pharmacologically suitable derivative thereof is therapeutically active or undergoes conversion to a therapeutically active form in vivo or in vitro. The "prazole compound" can be an R- or S-enantiomer, or a mixture thereof.

[0034] In some preferred embodiments, the disease associated with aortic calcification is aortic sclerosis. In some preferred embodiments, the disease associated with aortic calcification is aortic valve stenosis (aortic stenosis). Suitable prazoles include class 1, class 2, and class 3 proton pump inhibitors such as rabeprazole, omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole. See, e.g., U.S. Patent No. 9,351,966, which is incorporated herein by reference in its entirety. In some preferred embodiments, the prazole compound is rabeprazole. In some preferred embodiments, the prazole compound is omeprazole. In some preferred embodiments, the prazole compound is pantoprazole. In some preferred embodiments, the prazole compound is lansoprazole. In some preferred embodiments, the prazole compound is esomeprazole. In some preferred embodiments, the prazole compound is dexlansoprazole (dexlansoeprazole).

[0035] Prazol is generally safe and well-tolerated. It is currently used to treat the symptoms of gastroesophageal reflux disease (GERD), a condition in which stomach acid reflux causes heartburn and can damage the esophagus (the tube connecting the throat to the stomach) in adults and children 1 year of age and older. Prazol is used to treat damage from GERD in adults, allowing the esophagus to heal, and preventing further damage. It is also used to treat conditions involving excessive stomach acid production, such as Zollinger-Ellison syndrome, in adults. Prazol is used to treat ulcers (sores in the lining of the stomach or intestine) and is used with other medications to eradicate Helicobacter pylori (the bacteria that causes ulcers) in adults.

[0036] In some preferred embodiments, the prazole compound is rabeprazole, which has the following structure:

[0037] [ka]

[0038] In some preferred embodiments, the rabeprazole compound used in the present invention has the above structure.The rabeprazole compound useful in the present invention is described in U.S. Patent No. 5,054,552, which is incorporated herein by reference in its entirety.Additional rabeprazole compounds are described in WO1999 / 055157, U.S. Patent No. 6,093,734, U.S. Patent No. 6,174,902, EP1073333, U.S. Patent No. 200502341103, and WO2006 / 120701, which are all incorporated herein by reference in their entirety.As used herein, "rabeprazole compound" refers to a chemical substance that has structural homology with rabeprazole and has the activity of the rabeprazole molecule.Examples include R-rabeprazole and S-rabeprazole molecules, rabeprazole prodrugs, and rabeprazole derivatives.In some preferred embodiments, the rabeprazole compound is omeprazole. Omeprazole has the following structure:

[0039] [ka]

[0040] In some preferred embodiments, the omeprazole compound used in the present invention has the above structure.The omeprazole compound useful in the present invention is described in European Patent EP0005129B1 and U.S. Patent Nos. 4,956,366, 5,075,323, 5,589,491, 5,690,960, 6,162,816, 6,090,827 and 6,207,188, all of which are incorporated herein by reference in their entirety.As used herein, "omeprazole compound" refers to a chemical substance that has structural homology with omeprazole and has the activity of omeprazole molecule.For example, it includes R-omeprazole and S-omeprazole molecule, omeprazole prodrug and omeprazole derivative.

[0041] In some preferred embodiments, the prazole compound is pantoprazole, which has the following structure:

[0042] [ka]

[0043] In some preferred embodiments, the pantoprazole compound used in the present invention has the above structure.Pantoprazole compounds useful in the present invention are described in U.S. Patent Nos. 4,758,579, 7,629,361 and 5,997,903, as well as U.S. Patent No. 20080234326 and WO2007029124, all of which are incorporated herein by reference in their entirety.As used herein, "pantoprazole compound" refers to a chemical substance that has structural homology with pantoprazole and has the activity of pantoprazole molecule.Examples include R-pantoprazole and S-pantoprazole molecule, pantoprazole prodrug, and pantoprazole derivative.

[0044] In some preferred embodiments, the prazole compound is lansoprazole, which has the following structure:

[0045] [ka]

[0046] In some preferred embodiments, the lansoprazole compound used in the present invention has the above structure.Lansoprazole compounds useful in the present invention are described in U.S. Patent Nos. 4,628,098, 5,026,560, 6,909,004 and 7,285,668, as well as EP2535045 and WO20090324802, all of which are incorporated herein by reference in their entirety.As used herein, " lansoprazole compound " refers to the chemical substance that has structural homology with lansoprazole and has the activity of lansoprazole molecule.Examples include R-lansoprazole and S-lansoprazole molecule, lansoprazole prodrug and lansoprazole derivative.

[0047] In some preferred embodiments, the prazole compound is esomeprazole. Esomeprazole is the S-enantiomer of omeprazole. Esomeprazole has the following structure:

[0048] [ka]

[0049] In some preferred embodiments, the esomeprazole compound used in the present invention has the above structure.Esomeprazole compounds useful in the present invention are described in U.S. Patents 5,714,504, 7,563,812, and 8,063,074, as well as EP2106397B1, EP2143722A1, U.S. Patent No. 20110213155, WO2007142580, and WO2006120520, all of which are incorporated herein by reference in their entirety.As used herein, the term "esomeprazole compound" refers to a chemical substance that has structural homology with esomeprazole and has the activity of the esomeprazole molecule.Examples include R-esomeprazole and S-esomeprazole molecules, esomeprazole prodrugs, and esomeprazole derivatives.

[0050] In some preferred embodiments, the prazole compound is dexlansoprazole (dexlansoeprazole). Dexlansoprazole is the (R)-(+)-enantiomer of lansoprazole, which is a racemic mixture of its (R)-(+) and (S)-(-)-enantiomers. The structure of dexlansoprazole (dexlansoeprazole) is as follows:

[0051] [ka]

[0052] In some preferred embodiments, the dexlansoprazole (dexlansoeprazole) compound used in the present invention has the above structure. Dexlansoprazole (dexlansoeprazole) compounds useful in the present invention are described in U.S. Patent Nos. 6,462,058 and 6,664,276, and US20090263475, all of which are incorporated herein by reference in their entirety. As used herein, "dexlansoprazole (dexlansoeprazole) compound" refers to a chemical substance that has structural homology with dexlansoprazole (dexlansoeprazole) and has the activity of the dexlansoprazole (dexlansoeprazole) molecule. Examples include R-dexlansoprazole (dexlansoeprazole) and S-dexlansoprazole (dexlansoeprazole) molecules, dexlansoprazole (dexlansoeprazole) prodrugs, and dexlansoprazole (dexlansoeprazole) derivatives.

[0053] Gastric acid inhibitors, including proton pump inhibitors and their salts, hydrates, esters, hydrated salts, amides, enantiomers, isomers, tautomers, polymorphs, prodrugs and derivatives, can be prepared by using the standard procedures that those skilled in the art of organic synthetic chemistry will recognize.For example, see March, Advanced Organic Chemistry: Reactions, Mechanisms and Structure, 4th Ed., (New York: Wiley-Interscience, 1992); Leonard et al., Advanced Practical Organic Chemistry (1992); Howarth et al., Core Organic Chemistry (1998); and Weisermel et al., Industrial Organic Chemistry (2002).

[0054] "Pharmaceutically acceptable salts" or "salts" include salts of proton pump inhibitors prepared from formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, mesylic acid, stearic acid, salicylic acid, p-hydroxybenzoic acid, phenylacetic acid, mandelic acid, embonic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, toluenesulfonic acid, 2-hydroxyethanesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alginic acid, β-hydroxybutyric acid, galactaric acid, and galacturonic acid.

[0055] In one embodiment, acid addition salts are prepared from the free base form using methodology that includes, for example, reacting the free base with an appropriate acid. Acids suitable for preparing acid addition salts include both organic acids, such as, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, and inorganic acids, such as, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.

[0056] In other embodiments, the acid addition salt is reconverted to the free base by treatment with an appropriate base. In a further embodiment, the acid addition salt of the proton pump inhibitor is a halide salt. Halide salts are prepared, for example, using hydrochloric acid or hydrobromic acid. In yet another embodiment, the base salt is an alkali metal salt, for example, a sodium salt.

[0057] Salt forms of proton pump inhibitors include, but are not limited to, sodium salt forms such as esomeprazole sodium, omeprazole sodium, tenatoprazole sodium, rabeprazole sodium, and pantoprazole sodium; magnesium salt forms such as esomeprazole magnesium or omeprazole magnesium as described in U.S. Patent No. 5,900,424; calcium salt forms; potassium salt forms such as the potassium salt of esomeprazole as described in U.S. Patent No. 6,511,996; and sodium hydrate salt forms, including, but not limited to, sodium hydrate salt forms, such as tenatoprazole sodium hydrate or omeprazole sodium hydrate. Other salt forms of esomeprazole are described in U.S. Patent Nos. 4,738,974 and 6,369,085. Other salt forms of pantoprazole and lansoprazole are described in U.S. Patent Nos. 4,758,579 and 4,628,098, respectively.

[0058] The foregoing list of suitable salts of proton pump inhibitors is intended to be illustrative and not exhaustive, as one of ordinary skill in the art will recognize that other pharmaceutically acceptable salts of proton pump inhibitors may be made.

[0059] In one embodiment, preparation of esters involves functionalizing hydroxyl and / or carboxyl groups that may be present within the molecular structure of the drug. In another embodiment, the esters are acyl-substituted derivatives of free alcohol groups, e.g., moieties derived from carboxylic acids of the formula RCOOR1, where R1 is a lower alkyl group. Esters can be reconverted to the free acids, if desired, using procedures including, but not limited to, hydrogenolysis or hydrolysis.

[0060] "Amides" can be prepared using techniques known to those skilled in the art or described in the pertinent literature. For example, amides can be prepared from esters, using suitable amine reactants, or they can be prepared from an anhydride or an acid chloride by reaction with an amine group such as ammonia or a lower alkyl amine.

[0061] "Tautomers" of substituted bicyclic arylimidazoles include, for example, tautomers of omeprazole, as described in U.S. Patent Nos. 6,262,085; 6,262,086; 6,268,385; 6,312,723; 6,316,020; 6,326,384; 6,369,087; and 6,444,689.

[0062] Exemplary "isomers" of substituted bicyclic arylimidazoles are isomers of omeprazole, including, but not limited to, those described in Oishi et al., Acta Cryst. (1989), C45, 1921-1923; U.S. Patent No. 6,150,380; U.S. Patent Publication No. 02 / 0156284; and PCT Publication No. WO02 / 085889.

[0063] Exemplary "polymorphs" include those described in PCT Publication WO 92 / 08716, and U.S. Patent Nos. 4,045,563; 4,182,766; 4,508,905; 4,628,098; 4,636,499; 4,689,333; 4,758,579; 4,783,974; 4,786,505; 4,808,596; 4,853,230; 5,026,56 0;5,013,743;5,035,899;5,045,321;5,045,552;5,093,132;5,093,342;5,433,959;5th, 5,536,735; 5,576,025; 5,599,794; 5,629,305; 5,639,478; 5,690,960; 5,703,11 0;5,705,517;5,714,504;5,731,006;5,879,708;5,900,424;5,948,773;5,997,903;6th, 017,560;No. 6,123,962;No. 6,147,103;No. 6,150,380;No. 6,166,213;No. 6,191,148;No. 5,187,340;No. 6,268,38 5; No. 6,262,086; No. 6,262,085; No. 6;296,875; No. 6,316,020; No. 6,328,994; No. 6,326,384; No. 6,369,085; No. 6,369,087; No. 6,380,234; No. 6,428,810; No. 6,444,689; and No. 6,462,0577.

[0064] In one embodiment, at least one proton pump inhibitor is not enterically coated. In another embodiment, a portion of at least one proton pump inhibitor is optionally enterically coated. In another embodiment, a therapeutically effective portion of at least one proton pump inhibitor is optionally enterically coated. In another embodiment, about 5%, about 15%, about 20%, about 30%, about 40%, about 50%, or about 60% of at least one proton pump inhibitor is optionally enterically coated. In another embodiment, a portion of at least one proton pump inhibitor comprises a "thin enteric coating." As used herein, the term "thin enteric coating" refers to a pH-sensitive coating applied in a manner or amount that delays release of the coated material in gastrointestinal fluids for a period of time, but ultimately releases a portion of the coated material before passing through the duodenum.

[0065] In one embodiment, the at least one proton pump inhibitor has a D90, D80, D70 or D50 particle size by weight or number of less than about 900 μm, less than about 800 μm, less than about 700 μm, less than about 600 μm, less than about 500 μm, less than about 400 μm, less than about 300 μm, less than about 200 μm, less than about 150 μm, less than about 100 μm, less than about 80 μm, less than about 60 μm, less than about 40 μm, less than about 35 μm, less than about 30 μm, less than about 25 μm, less than about 20 μm, less than about 15 μm, less than about 10 μm, or less than about 5 μm.

[0066] In another embodiment, compositions are provided in which the micronized proton pump inhibitor is sized to allow greater than about 90%, greater than about 75%, or greater than about 50% of the proton pump inhibitor to be released from the dosage unit after placement in a standard dissolution test within about 1 hour, within about 50 minutes, within about 40 minutes, within about 30 minutes, within about 20 minutes, within about 10 minutes, or within about 5 minutes.

[0067] In still other embodiments, the disclosed compositions comprise a total amount of about 1 mg to about 3000 mg, about 1 mg to about 2000 mg, about 1 mg to about 1000 mg, about 1 mg to about 750 mg, about 1 mg to about 500 mg, about 1 mg to about 300 mg, about 5 mg to about 250 mg, about 5 mg to about 200 mg, about 5 mg to about 175 mg, about 5 mg to about 120 mg, about 5 mg to about 100 mg, about 5 mg to about 80 mg, or about 5 mg. The dosage ranges from about 100 mg to about 50 mg, e.g., about 5 mg, about 7.5 mg, about 10 mg, about 15 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or about 200 mg of two PPIs.

[0068] In yet another embodiment, the compositions of the present disclosure comprise two PPIs, each present in an amount of about 40 mg to about 160 mg, about 50 mg to about 150 mg, about 60 mg to about 140 mg, about 60 mg to about 130 mg, about 60 mg to about 120 mg, about 60 mg to about 110 mg, about 60 mg to about 100 mg, about 70 mg to about 100 mg, or about 80 mg to about 100 mg.

[0069] [Example] Example 1 Human valvular interstitial cells (VICs) are isolated from human aortic valves harvested during surgery for use in testing calcification inhibitors. Following isolation, the cells are induced to undergo calcification. During or after calcification induction, the VIC cells are contacted with test substances to measure inhibitor activity. The extent of calcification is measured by staining and spectroscopy. Figure 1 provides micrographs of control cells (no calcification induction, left panel), cells induced with calcification (center panel), and calcification in the presence of inhibitors (right panel). Figure 2 provides results demonstrating the inhibition of calcification by rabeprazole (labeled Rab in the figure). Figure 3 provides results demonstrating the inhibition of calcification by three other FDA-approved proton pump inhibitors (prazoles) (labeled Class 1, Class 2, and Class 3 in the figure) compared to rabeprazole.

[0070] Example 2 This example provides data showing that a protein with sequence homology to the proton pump α-subunit is present in aortic valve tissue.

[0071] Materials and Methods: To detect the presence of a protein with sequence homology to the proton pump α subunit (the polypeptide responsible for covalent binding of the prazole compound) in aortic valve tissue, crude protein extracts were isolated from human aortic valves using RIPA lysis buffer (Millipore) supplemented with protease inhibitors according to the manufacturer's instructions. Control crude protein extracts were prepared in a similar manner from rat tissues: stomach (positive control), muscle, and kidney (negative control). Protein detection was performed by Western blotting using an anti-ATP4A antibody (Abcam, EPR12251).

[0072] result: Four distinct protein bands with clear sequence homology to the human ATP4A protein were detected (see Figure 4). A single band with a Mw of ∼95 kDa obtained from the valve tissue matched with a positive control obtained from rat stomach, indicating the presence of the α subunit of the proton pump protein in the aortic valve tissue.

[0073] Significantly lower molecular weight bands of ~40 and 55 kDa, as well as a ~140 kDa band, were also detected. The bands in the human valve Western blot may indicate the presence of cross-reactivity with proteins unrelated to the proton pump α-subunit, protein aggregates / subunits, truncations, truncated forms, or proton pump inhibitors. (Both the presence of a putative protein homologous to the human proton pump α-subunit and the presence of protein aggregates / subunit truncated polypeptides are novel and have not been previously investigated.)

[0074] All publications, patents, patent applications, and accession numbers mentioned in the above specification are incorporated herein by reference in their entirety. Although the present invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications and variations of the described compositions and methods of the present invention will be apparent to those skilled in the art and are intended to be within the scope of the following claims. [Brief explanation of the drawings]

[0075] [Figure 1] These are micrographs of control cells (no induction of calcification, left panel), cells induced to calcify (center panel), and cells calcified in the presence of inhibitors (right panel). [Figure 2] 1 provides results showing the inhibition of calcification by the rabeprazole (referred to as Rab in the figures) compound of the present invention. [Figure 3] Results are provided showing the inhibition of calcification by three other FDA-approved proton pump inhibitors (prazoles), designated Class 1 (omeprazole), Class 2 (pantoprazole), and Class 3 (lansoprazole), compared with rabeprazole. [Figure 4] 1 shows Western blotting detection of proton pump alpha subunit (ATP4a) protein in human valves.

Claims

1. A prazole compound for use in inhibiting or preventing a disease associated with aortic calcification in a subject.

2. The use according to claim 1, wherein the prazole compound is a racemic mixture of S- and R-enantiomers of the prazole compound.

3. The use of claim 1, wherein the prazole compound is an S-enantiomer.

4. The use of claim 1, wherein the prazole compound is an R-enantiomer.

5. 2. The use of claim 1, wherein the prazole compound is selected from the group consisting of rabeprazole, omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole.

6. The use according to claim 1, wherein the prazole compound is a rabeprazole compound.

7. The use according to claim 1, wherein the prazole compound is an omeprazole compound.

8. The use according to claim 1, wherein the prazole compound is a lansoprazole compound.

9. The use according to claim 1, wherein the prazole compound is a pantoprazole compound.

10. The use according to claim 1, wherein the prazole compound is an esomeprazole compound.

11. The use according to any one of claims 1 to 10, wherein the disease associated with aortic calcification is aortic sclerosis.

12. The use according to any one of claims 1 to 10, wherein the disease associated with aortic calcification is aortic stenosis (aortic stenosis).

13. 13. The use according to any one of claims 1 to 12, wherein the subject is at risk of developing a disease associated with aortic calcification.

14. 14. The use according to any one of claims 1 to 13, wherein the subject has asymptomatic changes in the aortic valve.

15. The use according to any one of claims 1 to 12, wherein the subject has a biological valve prosthesis.

16. 13. The use according to any one of claims 1 to 12, wherein the subject has been diagnosed with rheumatic heart disease.

17. 13. The use according to any one of claims 1 to 12, wherein the subject has been diagnosed with peripheral vascular calcification.

18. 13. The use according to any one of claims 1 to 12, wherein the disease is congenital calcification.

19. 13. The use according to any one of claims 1 to 12, wherein the subject has been diagnosed with a pathological calcification disease in an area of ​​the body other than the aorta.

20. 10. The use of any one of claims 1 to 9, wherein administration of an effective amount of the prazole compound reduces the amount of aortic calcification in the subject.

21. 21. The use of any one of claims 1 to 20, wherein the prazole compound has the following structure: 【Chemical 1】 where: R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, optionally fluorinated alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl; R2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl; R3 and R5 are the same or different and each represents hydrogen, alkyl, C1-4 lower alkyl (e.g., methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy; R4 is hydrogen, alkyl, C1-4 lower alkyl (e.g., methyl, ethyl, etc.), optionally fluorinated alkoxy, or alkoxyalkoxy; Q is nitrogen, CH or CR; W is nitrogen, CH or CR; y is an integer from 0 to 4; Z is nitrogen, CH or CR1; or a free base, salt, ester, hydrate, hydrate salt, amide, enantiomer, isomer, tautomer, prodrug, polymorph or derivative thereof.

22. The use according to any one of claims 1 to 21, wherein the prazole compound is provided as a pharmaceutical composition comprising an effective amount of the prazole compound and a pharmaceutically acceptable carrier or diluent.

23. 23. The use of any one of claims 1 to 22, wherein the subject is at least 60 years old.

24. 24. The use of any one of claims 1 to 23, wherein the subject is at least 75 years old.

25. A method for treating, preventing, or inhibiting a disease associated with aortic calcification in a subject in need thereof, comprising administering to the subject an effective amount of a prazole compound.

26. 26. The method of claim 25, wherein the prazole compound is a racemic mixture of S- and R-enantiomers of the prazole compound.

27. 26. The method of claim 25, wherein the prazole compound is an S-enantiomer.

28. 26. The method of claim 25, wherein the prazole compound is an R-enantiomer.

29. 26. The method of claim 25, wherein the prazole compound is selected from the group consisting of rabeprazole, omeprazole, lansoprazole, rabeprazole, pantoprazole, and esomeprazole.

30. 26. The method of claim 25, wherein the prazole compound is a rabeprazole compound.

31. 6. The method of claim 5, wherein the prazole compound is an omeprazole compound.

32. 26. The method of claim 25, wherein the prazole compound is a lansoprazole compound.

33. 26. The method of claim 25, wherein the prazole compound is a pantoprazole compound.

34. 26. The method of claim 25, wherein the prazole compound is an esomeprazole compound.

35. 35. The method according to any one of claims 25 to 34, wherein the disease associated with aortic calcification is aortic sclerosis.

36. 35. The method according to any one of claims 25 to 34, wherein the disease associated with aortic calcification is aortic valve stenosis (aortic stenosis).

37. 37. The method of any one of claims 25 to 36, wherein the subject is at risk of developing a disease associated with aortic calcification.

38. 38. The method of any one of claims 25 to 37, wherein the subject has an asymptomatic change in the aortic valve.

39. 37. The method of any one of claims 25 to 36, wherein the subject has a biological valve prosthesis.

40. 37. The method of any one of claims 25 to 36, wherein the subject has been diagnosed with rheumatic heart disease.

41. 37. The method of any one of claims 25 to 36, wherein the subject has been diagnosed with peripheral vascular calcification.

42. 37. The method of any one of claims 25 to 36, wherein the subject has congenital calcification.

43. 37. The method of any one of claims 25 to 36, wherein the subject has been diagnosed with a pathological calcification disease in a region of the body other than the aorta.

44. 44. The method of any one of claims 25 to 43, wherein administering an effective amount of a prazole compound reduces the amount of aortic calcification in the subject.

45. 25. The method of any one of claims 14 to 24, wherein the prazole compound has the following structure: 【Chemistry 2】 where: R1 is hydrogen, alkyl, halogen, cyano, carboxy, carboalkoxy, carboalkoxyalkyl, carbamoyl, carbamoylalkyl, hydroxy, optionally fluorinated alkoxy, hydroxyalkyl, trifluoromethyl, acyl, carbamoyloxy, nitro, acyloxy, aryl, aryloxy, alkylthio, or alkylsulfinyl; R2 is hydrogen, alkyl, acyl, acyloxy, alkoxy, amino, aralkyl, carboalkoxy, carbamoyl, alkylcarbamoyl, dialkylcarbamoyl, alkylcarbonylmethyl, alkoxycarbonylmethyl, or alkylsulfonyl; R3 and R5 are the same or different and each represents hydrogen, alkyl, C1-4 lower alkyl (e.g., methyl, ethyl, etc.), alkoxy, amino, or alkoxyalkoxy; R4 is hydrogen, alkyl, C1-4 lower alkyl (e.g., methyl, ethyl, etc.), optionally fluorinated alkoxy, or alkoxyalkoxy; Q is nitrogen, CH or CR; W is nitrogen, CH or CR; y is an integer from 0 to 4; Z is nitrogen, CH or CR1; or a free base, salt, ester, hydrate, hydrate salt, amide, enantiomer, isomer, tautomer, prodrug, polymorph or derivative thereof.

46. 46. ​​The method of any one of claims 25 to 45, wherein the rabeprazole compound is provided as a pharmaceutical composition comprising an effective amount of the rabeprazole compound and a pharmaceutically acceptable carrier or diluent.

47. 47. The method of any one of claims 25 to 46, wherein the subject is at least 60 years old.

48. 48. The method of any one of claims 25 to 47, wherein the subject is at least 75 years old.

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