WO2014065370A1 - Agent thérapeutique contre l'hypertension pulmonaire - Google Patents

Agent thérapeutique contre l'hypertension pulmonaire Download PDF

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WO2014065370A1
WO2014065370A1 PCT/JP2013/078828 JP2013078828W WO2014065370A1 WO 2014065370 A1 WO2014065370 A1 WO 2014065370A1 JP 2013078828 W JP2013078828 W JP 2013078828W WO 2014065370 A1 WO2014065370 A1 WO 2014065370A1
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pulmonary hypertension
alogliptin
dpp
inhibitor
acid
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PCT/JP2013/078828
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English (en)
Japanese (ja)
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剛 原口
奨 細川
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国立大学法人 東京医科歯科大学
武田薬品工業株式会社
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Publication of WO2014065370A1 publication Critical patent/WO2014065370A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to a preventive or therapeutic agent for pulmonary hypertension and the like, which contains a dipeptidyl peptidase-IV (sometimes abbreviated as DPP-IV in this specification) inhibitor.
  • a dipeptidyl peptidase-IV sometimes abbreviated as DPP-IV in this specification
  • DPP-IV a kind of peptidase, specifically binds to a peptide containing proline (or alanine) second from the N-terminus, and produces a dipeptide by cleaving the C-terminal side of the proline (or alanine).
  • Serine protease DPP-IV has also been shown to be the same molecule as CD26, and has been reported to be related to the immune system. The role of DPP-IV in mammals has not been fully clarified, but it plays an important role in neuropeptide metabolism, T cell activation, cancer cell adhesion to endothelial cells, and HIV entry into cells.
  • DPP-IV is involved in inactivation of incretins GLP-1 (glucagon-like peptide-1) or GIP (Gastric inhibitory peptide / Glucose-dependent insulinotropic peptide).
  • GLP-1 has a short plasma half-life of 1-2 minutes
  • GLP-1 (9-36) amide a degradation product of DPP-IV, acts as an antagonist to the GLP-1 receptor. It is known that its physiological activity is significantly impaired by being decomposed into DPP-IV. From this, it is also known that suppressing the degradation of GLP-1 by inhibiting DPP-IV activity enhances the physiological activity of GLP-1 such as promoting insulin secretion in a glucose concentration-dependent manner. ing.
  • Pulmonary arterial hypertension is a serious disease that causes right heart failure and eventually death by increasing and sustaining pulmonary artery pressure.
  • the current main treatments are endothelin receptor antagonists, phosphodiesterase 5 inhibitors, and intravenous epoprostenol. Although these treatments improve the patient's subjective symptoms, the survival rate is It has not improved, and the fatality rate continues to be a high problem.
  • alogliptin benzoate can treat pulmonary hypertension for the first time, and have intensively studied to complete the present invention.
  • the present invention [1] A prophylactic or therapeutic agent for pulmonary hypertension comprising a dipeptidyl peptidase-IV inhibitor (preferably alogliptin or a salt thereof) (hereinafter sometimes abbreviated as the agent of the present invention); [2] The agent according to [1] above, wherein the dipeptidyl peptidase-IV inhibitor is alogliptin or a salt thereof; [3] The agent according to [1] above, wherein the dipeptidyl peptidase-IV inhibitor is alogliptin benzoate; [4] The agent according to [1], [2] or [3] above, wherein the pulmonary hypertension is pulmonary arterial pulmonary hypertension; [5] A method for preventing or treating pulmonary hypertension in a mammal, comprising administering an effective amount of a dipeptidyl peptidase-IV inhibitor (preferably alogliptin or a salt thereof) to the mammal; [6] Dipeptidyl peptidas
  • the agent of the present invention has an excellent DPP-IV inhibitory action and is useful as a preventive or therapeutic agent for pulmonary hypertension.
  • the agent of the present invention can be administered orally, it has few side effects such as infectious diseases and has an excellent therapeutic effect and prognosis improving effect on pulmonary hypertension.
  • FIG. 5 is a graph of a survival curve in Experimental Example 1.
  • 2 is a photomicrograph of immunohistochemical staining in Experimental Example 1.
  • HE shows a photomicrograph of immunohistochemical staining using hematoxylin and eosin staining, EVG using Elastica-Wangeson staining, SMa using smooth muscle ⁇ -actin antibody, and PCNA using nuclear proliferation antigen antibody.
  • 4 is a graph showing measurement results of mRNA expression of transforming growth factor (TGF) - ⁇ in Experimental Example 1.
  • 6 is a graph showing the results of cell proliferation assay in Experimental Example 1. It is a figure which shows the result of the western blotting in Experimental example 1.
  • the vertical axis shows the ratio of phosphorylated-nuclear factor-kappaB-p65 protein level to non-phosphorylated nuclear factor-kappaB-p65 protein level.
  • 4 is a photomicrograph of immunohistochemical staining in Experimental Example 2.
  • HE shows a photomicrograph of immunohistochemical staining using hematoxylin and eosin staining, EVG using Elastica-Wangeson staining, SMa using smooth muscle ⁇ -actin antibody, and PCNA using nuclear proliferation antigen antibody.
  • 4 is a photomicrograph of immunohistochemical staining using phosphorylated-nuclear factor-kappaBp65 antibody in Experimental Example 2.
  • Phosphorylated-nuclear factor-kappaB p65 positive cells are indicated by arrows.
  • 4 is a photomicrograph of immunohistochemical staining using CD8a antibody (CD8) and CD68 antibody (CD68) in Experimental Example 2.
  • HE shows a photomicrograph of hematoxylin and eosin staining. The numbers of CD8-positive and CD68-positive cells per field obtained from the photomicrograph of immunohistochemical staining in Experimental Example 2 (strong enlargement; 400 times) are shown.
  • the DPP-IV inhibitor means a compound that inhibits the enzyme activity of DPP-IV [Classification by International Union of Biochemistry (IUBMB): EC 3.4.14.5].
  • the compound may be either peptidic or non-peptidic, but is preferably non-peptidic.
  • the form of the DPP-IV inhibitor may be different before and after administration to the living body as long as the DPP-IV inhibitory activity is retained. That is, the DPP-IV inhibitor may be an “active metabolite” having DPP-IV inhibitory activity after becoming a structural change body after undergoing metabolism in vivo.
  • the DPP-IV inhibitor may be a “prodrug” that is converted into an active form by a reaction with an enzyme, gastric acid or the like under physiological conditions in vivo.
  • the DPP-IV inhibitory activity can be confirmed, for example, by a method utilizing “Method of Raymond et al. (Diabetes, 47, 1253-1258, 1998)”.
  • DPP-IV inhibitors include nitrogen-containing heterocyclic compounds, specifically the following compounds (1) to (7).
  • alogliptin or a salt thereof is preferable.
  • alogliptin benzoate is particularly preferable.
  • Examples of the salt of the above compound include pharmacologically acceptable salts such as salts with inorganic acids, salts with organic acids, salts with basic or acidic amino acids, and the like.
  • Preferable examples of the salt with inorganic acid include salts with hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid and the like.
  • Preferable examples of salts with organic acids include benzoic acid, formic acid, acetic acid, trifluoroacetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, and benzenesulfonic acid.
  • salts with p-toluenesulfonic acid and the like Preferable examples of the salt with basic amino acid include salts with arginine, lysine, ornithine and the like, and preferable examples of the salt with acidic amino acid include salts with aspartic acid, glutamic acid and the like.
  • alogliptin salt examples include salts with benzoic acid, trifluoroacetic acid, p-toluenesulfonic acid, hydrochloric acid and the like, and among them, the salt with benzoic acid is preferable.
  • the salt of trelagliptin examples include salts with trifluoroacetic acid, succinic acid, hydrochloric acid and the like, and among them, the salt with succinic acid is preferable.
  • the DPP-IV inhibitor can be produced according to the method described in US Patent Application Publication No. 2005/0261271, or a method analogous thereto.
  • the agent of the present invention has low toxicity (eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity), and the DPP-IV inhibitor is used as it is or pharmacologically acceptable.
  • toxicity eg, acute toxicity, chronic toxicity, genotoxicity, reproductive toxicity, cardiotoxicity, drug interaction, carcinogenicity
  • the DPP-IV inhibitor is used as it is or pharmacologically acceptable.
  • Prevention of pulmonary hypertension for mammals eg, humans, mice, rats, rabbits, dogs, cats, cows, horses, pigs, monkeys
  • the content of the DPP-IV inhibitor in the agent of the present invention varies depending on the type of DPP-IV inhibitor, the size of the preparation, etc., but is, for example, 1 to 90% by weight, preferably 5 to 80% by weight.
  • pharmacologically acceptable carrier various organic or inorganic carrier substances commonly used as pharmaceutical materials are used, and excipients, lubricants, binders, disintegrants in solid preparations; solvents in liquid preparations, It is blended as a solubilizing agent, suspending agent, isotonic agent, buffering agent, soothing agent and the like. If necessary, preparation additives such as preservatives, antioxidants, colorants, sweeteners and the like can also be used.
  • excipients include lactose, sucrose, D-mannitol, D-sorbitol, starch, pregelatinized starch, dextrin, crystalline cellulose, low-substituted hydroxypropylcellulose, sodium carboxymethylcellulose, gum arabic, pullulan, light Anhydrous silicic acid, synthetic aluminum silicate, magnesium magnesium metasilicate, etc. are mentioned.
  • lubricant examples include magnesium stearate, calcium stearate, talc, colloidal silica and the like.
  • Preferred examples of the binder include pregelatinized starch, sucrose, gelatin, gum arabic, methylcellulose, carboxymethylcellulose, sodium carboxymethylcellulose, crystalline cellulose, sucrose, D-mannitol, trehalose, dextrin, pullulan, hydroxypropylcellulose, hydroxy Examples thereof include propylmethylcellulose and polyvinylpyrrolidone.
  • disintegrant examples include lactose, sucrose, starch, carboxymethyl cellulose, carboxymethyl cellulose calcium, croscarmellose sodium, carboxymethyl starch sodium, light anhydrous silicic acid, low substituted hydroxypropyl cellulose and the like.
  • the solvent include water for injection, physiological saline, Ringer's solution, alcohol, propylene glycol, polyethylene glycol, sesame oil, corn oil, olive oil, cottonseed oil and the like.
  • solubilizer examples include polyethylene glycol, propylene glycol, D-mannitol, trehalose, benzyl benzoate, ethanol, trisaminomethane, cholesterol, triethanolamine, sodium carbonate, sodium citrate, sodium salicylate, sodium acetate. Etc.
  • suspending agent examples include surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate; polyvinyl alcohol, polyvinylpyrrolidone And hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; polysorbates, polyoxyethylene hydrogenated castor oil, and the like.
  • surfactants such as stearyltriethanolamine, sodium lauryl sulfate, laurylaminopropionic acid, lecithin, benzalkonium chloride, benzethonium chloride, glyceryl monostearate
  • polyvinyl alcohol polyvinylpyrrolidone
  • hydrophilic polymers such as sodium carboxymethylcellulose, methylcellulose, hydroxymethylcellulose, hydroxyethyl
  • the isotonic agent include sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose and the like.
  • buffer solutions such as phosphate, acetate, carbonate and citrate.
  • Benzyl alcohol etc. are mentioned as a suitable example of a soothing agent.
  • preservative examples include p-hydroxybenzoates, chlorobutanol, benzyl alcohol, phenethyl alcohol, dehydroacetic acid, sorbic acid and the like.
  • antioxidant examples include sulfite and ascorbate.
  • the colorant examples include water-soluble edible tar dyes (eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.), water-insoluble lake dyes (Eg, the aluminum salt of the water-soluble edible tar dye), natural dyes (eg, ⁇ -carotene, chlorophyll, bengara) and the like.
  • water-soluble edible tar dyes eg, edible dyes such as edible red Nos. 2 and 3, edible yellows Nos. 4 and 5, edible blue Nos. 1 and 2, etc.
  • water-insoluble lake dyes Eg, the aluminum salt of the water-soluble edible tar dye
  • natural dyes eg, ⁇ -carotene, chlorophyll, bengara
  • Suitable examples of the sweetening agent include saccharin sodium, dipotassium glycyrrhizinate, aspartame, stevia and the like.
  • the agent of the present invention is produced by mixing a DPP-IV inhibitor with a pharmacologically acceptable carrier according to a method known per se as a method for producing a pharmaceutical preparation (eg, a method described in the Japanese Pharmacopoeia, etc.).
  • a method for producing a pharmaceutical preparation eg, a method described in the Japanese Pharmacopoeia, etc.
  • the Examples of the dosage form of the agent of the present invention include tablets (including sugar-coated tablets, film-coated tablets, sublingual tablets, orally disintegrating tablets, buccal tablets, etc.), pills, powders, granules, capsules (soft capsules, microcapsules).
  • These preparations may be controlled-release preparations (eg, sustained-release microcapsules)
  • oral preparations contain active ingredients such as excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, pregelatinized starch, Arabic Rubber, carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc.) or lubricant (eg, talc, magnesium stearate, polyethylene glycol 6000, etc.), etc., and compression molded, and if necessary, taste masking, enteric
  • active ingredients such as excipients (eg, lactose, sucrose, starch, D-mannitol, etc.), disintegrants (eg, carboxymethylcellulose calcium, etc.), binders (eg, pregelatinized starch, Arabic Rubber, carboxymethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, etc.) or lubricant (eg, talc
  • the coating base examples include sugar coating base, water-soluble film coating base, enteric film coating base, sustained-release film coating base and the like.
  • sugar coating base sucrose is used, and one or more selected from talc, precipitated calcium carbonate, gelatin, gum arabic, pullulan, carnauba wax and the like may be used in combination.
  • water-soluble film coating base examples include cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose; polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), Rohm Pharma Co., Ltd.], synthetic polymers such as polyvinylpyrrolidone; polysaccharides such as pullulan.
  • cellulose polymers such as hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, and methylhydroxyethylcellulose
  • polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer E [Eudragit E (trade name), Rohm Pharma Co., Ltd.]
  • synthetic polymers such as polyvinylpyrrolidone
  • polysaccharides such as pullulan.
  • enteric film coating bases include cellulose-based polymers such as hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, and cellulose acetate phthalate; methacrylic acid copolymer L [Eudragit L (trade name), Acrylic polymers such as Rohm Pharma Co., Ltd., methacrylic acid copolymer LD [Eudragit L-30D55 (trade name), Rohm Pharma Co., Ltd.], and methacrylic acid copolymer S [Eudragit S (trade name), Rohm Pharma Co., Ltd.]; Examples include natural products such as shellac.
  • sustained-release film coating bases examples include cellulose polymers such as ethyl cellulose; aminoalkyl methacrylate copolymer RS [Eudragit RS (trade name), Rohm Pharma Co., Ltd.], ethyl acrylate / methyl methacrylate copolymer suspension Acrylic polymers such as suspensions (Eudragit NE (trade name), Rohm Pharma) are listed. Two or more kinds of the above-described coating bases may be mixed and used at an appropriate ratio. Moreover, you may use light-shielding agents, such as a titanium oxide, ferric oxide, etc. in the case of coating.
  • Injections contain active ingredients as dispersants (eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.), preservatives (eg, methyl paraben, propyl paraben, benzyl alcohol, chlorobutanol, Phenol), isotonic agents (eg, sodium chloride, glycerin, D-mannitol, D-sorbitol, glucose, etc.), etc., and aqueous solvents (eg, distilled water, physiological saline, Ringer's solution, etc.) or oily solvents (eg, , Olive oil, sesame oil, cottonseed oil, vegetable oils such as corn oil, propylene glycol, etc.) and the like.
  • dispersants eg, polysorbate 80, polyoxyethylene hydrogenated castor oil 60, polyethylene glycol, carboxymethyl cellulose, sodium alginate, etc.
  • preservatives eg,
  • additives such as a solubilizer (eg, sodium salicylate, sodium acetate, etc.), a stabilizer (eg, human serum albumin, etc.), a soothing agent (eg, benzyl alcohol, etc.) may be used as desired.
  • a solubilizer eg, sodium salicylate, sodium acetate, etc.
  • a stabilizer eg, human serum albumin, etc.
  • a soothing agent eg, benzyl alcohol, etc.
  • the agent of the present invention is useful for prevention or treatment of pulmonary hypertension.
  • the agent of the present invention is more preferably useful for the prevention or treatment of pulmonary arterial pulmonary hypertension.
  • prevention or treatment of pulmonary hypertension includes suppression of the progression of pulmonary hypertension.
  • the preventive or therapeutic effect of pulmonary hypertension for example, in the administration subject of the agent of the present invention, is improved survival rate, decreased medial thickness of pulmonary arteriole, decreased mRNA expression of transforming growth factor (TGF) - ⁇ Decreased expression of TGF- ⁇ protein, decreased expression of basic fibroblast growth factor (FGF2) mRNA or protein, suppressed proliferation of pulmonary artery smooth muscle cells, suppressed phosphorylated-nuclear factor-kappaB p65 (p-p65) protein level , Suppression of p-p65 nuclear translocation, suppression of infiltration of immune / inflammatory cells (eg, macrophages, T cells, etc.) into lung lesions, cell surface receptors involved in immune / inflammatory reactions or ligands thereof (eg, CTLA-4, CD86, LIGHT / TNFSF14, HVEM, etc.) are confirmed by evaluating the mRNA expression.
  • the average pulmonary artery pressure in resting position exceeds 25 mmHg, or in lung disease, sleep apnea syndrome, and alveolar hypoventilation syndrome Diagnosed as pulmonary hypertension if it exceeds 20 mmHg.
  • pulmonary hypertension includes various forms of pulmonary hypertension. Examples include idiopathic pulmonary arterial pulmonary hypertension; familial pulmonary arterial pulmonary hypertension; collagen vascular disease, congenital systemic or pulmonary shunt, portal hypertension, HIV infection, drugs or toxicants Pulmonary arterial hypertension; Thyroid disease, Glycogenosis, Goshe disease, Hereditary hemorrhagic telangiectasia, Abnormal hemoglobinosis, Myeloproliferative disease or Spleen removal surgery, Pulmonary hypertension; Pulmonary arterial hypertension; persistent neonatal pulmonary hypertension; chronic obstructive pulmonary disease, interstitial lung disease, alveolar hypoventilation caused by hypoxia, sleep disordered breathing caused by hypoxia or Pulmonary hypertension associated with chronic exposure to high altitude; pulmonary hypertension associated with abnormal occurrence; and pulmonary hypertension due to embolic obstruction of the distal pulmonary artery.
  • the dose of the agent of the present invention varies depending on the administration subject, administration route, target disease, and the like.
  • the active ingredient DPP-IV inhibitor when orally administered to an adult pulmonary hypertension patient, is usually administered in a single dose. About 0.01 to 100 mg / kg body weight, preferably 0.05 to 30 mg / kg body weight, more preferably 0.1 to 10 mg / kg body weight, and this amount can be administered once or twice a day. desirable.
  • the DPP-IV inhibitor is alogliptin or a salt thereof, 0.1 to 1 mg / kg body weight in terms of alogliptin free body is preferable, and it is desirable to administer this amount once a day.
  • the agent of the present invention can be used for the prevention or treatment of other pulmonary hypertension (eg, prostaglandin preparations, anticoagulants such as warfarin and aspirin, diuretics such as furosemide and spironolactone, cardiotonic drugs such as dopamine and digoxin, and ambri.
  • Endothelin antagonists such as sentan, bosentan, and macitentan, PDE5 inhibitors such as sildenafil and tadalafil, prostacyclin preparations such as epoprostenol, PDGF receptor kinase inhibitors such as imatinib, etc.
  • concomitant drugs may be low molecular weight compounds, and may be macromolecular proteins, polypeptides, antibodies, nucleic acids (including antisense nucleic acids, siRNA, shRNA), vaccines, and the like.
  • the administration timing of the DPP-IV inhibitor and the concomitant drug is not limited, and these may be administered simultaneously to the administration subject or may be administered with a time difference.
  • dosage forms include (1) administration of a single preparation obtained by simultaneously formulating a DPP-IV inhibitor and a concomitant drug, and (2) formulating the DPP-IV inhibitor and the concomitant drug separately. Simultaneous administration of the two preparations obtained by the same administration route, and (3) a time difference in the same administration route of the two preparations obtained by separately formulating the DPP-IV inhibitor and the concomitant drug.
  • the dose of the concomitant drug can be appropriately selected based on the clinically used dose.
  • the mixing ratio of the DPP-IV inhibitor and the concomitant drug can be appropriately selected depending on the administration subject, administration route, target disease, symptom, combination and the like. For example, when the administration subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the DPP-IV inhibitor.
  • the above concomitant drugs may be used in combination of two or more at an appropriate ratio.
  • the amount of each agent can be reduced within a safe range considering the opposite effects of those agents. Thus, the adverse effects that would be caused by these agents can be safely prevented.
  • the present invention further relates to “a method for preventing or treating pulmonary hypertension in a mammal, which comprises administering an effective amount of a dipeptidyl peptidase-IV inhibitor to the mammal”.
  • a method for preventing or treating pulmonary hypertension in a mammal which comprises administering an effective amount of a dipeptidyl peptidase-IV inhibitor to the mammal.
  • examples of the pulmonary hypertension and dipeptidyl peptidase-IV inhibitor include those described above.
  • the “effective amount” refers to a therapeutically effective amount of a dipeptidyl peptidase-IV inhibitor for the prevention or treatment of pulmonary hypertension.
  • the present invention further relates to a “dipeptidyl peptidase-IV inhibitor for use as a preventive or therapeutic agent for pulmonary hypertension”.
  • examples of the pulmonary hypertension and dipeptidyl peptidase-IV inhibitor include those described above.
  • alogliptin described in the following experimental examples means alogliptin benzoate.
  • dose the dose and concentration of alogliptin are shown in terms of free form.
  • MCT monocrotaline
  • TGF transforming growth factor
  • TGF- ⁇ Altered bone morphogenetic protein and transforming growth factor-beta signaling in rat.
  • the sequence of TGF- ⁇ is Forward; TGGCGTTACCTTGGTAACC (SEQ ID NO: 1), Reverse; GGTGTTGAGCCCTTTCCAG (SEQ ID NO: 2).
  • the housekeeping gene ⁇ -actin was used as a control. The results are shown in FIG. In the MCT + alogliptin group, TGF- ⁇ mRNA expression decreased.
  • PASMC pulmonary artery smooth muscle cells
  • TGF- ⁇ 1 protein (Abcam, Cambridge, UK) (final concentration 10 ng / ml) was administered to each well (37 ° C., 24 hours). Thereafter, WST-8 (0.5 mg / ml), which is a formazan salt, was added to each well and incubated at 37 ° C. for 30 to 240 minutes. Absorbance at 450 nm was measured using a Bio-Rad automated EIA analyzer (Bio-Rad Laboratories, Hercules, CA, US). The results are shown in FIG. Alogliptin inhibited the proliferation of pulmonary artery smooth muscle cells induced by TGF- ⁇ in a dose-dependent manner.
  • Samples are diluted with SDS-PAGE sample buffer (62.5 mM Tris-HCl pH 6.8, 25% glycerol, 2% SDS, 0.5% beta-mercaptoethanol, 0.01% bromophenol blue), heated at 95 ° C for 10 minutes, and then And separated on a 10% SDS polyacrylamide gel. Samples were separated by electrophoresis and transferred to a 0.45 ⁇ m nitrocellulose membrane (Bio-Rad). After the transfer, this membrane was blocked with 5% skim milk using Tris-Buffered Saline and Tween 20 (TTBS) for 2 hours at room temperature.
  • SDS-PAGE sample buffer 62.5 mM Tris-HCl pH 6.8, 25% glycerol, 2% SDS, 0.5% beta-mercaptoethanol, 0.01% bromophenol blue
  • the primary antibody phosphorylated NF-kappaB p65 polyclonal antibody (Cell Signaling, Danvers, US) was diluted 1000 times with TTBS, placed on the membrane, and shaken at 4 ° C. overnight. The next day, the membrane was washed with TTBS, the secondary antibody HRP-linked anti-rabbit IgG was diluted 5000 times with TTBS, placed on the membrane, and waited at room temperature for 1 hour. PCNA was used as positive control. Protein quantification was performed using LAS-1000 (GE Healthcare, UK), and the intensity of the obtained band was analyzed using Image J software. As a result, alogliptin suppressed the phosphorylated-nuclear factor-kappaB p65 protein level induced by TGF- ⁇ (FIG. 5).
  • DPP-IV is thought to be involved in the progression of pulmonary hypertension by causing TGF- ⁇ -induced inflammation.
  • DPP-IV inhibitors such as alogliptin or a salt thereof are effective as a novel preventive or therapeutic agent for pulmonary hypertension.
  • Experimental example 2 In the present experimental example (and experimental example 3), the following experiment was performed using lung tissue collected from the rat sacrificed in experimental example 1 (2).
  • the same amount of physiological saline was subcutaneously injected instead of MCT, and distilled water was orally administered daily for 2 weeks. It was.
  • (1) Immunohistochemical staining Paraffin continuous sections (1 section 3 ⁇ m) prepared from lung tissues collected from each group of rats were pretreated in the same manner as in Experimental Example 1 (3), and immunohistochemical staining was performed.
  • ⁇ -SMa antibody and PCNA antibody in addition to the ⁇ -SMa antibody and PCNA antibody described above, phosphorylated NF-kappaB p65 polyclonal antibody (Cell Signaling, Danvers, US), CD8a antibody (BD Biosciences, San Jose, US), CD68 antibody (Santa Cruz, Dallas, US) was used.
  • secondary antibody simple stain rat MAX PO (Nichireihist Fine, Tokyo, Japan) was used.
  • ⁇ -SMa and PCNA were also subjected to hematoxylin and eosin staining (HE) and elastica-Wangeson staining (EVG), and CD8 and CD68 were also subjected to hematoxylin and eosin staining (HE).
  • alogliptin decreased the medial thickness of the pulmonary arteriole as in Experimental Example 1 (3) (FIG. 6).
  • alogliptin suppresses phosphorylated NF-kappaB p65 levels (thus, NF ⁇ B translocation into the nucleus) (Fig. 7), and CTL (CD8 positive) and macrophages (CD68 positive) around the blood vessels of small pulmonary arteries was suppressed (FIGS. 8 and 9).
  • Experimental Example 4 According to the method of Experimental Example 1 (1), 5 new MCT + Alogliptin groups were prepared, and the survival of the rats up to 30 days after MCT administration was examined, and combined with the results of Experimental Example 1 (2) (that is, MCT + Alogliptin) The survival rate of each group was shown by the Kaplan-Meier curve (FIG. 14). The survival rate at 30 days after MCT administration was 5% (1/20) in the MCT group, compared with 44% (11/25) in the MCT + alogliptin group.
  • the agent of the present invention contains a dipeptidyl peptidase-IV inhibitor and is useful as a preventive or therapeutic agent for pulmonary hypertension and the like.

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  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un agent préventif ou thérapeutique contre l'hypertension pulmonaire qui présente une excellente efficacité pharmacologique. La présente invention concerne un agent préventif ou thérapeutique contre l'hypertension pulmonaire qui contient un inhibiteur de dipeptidyle peptidase IV, et spécifiquement, contient de l'alogliptine ou un sel de celle-ci.
PCT/JP2013/078828 2012-10-25 2013-10-24 Agent thérapeutique contre l'hypertension pulmonaire WO2014065370A1 (fr)

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JPPCT/JP2012/077640 2012-10-25
PCT/JP2012/077640 WO2014064811A1 (fr) 2012-10-25 2012-10-25 Agent thérapeutique de lutte contre l'hypertension pulmonaire

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107303390A (zh) * 2017-01-22 2017-10-31 复旦大学附属华山医院 Dpp4抑制剂在制备治疗低氧性肺动脉高压药物中的用途

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2010500996A (ja) * 2006-08-17 2010-01-14 アミリン・ファーマシューティカルズ，インコーポレイテッド 選択可能な特性を持つｄｐｐ−ｉｖ耐性ｇｉｐハイブリッドポリペプチド
WO2012057343A1 (fr) * 2010-10-28 2012-05-03 国立大学法人九州大学 Inhibiteur de nad(p)h oxydase, agent thérapeutique pour des maladies associées au stress oxydatif, procédé thérapeutique pour des maladies associées au stress oxydatif, et procédé de criblage

Patent Citations (2)

* Cited by examiner, † Cited by third party
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JP2010500996A (ja) * 2006-08-17 2010-01-14 アミリン・ファーマシューティカルズ，インコーポレイテッド 選択可能な特性を持つｄｐｐ−ｉｖ耐性ｇｉｐハイブリッドポリペプチド
WO2012057343A1 (fr) * 2010-10-28 2012-05-03 国立大学法人九州大学 Inhibiteur de nad(p)h oxydase, agent thérapeutique pour des maladies associées au stress oxydatif, procédé thérapeutique pour des maladies associées au stress oxydatif, et procédé de criblage

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Title
CHRISTOPHER R ET AL.: "Pharmacokinetics, pharmacodynamics, and tolerability of single increasing doses of the dipeptidyl peptidase-4 inhibitor alogliptin in healthy male subjects", CLIN THER., vol. 30, no. 3, 2008, pages 513 - 527 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN107303390A (zh) * 2017-01-22 2017-10-31 复旦大学附属华山医院 Dpp4抑制剂在制备治疗低氧性肺动脉高压药物中的用途

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