WO2018198842A1 - Agent thérapeutique pour la stéatose hépatique non alcoolique - Google Patents

Agent thérapeutique pour la stéatose hépatique non alcoolique Download PDF

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Publication number
WO2018198842A1
WO2018198842A1 PCT/JP2018/015629 JP2018015629W WO2018198842A1 WO 2018198842 A1 WO2018198842 A1 WO 2018198842A1 JP 2018015629 W JP2018015629 W JP 2018015629W WO 2018198842 A1 WO2018198842 A1 WO 2018198842A1
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Prior art keywords
fatty liver
liver
aldehyde oxidase
liver disease
mna
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PCT/JP2018/015629
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English (en)
Japanese (ja)
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祐次 石井
竹内　健二
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国立大学法人九州大学
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Priority to JP2019514396A priority Critical patent/JPWO2018198842A1/ja
Publication of WO2018198842A1 publication Critical patent/WO2018198842A1/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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/455—Nicotinic acids, e.g. niacin; Derivatives thereof, e.g. esters, amides
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention provides an effective therapeutic agent based on a new theory for nonalcoholic steatohepatitis (NASH), for which no effective treatment is currently widespread. More specifically, the present invention provides a therapeutic agent for non-alcoholic steatohepatitis comprising an aldehyde oxidase inhibitor or an aldehyde oxidase inhibitor and a composition of nicotinic acid and / or a nicotinic acid derivative as active ingredients. .
  • NASH nonalcoholic steatohepatitis
  • NAFLD nonalcoholic fatty liver disease
  • NAFLD is a pathological condition that begins with accumulation of triglyceride (hereinafter sometimes abbreviated as "TG") in the liver, but most of them are based on lifestyle-related diseases such as obesity, dyslipidemia, and diabetes. ⁇ ⁇ (for example, Ekstedt et al., 2006, Hepatology., 44, 865-873; Lonardo et al., 2013, Curr) Pharm Des., 19, 5177-5192).
  • TG triglyceride
  • NAFLD nonalcoholic fatty liver cirrhosis
  • ⁇ NAFL '' non-alcoholic fatty acid liver
  • NASH non-alcoholic steatohepatitis
  • NAFL has been thought to have no pathological significance, but in recent years if it is left untreated, the pathology is considered to develop NASH at a certain rate (for example, Vernon et al., 2011, Aliment Pharmacol Ther., 34, 274-285).
  • NAFLD is not necessarily a disease with a good prognosis, and in some cases, appropriate treatment including drug therapy needs to be performed.
  • the amount of TG accumulated in the liver is determined by the balance between the increase factor (fatty acid inflow into the liver, fatty acid synthesis in the liver) and the decrease factor (fatty acid metabolism in the liver, fatty acid excretion from the liver) ⁇ (for example, Antony and Landau, 1968, J Lipid Res., 9, 267-269; Donnelly et al., 2005, J Clin Invest.,. 115, 1343- 1351; Wetterau and Zilversmit, 1984, J Biol Chem., 259, 10863-10866).
  • insulin resistance causes an increase in fatty acid supply from the adipose tissue to the liver and increased fatty acid de novo synthesis in hepatocytes, resulting in an excessive increase in the liver It is considered that the processed fatty acid cannot be completely processed (for example, Gastadeli et al., 2007, Gastroenterology, 133, 496-507).
  • ⁇ -oxidation in mitochondria mainly functions in fatty acid metabolism in the liver, and in addition, ⁇ -oxidation in peroxisomes and ⁇ -oxidation in microsomes contribute ( ⁇ ⁇ Lu and Coon, 1968, J Biol Chem., 243, 1331-1332).
  • the present inventor is particularly effective in the prevention and treatment of nonalcoholic fatty liver disease non (nonalcoholic fatty ase disease: NAFLD), and thus nonalcoholic steatohepatitis NASH.
  • NAFLD nonalcoholic fatty ase disease
  • nicotinamide vitamin B3
  • NNMT nicotinamide N 1 -methyl transferase
  • Aldehyde Oxidase which is the metabolic enzyme of methylated amide
  • a therapeutic agent for nonalcoholic steatohepatitis characterized by comprising an aldehyde oxidase inhibitor as an active ingredient is provided.
  • the therapeutic agent for non-alcoholic steatohepatitis characterized by using an aldehyde oxidase inhibitor and nicotinic acid and / or a nicotinic acid derivative as an active ingredient is provided.
  • nicotinic acid and nicotinic acid derivatives in the constitution of the present invention are known as pharmaceutical and cosmetic materials, and are also known as therapeutic agents for liver diseases when used in various applications.
  • Patent Document 1 discloses that a specific pharmaceutical composition contains a nicotinic acid derivative for the treatment of nonalcoholic fatty liver disease.
  • a specific pharmaceutical composition contains a nicotinic acid derivative for the treatment of nonalcoholic fatty liver disease.
  • the patent document discloses the technical idea of nicotinic acid side effects and solutions that have been used for the treatment of dyslipidemia, but there is no mention or suggestion of the action mechanism of the present invention, and treatment Different theories.
  • Patent Document 2 discloses that a specific sustained-release preparation can be applied to non-alcoholic fatty liver disease, and that nicotinic acid can be used as an active agent in the sustained-release preparation.
  • nicotinic acid is merely a disclosure that can be used as a drug for lipid control, and there is no description that discloses or suggests the constitution of the present invention.
  • a novel pharmaceutical composition comprising nicotinic acid and / or nicotinamide and / or related compounds for beneficially affecting intestinal microflora and blood lipid levels is disclosed.
  • NASH non-alcoholic steatohepatitis
  • the formulation includes a description of so-called prodrug ideas in addition to making the high dose out of range and the active body to be nicotinic acid or nicotinamide. Nicotinic acid and nicotinamide, etc.
  • an object of the present invention is to provide fatty liver (NAFL) and early non-alcoholic fatty liver disease (NAFLD) among which non-alcoholic fatty liver disease is not widely used.
  • the purpose is to provide a preventive / therapeutic agent that can improve alcoholic steatohepatitis (NASH).
  • NAFLD nonalcoholic fatty liver disease
  • NASH early nonalcoholic steatohepatitis
  • MNA N1-methylnicotinamide
  • MNA is an N atom in the pyridine ring of nicotinamide, which is a kind of vitamin B3, by NNMT (nicotinamide N-methyltransferase), which is localized in the cytosolic fraction of the liver. Is produced by undergoing a methylation reaction.
  • MNA is easily metabolized, and it is necessary to use a high dose to obtain its effect.
  • the main metabolic enzyme of MNA is aldehyde oxidase (AO). (5) By suppressing the metabolism of MNA by aldehyde oxidase and maintaining the concentration of MNA in the liver, there is a possibility that the effect of improving fatty liver can be derived (hypothesis; FIG. 3).
  • hepaRG cells in which fat formation was induced by addition of oleic acid were used to confirm the fat reducing action of DHEAS and PB in human hepatocytes. This was discussed in relation to the effect of improving fatty liver observed in the in vivo animal model of fatty liver.
  • NNMT nicotinamide N 1 -methyl transferase
  • vitamin B3 a methylating enzyme of nicotinamide
  • the therapeutic agent for non-alcoholic fatty liver disease described in the following (1) to (5) is provided.
  • a therapeutic agent for non-alcoholic fatty liver disease comprising an aldehyde oxidase inhibitor as an active ingredient.
  • the therapeutic agent for nonalcoholic fatty liver disease according to (1) wherein the aldehyde oxidase inhibitor is hydralazine hydrochloride and derivatives thereof.
  • the therapeutic agent for nonalcoholic fatty liver disease according to (1) or (2) wherein nicotinic acid and / or a nicotinic acid derivative is used in combination as the active ingredient.
  • the nicotinic acid derivative is nicotinic acid amide or N 1 -methylnicotinic acid amide.
  • the non-alcoholic fatty liver disease is non-alcoholic steatohepatitis that develops due to a metabolic pathway in which nicotinamide N 1 -methyl transferase (NNMT) and aldehyde oxidase function
  • NNMT nicotinamide N 1 -methyl transferase
  • the therapeutic agent for non-alcoholic fatty liver disease as described in thru
  • non-alcoholic fatty liver disease for which effective treatment is not widespread, especially non-alcoholic disease caused by metabolic pathways in which nicotinamide N 1 -methyl transferase (NNMT) and aldehyde oxidase function.
  • An effective prophylactic / therapeutic agent for alcoholic steatohepatitis is provided.
  • the latter combination drug since the latter combination drug exhibits a synergistic effect, it can be applied at a low dose, and is highly safe and can be expected to have a prophylactic / therapeutic effect by long-term administration.
  • NAFLD nonalcoholic fatty liver disease
  • an ingredient composed of an aldehyde oxidase inhibitor or an aldehyde oxidase inhibitor and nicotinic acid and / or a nicotinic acid derivative can be used as an active ingredient.
  • Aldehyde oxidase is a molybdenum-containing flavin protein that is mainly distributed in the liver, has a wide substrate specificity, and recent studies have shown that it plays an important role as a drug-metabolizing enzyme.
  • methylated nicotinamide produced by methylation metabolism of nicotinamide is It is oxidized by aldehyde oxidase into two more metabolites (N 1 -methyl-2-pyridone-5-carboxamide (2-pyr), N 1 -methyl-4-pyridone-3-carboxamide (4-pyr))
  • Specific examples include raloxifene, perphenazine, thioridazine, menadione, trifloperazine, amitriptyline, estradiol, felodipine, clomipramine, loratadine, promethazine, chlorpromazine, ethinylestradiol, norclomifene, perphenazine, thiori
  • hydralazine hydrochloride is still widely used as a therapeutic agent for hypertension.
  • HOD hydralazine hydrochloride
  • examples of the drug used in combination with the aldehyde oxidase inhibitor include prevention / treatment of nonalcoholic fatty liver disease (NAFLD) by a combined drug of nicotinic acid or a nicotinic acid derivative.
  • NAFLD nonalcoholic fatty liver disease
  • FIG. 3 the details of the mechanism of action in the metabolic pathway of nicotinamide and MNA (FIG. 3) are not clear, a synergistic effect of the concomitant drug with the aldehyde oxidase inhibitor has been found in the present invention.
  • variable doses are possible. Particularly, when side effects due to long-term administration are concerned, a stable prevention / improvement effect can be expected with a small amount of formulation, which is very useful.
  • the nicotinic acid derivative in the present invention includes nicotinamide and related substances, so-called prodrugs.
  • ⁇ Either oral or parenteral is acceptable as the form of application in the present invention.
  • an oral form for example, it can be freely used after being formulated into a pharmaceutically acceptable form such as a capsule, tablet, granule, powder, syrup, or liquid.
  • the parenteral preparation of the present invention includes a form acceptable as a pharmaceutical category, and the dosage form is not particularly limited as long as the object of the present invention is not impaired. Examples include injections, suppositories, creams, ointments, emulsions, liniments, pastes, lotions, emulsions, essences, gels, and tonics.
  • percutaneous absorption enhancer For parenteral (transdermal) application, the use of a known percutaneous absorption enhancer is optional, and the formulation is optimally designed according to the site of use.
  • formulation bases at the time of oral and parenteral formulation design, any liquid and solid raw materials that are acceptable for application can be used widely.
  • various general-purpose additives such as a humectant, a preservative, and an antioxidant can be added as necessary.
  • IC 50 aldehyde oxidase inhibitory activity (IC 50 ) of HYD 1) Test method Sprague-Dawley male rat liver cytosol fraction (commercial pooled sample) and human liver cytosol fraction (commercial pooled sample, consent and ethics committee approved) N 1 -Methylnicotinamide (MNA) is metabolized by aldehyde oxidase and reported as a typical aldehyde oxidase inhibitor (Obach, RS, et al., 2004, J Clin Pharmacol., 44, 7-19) Inhibition constants (IC 50 ) were calculated for each compound.
  • MNA Methylnicotinamide
  • Liver cytosol concentration 2 mg / mL
  • substrate (MNA) concentration 1 ⁇ M
  • inhibitor concentration 0.0001-100 ⁇ M
  • reaction time 120 min (linearity confirmed)
  • n 3
  • the decay of the MNA concentration in the reaction solution was measured by HPLC (Alliance, M., et al., 2013, J Chromatogr B Analyt Technol Biomed Life Sci., 921-922, 87-95). Waters).
  • Table 1 shows the analysis results of rat and human IC 50 and clinical blood C max of each inhibitor.
  • ⁇ FL + MNA '' group, ⁇ FL + MNA & Hydralazine (HYD) '' group, ⁇ FL + HYD '' group are MNA (30 mg / kg, SIGMA ALDRICH), HYD (50 mg / kg, SIGMA ALDRICH) was orally administered once a day alone or in combination.
  • the evaluation of fatty liver improvement was performed based on (a) body weight, liver weight and gross findings of the isolated liver, (b) measurement of TG in the liver, and (c) measurement results of MNA and nicotinamide concentrations in the liver. It was.
  • the absolute liver weight and the relative liver weight were significantly increased as compared with the Control group.
  • the relative liver weight was significantly increased in the “MNA” group, the “MNA & HYD” group, and the “HYD” group as compared with the Control group.
  • the liver of the “Fatty liver” group was faded yellowish white, whereas the liver of the Control group was reddish brown.
  • the color of the liver returned to the same reddish brown color as in the Control group.
  • the reddish brown color tended to recover.
  • the amount of TG in the liver increased to about 5 times that of the Control group in the “Fatty liver” group, and decreased to about 30% of the “Fatty liver” group and about 1.5 times that of the Control group by the combined administration of “MNA & HYD”. Confirmed to be (Fig. 6).
  • the amount of TG in the liver of the “MNA” single administration group was maintained at almost the same level as that of the Fatty liver ⁇ group, but the amount of TG in the liver was decreased in the “HYD” single administration group, The level of about 60% of the “Fatty Liver” group was about 3 times that of the Control group (Fig. 6).
  • the MNA concentration in the liver showed a significant increase (about 1.6 times) in the “MNA & HYD” combined administration group compared with the “Fatty liver” group (FIG. 7).
  • the concentration of nicotinamide in the liver decreased to about 60% of the control group in the “Fatty ⁇ liver ”group, and in the MNA and HYD single or combined administration group, about the same as in the“ Fatty liver ”group, A wrinkle showing a value reduced to 50 to 70% wrinkle (FIG. 7).
  • hydralazine hydrochloride which is known as an antihypertensive drug and known as a potent inhibitor of aldehyde oxidase, was selected and tested by oral administration to NAFL model rats. It was.

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Abstract

L'invention concerne un médicament prophylactique/thérapeutique susceptible d'améliorer la stéatose hépatique non alcoolique (NAFL) et la stéatohépatite non alcoolique (NASH) précoce, parmi les stéatoses hépatiques non alcooliques (NAFLD) pour lesquelles aucune méthode de traitement efficace n'est largement disponible actuellement. La présente invention a comme principe actif principal un inhibiteur de l'aldéhyde oxydase, et comme principes actifs secondaires un inhibiteur de l'aldéhyde oxydase ainsi que de l'acide nicotinique et/ou un dérivé de l'acide nicotinique, permettant ainsi de prévenir/traiter efficacement et d'améliorer la stéatose hépatique non alcoolique, en particulier la stéatohépatite non alcoolique (NASH) provoquée par une voie métabolique à laquelle participent la nicotinamide N1-méthyl transférase (NNMT) et l'aldéhyde oxydase (fig. 3).
PCT/JP2018/015629 2017-04-23 2018-04-14 Agent thérapeutique pour la stéatose hépatique non alcoolique WO2018198842A1 (fr)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017500311A (ja) * 2013-12-13 2017-01-05 コナリス リサーチ インスティチュート アーゲー ニコチン酸および／またはニコチンアミドを含む、腸内微生物叢を改変することにより血中脂質レベルに有益に影響を及ぼすための医薬組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2017500311A (ja) * 2013-12-13 2017-01-05 コナリス リサーチ インスティチュート アーゲー ニコチン酸および／またはニコチンアミドを含む、腸内微生物叢を改変することにより血中脂質レベルに有益に影響を及ぼすための医薬組成物

Non-Patent Citations (12)

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Title
HARA, MASUMI ET AL.: "Nicotinic acid significantly alleviates fatty liver of a mouse administered with monosodium glutamate, but causes hyperglycemia after meals", JOURNAL OF JAPAN SOCIETY FOR THE STUDY OF OBESITY, vol. 19, 2013, pages 165 *
HIROSE, TORU ET AL.: "Importance of alleviating high blood pressure by AT 1 receptor blocker in treating non-alcoholic steatohepatitis (NASH)", THE JOURNAL OF THE JAPANESE SOCIETY OF INTERNAL MEDICINE, vol. 96, 2007, pages 175 *
HONG, SHANGYU ET AL.: "Nicotinamide N- methyltransferase regulates hepatic nutrient metabolism through Sirtl protein stabilization", NAT. MED., vol. 21, no. 8, 13 July 2015 (2015-07-13), pages 887 - 894, XP055528273 *
KOZONO, MASAYA ET AL.: "Antihypertensive therapy improves insulin resistance and serum levels of interleukin-6 and -10 in spontaneously hypertensive rats with steatohepatitis", MOLECULAR MEDICINE REPORTS, vol. 14, no. 6, 21 October 2016 (2016-10-21), pages 5385 - 5394, XP055528260 *
LEE, E. B. ET AL.: "Abstrac FC8.6: Metabolic Effects of ADP355, Protein-Based Adiponectin Receptor Agonist, on Mice with Hifh-Fat Diet Induced Fatty Liver Disease", EUROPEAN SOCIETY FOR PAEDIATRIC ENDOCRINOLOGY (ESPE ), vol. 84, no. 1, 2015, XP055528257 *
LUO, FANGQIONG ET AL.: "Raloxifene Ameliorates Liver Fibrosis of Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice", DIGESTIVE DISEASES AND SCIENCES, vol. 60, no. 9, 14 April 2015 (2015-04-14), pages 2730 - 2739, XP055528252 *
MIYASHITA, TAISHI ET AL.: "Hepatoprotective effect of tamoxifen on steatosis and non-alcoholic steatohepatitis in mouse models", THE JOURNAL OF TOXICOLOGICAL SCIENCES, vol. 37, no. 5, 2012, pages 931 - 942, XP055528250 *
NAJJAR, V. A. ET AL.: "THE DEMETHYLATION OF Nl-METHYLNICOTINAMIDE AND THE INFLUENCE OF THE METHYL GROUPON THE FATTY LIVER OF RATS", J. BIOL. CHEM., vol. 162, 8 February 1946 (1946-02-08), pages 741 - 742, XP055528270 *
SHEN, CHEN ET AL.: "Nicotinamide protects hepatocytes against palmitate-induced lipotoxicity via SIRT1-dependent autophagy induction", NUTRITION RESEARCH, vol. 40, 14 March 2017 (2017-03-14), pages 40 - 47, XP085013703 *
TAKEUCHI, KENJI ET AL.: "Alleviation of fatty liver by administration of dehydroepiandrosterone sulfate and phenobarbital using model rat with choline- deficiency induced fatty liver", LECTURE ABSTRACTS OF 33TH KYUSHU BRANCH CONFERENCE OF THE PHARMACEUTICAL SOCIETY OF JAPAN, vol. 33, 2016, pages 112 *
TAKEUCHI, KENJI ET AL.: "Dehydroepiandrosterone sulfate and cytochrome P450 inducers alleviate fatty liver in male rats fed an orotic acid- supplemented diet", THE JOURNAL OF TOXICOLOGICAL SCIENCES, vol. 40, no. 2, 2015, pages 181 - 191, XP055528249 *
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