WO2022039178A1 - 脂肪性肝疾患の治療薬 - Google Patents
脂肪性肝疾患の治療薬 Download PDFInfo
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- NPDVBBRDXJPEMJ-UHFFFAOYSA-N CC(C)(Cc1ccc(C(Oc(ccc(C(N)=N)c2)c2F)=O)[s]1)C(O)=O Chemical compound CC(C)(Cc1ccc(C(Oc(ccc(C(N)=N)c2)c2F)=O)[s]1)C(O)=O NPDVBBRDXJPEMJ-UHFFFAOYSA-N 0.000 description 2
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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
- A61K31/40—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
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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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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- 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
Definitions
- the present invention relates to a therapeutic agent for fatty liver disease.
- Non-alcoholic fatty liver disease which is one of the fatty liver diseases, is a liver disease caused by the accumulation of excess lipid in the liver due to metabolic syndrome such as obesity, diabetes, dyslipidemia, and hypertension. ..
- NAFLD non-alcoholic steatohepatitis
- NASH non-alcoholic steatohepatitis
- it may cause liver cirrhosis, which may eventually lead to liver cancer or cardiovascular disease (Non-Patent Document 1).
- the definitive diagnosis of NASH is made by pathological diagnosis.
- Activity is classified based on NAS (NAFLD activity score), which is the total score of fatty degeneration, inflammatory cell infiltration, and balloon-like swelling.
- the stages are classified based on the degree of liver fibrosis. Specifically, stage 1 is fibrosis around the central vein, stage 2 is further fibrosis around the portal vein, and stage 3 is bridging fibrosis. , Stage 4 is cirrhosis.
- Non-Patent Document 2 the endpoints after the second phase of clinical trials need to show either histological improvement effect, that is, improvement of NAS or improvement of liver fibrosis. Has been done.
- Thiazolidinedione drugs and vitamin E which are PPAR ⁇ agonists, are recommended as therapeutic agents for NASH, but since they are indirect effects associated with diabetes treatment, their effects on preventing the onset of liver cirrhosis and liver cancer have not been proven. Rather, there is a great concern about side effects due to long-term administration.
- FXR agonists obeticholic acid, Tropifexor, etc.
- SCD1 inhibitors Aramchol
- ASK1 inhibitors ariessertib
- PPAR ⁇ / ⁇ agonists Elafibranor
- Noncirrhotic Nonalcoholic Steatohepatitis With Liver Fibrosis Developing Drugs for Treatment Guidance for Industry
- An object of the present invention is to provide a therapeutic agent for fatty liver disease.
- the present invention includes the following embodiments.
- a therapeutic agent for steatohepatitis which comprises a compound represented by the above or a pharmaceutically acceptable salt thereof.
- the therapeutic agent according to [1], wherein the pharmaceutically acceptable salt is hydrochloride.
- the therapeutic agent according to [1] or [2], wherein the fatty liver disease is non-alcoholic steatohepatitis (NAFLD) or non-alcoholic steatohepatitis (NASH).
- NAFLD non-alcoholic steatohepatitis
- NASH non-alcoholic steatohepatitis
- the therapeutic agent according to [3] wherein the fatty liver disease is NAFLD.
- the therapeutic agent according to [4], wherein the NAFLD is associated with liver fibrosis.
- [A] A method for treating adipose liver disease, in which a therapeutically effective amount of a compound represented by the formula (1) defined in the above [1] or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment. Methods that include doing.
- [B] A compound represented by the formula (1) defined in the above [1] or a pharmaceutically acceptable salt thereof for use in the treatment of fatty liver disease.
- [C] Use of the compound represented by the formula (1) defined in the above [1] or a pharmaceutically acceptable salt thereof for use in the treatment of fatty liver disease.
- [D] Use of the compound represented by the formula (1) defined in the above [1] or a pharmaceutically acceptable salt thereof in the manufacture of a therapeutic agent for steatohepatitis.
- FIG. 1A shows plasma ALT 12 weeks after administration of the administered substance.
- FIG. 1B shows plasma ALT 18 weeks after administration of the administered substance.
- FIG. 1C shows plasma AST 18 weeks after administration of the administered substance.
- FIG. 2 shows plasma Tcho at 18 weeks after administration of the administered substance.
- FIG. 3 shows TG in the liver at 18 weeks after administration of the administered substance.
- FIG. 4 shows the Sirius Red positive area rate of the liver at 18 weeks after administration of the administered substance.
- FIG. 5 shows the number of CD68-positive hCLS by immunostaining of the liver at 18 weeks after administration of the administered substance.
- An embodiment of the present invention has the following formula (1):
- the present invention relates to a therapeutic agent for steatohepatitis, which comprises a compound represented by the above or a pharmaceutically acceptable salt thereof.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof can be prepared by those skilled in the art by referring to the synthesis methods described in, for example, International Publication No. 2015/137407 and International Publication No. 2015/137408. Can be easily synthesized.
- the pharmaceutically acceptable salt of the compound represented by the formula (1) is not particularly limited as long as it can be used as a medicine, and for example, a hydrochloride, a sulfate, a nitrate, a hydrobromide, and a phosphate.
- Inorganic acid salts such as salts, and fumarate, maleate, malate, tartrate, citrate, succinate, methanesulfonate, p-toluenesulfonate, lactate, acetate, palmitin.
- Organic acid salts such as acid salts can be mentioned.
- the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may form a solvate such as a hydrate.
- the solvate is included in the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof.
- the therapeutic agent of the present embodiment may contain only the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof, or may further contain other components.
- Other components may vary depending on the dosage form and the like, but are, for example, excipients, binders, lubricants, disintegrants, surfactants, suspending agents, emulsifiers, preservatives, colorants and fragrances. Agents, sweeteners, flavoring agents, stabilizers, and thickeners can be mentioned.
- the therapeutic agent of this embodiment can be administered orally or parenterally.
- Dosage forms for oral administration include, for example, tablets, pills, granules, powders, capsules, syrups, emulsions, and suspensions.
- Dosage forms for parenteral administration include, for example, injections, infusions, infusions, eye drops, and suppositories.
- the therapeutic agent of this embodiment can treat steatohepatitis.
- Treatment includes preventing the onset of steatohepatitis, suppressing the progression of steatohepatitis, alleviating the symptoms of steatohepatitis, and curing steatohepatitis. Things etc. are included.
- fatty liver disease examples include NAFLD, NASH, metabolism-related fatty liver disease (MAFLD), and fatty liver.
- the therapeutic agent of the present embodiment can be suitably used for treating NAFLD and / or NASH.
- the therapeutic agent of the present embodiment has liver disorders (eg, elevation of ALT and / or AST in plasma), abnormal lipid metabolism (eg, elevation of total cholesterol in plasma), and liver fattening (eg, elevation of total plasma cholesterol) in the treatment of fatty liver disease.
- liver disorders eg, elevation of ALT and / or AST in plasma
- abnormal lipid metabolism eg, elevation of total cholesterol in plasma
- liver fattening eg, elevation of total plasma cholesterol
- liver fibrosis eg, increased Sirius Red positive area rate
- liver inflammation eg, increased hCLS number
- the effect of the test drug was evaluated using a high-fat diet and high fructose-induced NASH model (Fast Food Diet model: FFD model).
- FFD model See BMC Gastroenterol. 2020; 20: 210.
- the test drug was prepared by adding a hydrochloride of the compound represented by the above formula (1) (hereinafter referred to as "Compound 1”) to 0.5% MC and ultrasonically crushing the test drug.
- mice 6-week-old C57BL / 6Jms Slc male mice were fed a standard diet (D09100304, Research Diet) or an FFD diet for pathological onset (D09100310N, Research Diet) for 20 weeks. Then, based on the three items of plasma alanine aminotransferase (ALT) level, body weight, and fasting blood glucose level, grouping was performed as shown in Table 1.
- a standard diet D09100304, Research Diet
- D09100310N pathological onset
- ALT was measured by tail vein blood sampling at 12 weeks after administration. An necropsy was performed 18 weeks after administration, and plasma aspartate aminotransferase (AST), plasma total cholesterol (Tcho), and liver triglyceride (TG) were measured. In addition, the Sirius Red positive area rate and the number of Hepatic crown-like structures (hCLS) were measured by liver pathological analysis.
- AST plasma aspartate aminotransferase
- Tcho plasma total cholesterol
- TG liver triglyceride
- Sirius Red positive area rate and the number of Hepatic crown-like structures were measured by liver pathological analysis.
- ⁇ Plasma ALT and AST> 1A shows the plasma ALT at the 12th week of administration
- FIG. 1B shows the plasma ALT at the 18th week of administration
- FIG. 1C shows the plasma AST at the 18th week of administration.
- the Vehicle group showed a statistically significant increase in plasma ALT and AST compared to the Normal group.
- the compound 1 (60) group showed a statistically significant effect of suppressing the increase in plasma ALT and AST with respect to the Vehicle group. From this result, it was confirmed that Compound 1 ameliorated liver damage.
- FIG. 2 shows the plasma Tcho value at 18 weeks after administration.
- the Vehicle group showed a statistically significant increase in plasma Tcho compared to the Normal group.
- the compound 1 (60) group showed a statistically significant effect of suppressing the increase in plasma Tcho with respect to the Vehicle group. From this result, it was confirmed that compound 1 improves lipid metabolism.
- ⁇ TG in the liver> The liver sample was homogenized with phosphate buffer, methanol and chloroform were added, and the mixture was extracted overnight, and then chloroform and distilled water were further added. The mixture was centrifuged to separate the chloroform layer, and the solvent was dried. The residue was dissolved in isopropanol / Triton X-100, which was used as a measurement sample, and measured using Triglyceride E-Test Wako (Fuji Film Wako Pure Chemical Industries, Ltd.).
- FIG. 3 shows the value of TG in the liver at 18 weeks after administration.
- the Vehicle group showed a statistically significant increase in TG in the liver compared to the Normal group.
- the compound 1 (30) group and the compound 1 (60) group showed a statistically significant inhibitory effect on the increase in TG in the liver with respect to the Vehicle group. From this result, it was confirmed that Compound 1 has an inhibitory effect on the liver.
- ⁇ Sirius Red positive area rate> The removed liver was fixed with a 10% neutral buffered formalin solution and embedded in paraffin according to a conventional method to prepare a Sirius Red-stained specimen. Positive area ratios were calculated using Sirius Red stained specimens. The positive area rate of the Normal group was averaged and used as the background.
- FIG. 4 shows the Sirius Red positive area rate of the liver at 18 weeks after administration.
- the Vehicle group showed a statistically significant increase in the Sirius Red positive area rate of the liver compared to the Normal group.
- the compound 1 (60) group showed a statistically significant effect of suppressing an increase in the Sirius Red positive area ratio of the liver with respect to the Vehicle group. From this result, it was confirmed that Compound 1 has an antifibrotic effect on the liver.
- FIG. 5 shows the number of CD68-positive hCLS by liver immunostaining at 18 weeks after administration.
- the Vehicle group showed a statistically significant increase in the number of hCLS in the liver compared to the Normal group.
- the compound 1 (10) group and the compound 1 (60) group showed a statistically significant effect of suppressing the increase in the number of hCLS in the liver with respect to the Vehicle group. From this result, it was confirmed that Compound 1 has an anti-inflammatory effect on the liver.
- Table 2 shows the findings of the histopathology of the liver. In pathological analysis, it was confirmed that Compound 1 has an effect of improving liver fattening and fibrosis.
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Abstract
Description
[1]
下記式(1):
で表される化合物又はその医薬上許容可能な塩を含む、脂肪性肝疾患の治療薬。
[2]
前記医薬上許容可能な塩が塩酸塩である、[1]に記載の治療薬。
[3]
前記脂肪性肝疾患が、非アルコール性脂肪性肝疾患(NAFLD)又は非アルコール性脂肪性肝炎(NASH)である、[1]又は[2]に記載の治療薬。
[4]
前記脂肪性肝疾患がNAFLDである、[3]に記載の治療薬。
[5]
前記NAFLDが肝臓の線維化を伴っている、[4]に記載の治療薬。
[6]
前記NAFLDが肝臓の炎症を伴っている、[4]に記載の治療薬。
[7]
前記脂肪性肝疾患がNASHである、[3]に記載の治療薬。
[8]
前記NASHが肝臓の線維化を伴っている、[7]に記載の治療薬。
[9]
前記NASHが肝臓の炎症を伴っている、[7]に記載の治療薬。
[A]
脂肪性肝疾患を治療する方法であって、治療の必要のある患者に治療有効量の上記[1]で定義される式(1)で表される化合物又はその医薬上許容可能な塩を投与することを含む方法。
[B]
脂肪性肝疾患の治療に使用するための、上記[1]で定義される式(1)で表される化合物又はその医薬上許容可能な塩。
[C]
脂肪性肝疾患の治療に使用するための、上記[1]で定義される式(1)で表される化合物又はその医薬上許容可能な塩の使用。
[D]
脂肪性肝疾患の治療薬の製造における、上記[1]で定義される式(1)で表される化合物又はその医薬上許容可能な塩の使用。
・0.5%(w/v)メチルセルロース溶液(以下「0.5%MC」という。)
・試験薬
試験薬は、上記式(1)で表される化合物の塩酸塩(以下「化合物1」という。)を、0.5%MCに添加し、超音波破砕して調製した。
6週齢のC57BL/6J Jms Slc雄性マウスに、標準餌(D09100304、リサーチダイエット社)又は病態発症用のFFD餌(D09100310N、リサーチダイエット社)を20週間供与した。その後、血漿中アラニンアミノトランスフェラーゼ(ALT)値、体重、及び空腹時血糖値の3項目に基づいて、表1に示すように群分けを行った。
投与12週目に尾静脈採血によってALTを測定した。投与18週目に剖検を実施し、血漿中アスパラギン酸アミノトランスフェラーゼ(AST)、血漿中総コレステロール(Tcho)、及び肝臓中トリグリセリド(TG)を測定した。また、肝臓病理解析によりSirius Red陽性面積率及びHepatic crown-like structure(hCLS)数を測定した。
GraphPad Prism 6(GraphPad Software, Inc.)を用いて統計解析を行った。Normal群とVehicle群については、t検定又はMann-Whitney’s検定を実施した。Vehicle群と化合物1群についてはDunnett型多重検定又はDunn’s型多重検定を実施した。各パラメータの分布に応じて、適切ないずれかの検定法を選択した。全ての検定の有意水準はp=0.05とした。
図1Aに投与12週目の血漿中ALTを示し、図1Bに投与18週目の血漿中ALTを示し、図1Cに投与18週目の血漿中ASTを示す。Vehicle群は、Normal群に対して統計学的に有意な血漿中ALT及びASTの上昇を示した。また、化合物1(60)群は、Vehicle群に対して統計学的に有意な血漿中ALT及びASTの上昇抑制作用を示した。この結果から、化合物1が肝障害を改善することを確認した。
図2に投与18週目の血漿中Tchoの値を示す。Vehicle群は、Normal群に対して統計学的に有意な血漿中Tchoの上昇を示した。また、化合物1(60)群は、Vehicle群に対して統計学的に有意な血漿中Tchoの上昇抑制作用を示した。この結果から、化合物1が脂質の代謝を改善することを確認した。
肝臓サンプルをリン酸緩衝液でホモジナイズし、メタノールとクロロホルムを加えて一晩抽出した後、さらにクロロホルムと蒸留水を添加した。混合液を遠心分離してクロロホルム層を分取し、溶媒を乾固した。残渣をイソプロパノール/TritonX-100で溶解し、これを測定サンプルとし、トリグリセライド E-テストワコー(富士フィルム和光純薬株式会社)を用いて測定した。
摘出した肝臓を10%中性緩衝ホルマリン溶液で固定し、定法に従ってパラフィン包埋し、Sirius Red染色標本を作製した。Sirius Red染色標本を使用し、陽性面積率を算出した。Normal群の陽性面積率を平均してバックグランドとした。
CD68免疫染色標本(ウサギ抗CD68ポリクロ―ナル抗体[ab125212]、abcam社)を作製し、hCLSを計数した。
図5に投与18週目の肝臓免疫染色によるCD68陽性hCLS数を示す。Vehicle群は、Normal群に対して統計学的に有意な肝臓のhCLS数の増加を示した。また、化合物1(10)群及び化合物1(60)群は、Vehicle群に対して統計学的に有意な肝臓のhCLS数の増加抑制作用を示した。この結果から、化合物1が肝臓に対する抗炎症作用を有することを確認した。
化合物1は、血漿中ALT/AST/Tcho、及び肝臓中TGの上昇を抑制したことから、脂肪性肝疾患に関わる指標(肝逸脱酵素及び脂質代謝)を有意に改善した。更に、化合物1は、Sirius Red陽性面積率及びhCLS数も有意に抑制し、肝臓の線維化や炎症の指標を改善した。病理組織所見も、これらの改善効果を裏付ける結果を示した。以上の結果から、NASHモデルにおける化合物1の薬効が確認された。
Claims (9)
- 前記医薬上許容可能な塩が塩酸塩である、請求項1に記載の治療薬。
- 前記脂肪性肝疾患が、非アルコール性脂肪性肝疾患(NAFLD)又は非アルコール性脂肪性肝炎(NASH)である、請求項1又は2に記載の治療薬。
- 前記脂肪性肝疾患がNAFLDである、請求項3に記載の治療薬。
- 前記NAFLDが肝臓の線維化を伴っている、請求項4に記載の治療薬。
- 前記NAFLDが肝臓の炎症を伴っている、請求項4に記載の治療薬。
- 前記脂肪性肝疾患がNASHである、請求項3に記載の治療薬。
- 前記NASHが肝臓の線維化を伴っている、請求項7に記載の治療薬。
- 前記NASHが肝臓の炎症を伴っている、請求項7に記載の治療薬。
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JP2022543965A JP7286222B2 (ja) | 2020-08-19 | 2021-08-18 | 脂肪性肝疾患の治療薬 |
BR112023002069A BR112023002069A2 (pt) | 2020-08-19 | 2021-08-18 | Agente terapêutico para doença hepática gordurosa |
CA3183428A CA3183428A1 (en) | 2020-08-19 | 2021-08-18 | Therapeutic agent for fatty liver disease |
AU2021328824A AU2021328824A1 (en) | 2020-08-19 | 2021-08-18 | Therapeutic agent for fatty liver disease |
EP21858322.7A EP4166137B1 (en) | 2020-08-19 | 2021-08-18 | Therapeutic agent for fatty liver disease |
KR1020227036729A KR20230052845A (ko) | 2020-08-19 | 2021-08-18 | 지방성 간 질환의 치료약 |
CN202180035572.1A CN115605198A (zh) | 2020-08-19 | 2021-08-18 | 脂肪性肝病的治疗药 |
MX2023001742A MX2023001742A (es) | 2020-08-19 | 2021-08-18 | Agente terapeutico para la enfermedad de higado graso. |
US18/171,126 US20230201163A1 (en) | 2020-08-19 | 2023-02-17 | Therapeutic agent for fatty liver disease |
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EP3437651A1 (en) * | 2017-08-03 | 2019-02-06 | Université de Strasbourg | Peptides for treatment and prevention of nonalcoholic fatty liver disease |
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WO2013187533A1 (en) * | 2012-06-14 | 2013-12-19 | Ajinomoto Co., Inc. | Heteroarylcarboxylic acid ester derivative |
WO2015137407A1 (ja) | 2014-03-11 | 2015-09-17 | 味の素株式会社 | ヘテロアリールカルボン酸エステル誘導体の製造方法、その製造中間体及び結晶 |
WO2015137408A1 (ja) | 2014-03-11 | 2015-09-17 | 味の素株式会社 | ヘテロアリールカルボン酸エステル誘導体の製造方法及びその製造中間体 |
US20170281739A1 (en) * | 2014-09-22 | 2017-10-05 | Hadasit Medical Research Services And Development Ltd. | Alpha-1 anti-trypsin for treating liver diseases |
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AM J PHYSIOL GASTROINTEST LIVER PHYSIOL., vol. 305, no. 7, 1 October 2013 (2013-10-01), pages G483 - 95 |
BMC GASTROENTEROL, vol. 20, 2020, pages 210 |
HEPATOLOGY, vol. 67, no. 1, January 2018 (2018-01-01), pages 328 - 357 |
See also references of EP4166137A4 |
TOONEN ERIK J M, MIREA ANDREEA-MANUELA, TACK CEES J, STIENSTRA RINKE, BALLAK DOV B, VAN DIEPEN JANNA A, HIJMANS ANNEKE, CHAVAKIS T: "Activation of Proteinase 3 Contributes to Nonalcoholic Fatty Liver Disease and Insulin Resistance", MOLECULAR MEDICINE, FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH, WASHINGTON , DC, vol. 22, no. 1, 1 January 2016 (2016-01-01), Washington , DC , pages 202 - 214, XP055902546, ISSN: 1076-1551, DOI: 10.2119/molmed.2016.00033 * |
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JP2023103420A (ja) | 2023-07-26 |
CA3183428A1 (en) | 2022-02-24 |
BR112023002069A2 (pt) | 2023-03-07 |
KR20230052845A (ko) | 2023-04-20 |
JP7286222B2 (ja) | 2023-06-05 |
TW202214231A (zh) | 2022-04-16 |
JPWO2022039178A1 (ja) | 2022-02-24 |
CN115605198A (zh) | 2023-01-13 |
AU2021328824A1 (en) | 2023-02-02 |
EP4166137A4 (en) | 2023-06-28 |
EP4166137A1 (en) | 2023-04-19 |
US20230201163A1 (en) | 2023-06-29 |
EP4166137B1 (en) | 2024-05-29 |
MX2023001742A (es) | 2023-02-22 |
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