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WO2019121764A1 - Médicament pour le traitement de la fibrose hépatique et de la cirrhose du foie - Google Patents

Médicament pour le traitement de la fibrose hépatique et de la cirrhose du foie Download PDF

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Publication number
WO2019121764A1
WO2019121764A1 PCT/EP2018/085625 EP2018085625W WO2019121764A1 WO 2019121764 A1 WO2019121764 A1 WO 2019121764A1 EP 2018085625 W EP2018085625 W EP 2018085625W WO 2019121764 A1 WO2019121764 A1 WO 2019121764A1
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WO
WIPO (PCT)
Prior art keywords
liver
cirrhosis
treatment
prevention
fibrosis
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2018/085625
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English (en)
Inventor
Jochen Hampe
Raghavan THANGAPANDI
Mario BROSCH
Clemens Schafmeyer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Technische Universitaet Dresden
Christian Albrechts Universitaet Kiel
Original Assignee
Technische Universitaet Dresden
Christian Albrechts Universitaet Kiel
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Technische Universitaet Dresden, Christian Albrechts Universitaet Kiel filed Critical Technische Universitaet Dresden
Publication of WO2019121764A1 publication Critical patent/WO2019121764A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A61K31/4162—1,2-Diazoles condensed with heterocyclic ring systems
    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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 concerns a medicament for use in the treatment and/or prevention of liver fibrosis and/or of cirrhosis of liver.
  • the medicament is effective in the treatment of and preferably also in the prevention of liver fibrosis and/or of cirrhosis of liver, independent of the presence of inflammation in the liver.
  • the medicament can be for use in the treatment and/or prevention of liver fibrosis and/or of cirrhosis of liver in the presence of inflammation, e.g. inflammation caused by viral infection, e.g. by hepatitis B virus, by hepatitis C virus, or for use in the treatment of and/or prevention of liver fibrosis and/or of cirrhosis of liver in the absence of inflammation, e.g.
  • alcoholic liver disease ALD
  • NAFLD non-alcoholic liver disease
  • NASH non-alcoholic steatohepatitis
  • GPR55 Arifin and Falasca, Metabolites 6, 6 (2016) (DOI: l0.3390/metabo6010006) describe that the mRNA encoding the human receptor GPR55 was found in certain brain regions, adipose tissue, testis, myometrium, tonsil, adenoid and spleen. GPR55 is described as an atypical cannabinoid receptor, and as a receptor of the agonist lysophospholipid LPI.
  • liver fibrosis can be countered by liver transplantation or by treatment an inflammation underlying the fibrosis or by reducing the intake of alcohol, of intoxicating compounds, or by reducing intake of fat or reducing body weight, but no direct curative treatment for liver fibrosis is known.
  • the present invention achieves the objective by the features of the claims and especially by providing compounds, especially inhibitors of GPR55, for use as a medicament in the treatment and/or prevention of liver fibrosis and/or of cirrhosis of liver.
  • Treatment and/or prevention of liver fibrosis and/or of cirrhosis of liver is achieved by administration of an inhibitor of GPR55 to a patient who is suspected of having liver fibrosis or cirrhosis of liver, who is diagnosed as having liver fibrosis or cirrhosis of liver or who is considered to have an increased risk of developing liver fibrosis or cirrhosis of liver.
  • GPR55 is encoded by the GPR55 gene, in humans by nucleotides 230907318 to 230961066 of chromosome 2, in mouse by nucleotides 85938318 to 85961007 of chromosome 1.
  • GPR55 is a class A G-protein-coupled receptor and has been shown to be activated by L-a- lysophopsphatidylinosito 1.
  • the treatment using an inhibitor of GPR55 is independent of the presence of a mutation in the MBOAT7 and TM6SF2 and in the PNPLA3 genes, e.g. independent from the SNP rs738409 in the PNPLA3 gene. Accordingly, the medicament can be used in patients having the wild-type allele of the MBOAT7 and TM6SF2 and the PNPLA3 genes, and/or in a human, also termed patient, having a mutation in at least one of the MBOAT7 and TM6SF2 and the PNPLA3 genes.
  • the compounds which especially are inhibitors of GPR55, are for use in patients having a mutation in at least one of the genes MBOAT7, TM6SF2 and/or PNPLA3, wherein the mutation preferably reduces activity of the gene product, e.g. in comparison to the activity of the product of the wild-type gene, which patients are considered to have an increased risk of developing liver fibrosis.
  • An exemplary mutation of the MBOAT7 encoding gene that was found to reduce activity is the SNP rs64l738, which was found to result in lower expression of the MBOAT7 gene product, and to lead to severe NAFLD.
  • an inhibitor of GPR55 in the treatment of liver fibrosis and/or of cirrhosis of liver can be independent from the treatment of the causative agent of the liver fibrosis, which causative agent may e.g. be a virus or toxic substance like alcohol or drug abuse.
  • the use of an inhibitor of GPR55 in the treatment of liver fibrosis is coupled with the treatment of the causative agent of the liver fibrosis and/or of cirrhosis of liver, which causative agent may e.g. be a virus and or abuse of a toxic substance like alcohol in the case of alcoholic liver disease, or drug abuse or obesity in the case of non-alcoholic liver disease.
  • the treatment of the causative agent of the liver fibrosis and/or of cirrhosis of liver can e.g. be the use of an antiviral agent for treatment of the viral infection or the prevention of further intake of the toxic substance, or a diet suitable in the prevention of non-alcoholic liver disease.
  • an inhibitor of GPR55 also in the presence of inflammation reduces and/or prevents liver fibrosis, e.g. inflammation caused by viral infection.
  • Inhibitors of GPR55 can be determined by the process described by Kotsikorou et al, Biochemistry 2013 (loc. cit).
  • Exemplary compounds for use in the treatment of or in the prevention of liver fibrosis and/or of cirrhosis of liver, which preferably are inhibitors of GPR55, are comprised in the group comprising or consisting of 5 -phenyl-3 - ⁇ 1 - [ 1 -(/ -tolyl)cyclopropanc-carbonyl]pipcridin-4-yl ⁇ -1,3,4- oxadiazol-2(37 )-one (CID23612552), ⁇ furan-2-yl[4-(2-methyl-5,6,7,8- tetrahydrobenzo[4,5]thieno[2,3- ⁇ i]pyrimidin-4-yl)piperazin-l-yl]methanone ⁇ (CID 1434953), (A- j 4-[/V-
  • Fig. 1 a graph on the proportion of MAF in human patients without diagnosed liver fibrosis (F0, left col.) and with diagnosed liver fibrosis (Fl-4, right col.) both for no inflammation (INF 0) and for inflammation present (INF 1),
  • Fig. 2 shows cell numbers in wild-type and in MBOAT7 knock-out mice, in a) of macrophage, in b) of monocytes, in c) of CD8+ T-cells, in d) of CD4+ T-cells, and in e) of neutrophils,
  • Fig. 3 a shows levels of collagen type I and III, determined by Pikrosirius staining of liver tissue, in b) relative hydroxyproline levels in liver tissue of wild-type (WT) and of MBOAT7 knock-out (KO) mice, and in c) a Pikrosirius stain of liver tissue of an MBOAT7 knock-out mouse and in d) a Pikrosirius stain of liver tissue of a wild-type mouse,
  • - Fig. 4 shows relative RNA levels, in a) of TGFP transcripts, in b) of a-SMA
  • transcripts in c) of Sphkl transcripts, and in d) of Coll A transcripts in liver tissue of wild-type (WT) and of MBOAT7 knock-out (KO) mice,
  • Fig. 5 shows relative RNA levels, in a) for IL6 transcripts, in b) for ILl-b (ILl-b) transcripts, in c) for TNFa (TNFa) transcripts, in d) for IFNy (IFNg) transcripts in liver tissue of wild-type (WT) and of MBOAT7 knock-out (KO) mice, and
  • Fig. 6 a the relative transcripts of SPKH1 encoding mRNA
  • Fig. 6 b the relative transcripts of COL la encoding mRNA
  • Fig. 6 c the relative transcripts of a-SMA encoding mRNA
  • Fig. 6 d the relative transcripts of TGFP encoding mRNA
  • - Fig. 7 shows levels of phosphatidyl inositol compounds in liver of wild-type mice (left col.) and of MBOAT7 knock-out mice (right col.),
  • - Fig. 8 shows levels of phosphatidyl inositol compounds in liver for NASH (left col.) and NAFLD (center col.) and for patients healthy persons (ho, right col.),
  • Fig. 9 shows formulae of exemplary compounds for use in the treatment or prevention of liver fibrosis and/or of cirrhosis of liver, which are exemplary and preferred inhibitors of GPR55.
  • the examples show that reduction of the activity of MBOAT7, e.g. represented by a knock out of the MBOAT7 encoding gene, results in increased occurrence of liver fibrosis.
  • the knock-out of MBOAT7 is not correlated with inflammation, providing an example for liver fibrosis which is independent from inflammation and not caused by an infectious agent, e.g. not caused by viral infection.
  • liver fibrosis was induced by the knock-out of the MBOAT7 encoding gene and by a high- fat, choline-deficient, methionine supplemented diet. Further, the examples show that the inhibition of GPR55 reduces or prevents liver fibrosis in the experimental genetic knock-out of the MBOAT7 encoding gene and in wild-type mice by way of administration of the exemplary GPR55 inhibitor CID 16020046.
  • MBOAT7 knock-out mice were generated by crossing Mboat7 fl/fl mice, obtained from MRC Harwell, London, with C57LB1/6 Alb Cre mice, obtained from Jacksons Laboratory, giving the deletion of the MBOAT7 gene.
  • the deletion of the MBOAT7 gene in hepatocytes was confirmed by genotyping using PCR and by quantitative reverse PCR for transcripts of MBOAT7.
  • Fig. 2 in a) to e) shows that in comparison to wild-type, the MBOAT7 knock-out did not significantly influence presence of immune cells, exemplified by macrophage, monocytes, CD8+ T-cells and CD4+ T-cells and neutrophils in the liver tissue.
  • the knock-out of MBOAT7 increased fibrosis in mice fed on a NASH diet as shown by the increase of positive area in Pikrosirius staining of liver tissue, indicating collagen I and III, as depicted in Fig. 3 a).
  • liver tissue in the MBOAT7 knock-out mice showed a significant increase, as depicted in Fig. 3b).
  • a pikrosirius stain of liver tissue from a MBOAT7 knock-out mouse is shown in Fig. 3 c), and from a wild-type mouse in Fig. 3 d), showing increased characteristics of liver fibrosis in the MBOAT7 knock-out mouse only.
  • the MBOAT7 knock-out (KO) mice and wild-type (WT) mice were treated with 0.5 mg/kg CID 16020046 (obtained from Tocris bioscience, UK), which is a known inhibitor of GPR55, and for comparison in parallel treated with 1% DMSO.
  • the analytical results are depicted in Fig. 6, showing that administration of the inhibitor of GPR55 results in a reduced
  • Phosphatidyl inositol (PI) lipid compounds were analysed using liver tissue samples. The analyses of the phosphatidyl inositol (PI) lipid compounds in the liver of the MBOAT7 knock-out mice and wild-type mice showed that the lack of MBOAT7 affects the levels of some PI species, especially results in a decreased level of lysophosphatityl inositol (PI 38:4:0). Fig. 7 depicts the analytical results for the wild-type (left col.) and for the MBOAT7 knock-out (right col.).
  • PI phosphatidyl inositol
  • NASH non-alcoholic liver disease
  • NAFLD non-alcoholic steatohepatitis
  • the person to be treated preferably has a reduced level of lysophosphatidyl inositol, e.g. in a blood or in a liver sample.
  • the inhibitor of GPR55 used in the treatment or prevention of liver fibrosis and/or cirrhosis of liver acts by way of affecting the level of lysophosphatidyl inositol, preferably increasing its level, by inhibiting GPR55.

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  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne un médicament destiné à être utilisé dans le traitement et/ou la prévention de la fibrose hépatique et/ou de la cirrhose du foie. Le médicament est un inhibiteur de GPR55 Et est efficace dans le traitement et de préférence également dans la prévention de la fibrose hépatique et/ou de la cirrhose du foie, indépendamment de la présence d'inflammation dans le foie.
PCT/EP2018/085625 2017-12-21 2018-12-18 Médicament pour le traitement de la fibrose hépatique et de la cirrhose du foie Ceased WO2019121764A1 (fr)

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EP17209754 2017-12-21

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119157906A (zh) * 2024-09-30 2024-12-20 广州飞来爱生命科技有限公司 一种脐带间充质干细胞制剂及其在治疗肝脏疾病的用途

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008050344A2 (fr) * 2006-10-25 2008-05-02 Yissum Research Development Company Of The Hebrew University Of Jerusalem Traitement de l'encéphalopathie hépatique et de la cirrhose du foie

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008050344A2 (fr) * 2006-10-25 2008-05-02 Yissum Research Development Company Of The Hebrew University Of Jerusalem Traitement de l'encéphalopathie hépatique et de la cirrhose du foie

Non-Patent Citations (11)

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Title
ARIFIN; FALASCA, METABOLITES, vol. 6, 2016, pages 6
BUCH ET AL., NATURE GENETICS, vol. 47, no. 22, 2015, pages 1443 - 1448
E RYBERG ET AL: "The orphan receptor GPR55 is a novel cannabinoid receptor : GPR55, a novel cannabinoid receptor", BRITISH JOURNAL OF PHARMACOLOGY, vol. 152, no. 7, 1 December 2007 (2007-12-01), UK, pages 1092 - 1101, XP055562624, ISSN: 0007-1188, DOI: 10.1038/sj.bjp.0707460 *
HONGJUN ZHANG ET AL: "Magnolol Attenuates Concanavalin A-induced Hepatic Fibrosis, Inhibits CD4+ T Helper 17 (Th17) Cell Differentiation and Suppresses Hepatic Stellate Cell Activation: Blockade of Smad3/Smad4 Signalling", BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY, vol. 120, no. 6, 7 March 2017 (2017-03-07), COPENHAGEN, DK, pages 560 - 570, XP055562727, ISSN: 1742-7835, DOI: 10.1111/bcpt.12749 *
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JU-HEE LEE ET AL: "Combination of honokiol and magnolol inhibits hepatic steatosis through AMPK-SREBP-1?c pathway", EXPERIMENTAL BIOLOGY AND MEDICINE, vol. 240, no. 4, 14 August 2014 (2014-08-14), GB, pages 508 - 518, XP055563052, ISSN: 1535-3702, DOI: 10.1177/1535370214547123 *
KOTSIKOROU ET AL., BIOCHEMISTRY, 2013
KOTSIKOROU ET AL., BIOCHEMISTRY, vol. 52, 2013, pages 9456 - 9469
QUOTING MORENO-NAVERRETE ET AL.: "The I-a-lysophosphatidylinositol/GPR55 system and its potential role in human obesity", DIABETES, vol. 61, 2012, pages 281 - 291
THABET ET AL., NATURE COMMUNICATIONS, vol. 7, 2016, pages 12757
VIKTOR REMPEL ET AL: "Magnolia Extract, Magnolol, and Metabolites: Activation of Cannabinoid CB 2 Receptors and Blockade of the Related GPR55", ACS MEDICINAL CHEMISTRY LETTERS, vol. 4, no. 1, 26 November 2012 (2012-11-26), pages 41 - 45, XP055563142, ISSN: 1948-5875, DOI: 10.1021/ml300235q *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN119157906A (zh) * 2024-09-30 2024-12-20 广州飞来爱生命科技有限公司 一种脐带间充质干细胞制剂及其在治疗肝脏疾病的用途

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