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WO2016001682A1 - Traitement de l'hypertransaminasémie - Google Patents

Traitement de l'hypertransaminasémie Download PDF

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Publication number
WO2016001682A1
WO2016001682A1 PCT/GB2015/051943 GB2015051943W WO2016001682A1 WO 2016001682 A1 WO2016001682 A1 WO 2016001682A1 GB 2015051943 W GB2015051943 W GB 2015051943W WO 2016001682 A1 WO2016001682 A1 WO 2016001682A1
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WO
WIPO (PCT)
Prior art keywords
composition
uur
utrophin
treating
treatment
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/GB2015/051943
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English (en)
Inventor
Jonathon Mark Tinsley
Francis Xavier Wilson
Bindu Tejura
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Summit Therapeutics Ltd
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Summit Therapeutics Ltd
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Filing date
Publication date
Application filed by Summit Therapeutics Ltd filed Critical Summit Therapeutics Ltd
Publication of WO2016001682A1 publication Critical patent/WO2016001682A1/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
    • A61K31/42—Oxazoles
    • A61K31/423—Oxazoles condensed with carbocyclic 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

  • compositions for use in the treatment of a disease associated with loss of cellular membrane integrity in non-muscle cells relate to compositions comprising a utrophin upregulator for use in a method of restoring non-muscle cell membrane integrity, for example in the treatment of hypertransaminasemia and liver diseases associated with hypertransaminasemia, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • NAFLD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • the invention also relates to the corresponding therapeutic methods.
  • DBMD Duchenne and Becker muscular dystrophy
  • Dystrophin is normally present at the sarcolemma together with a group of proteins known as the dystrophin protein complex (DPC).
  • Dystrophin binds to the intracellular cytoskeleton by associating with actin filaments at the N-terminus, while the C- terminus binds members of the DPC, including ⁇ -dystroglycan.
  • Extracellular a- dystroglycan binds to ⁇ -dystroglycan and acts as a receptor for the extracellular- matrix protein laminin.
  • dystrophin together with the DPC links the extracellular matrix with the intracellular cytoskeleton to providing structural integrity to muscle fibers.
  • dystrophin in muscles of DMD patients disrupts the DPC and leads to sarcolemmal instability.
  • Transient microdisruptions in the sarcolemma also occur in DMD and lead to increased levels of intracellular Ca 2+ and subsequent aberrant Ca 2+ - mediated signaling activating calpain-mediated proteolysis.
  • other signalling cascades are also probably affected, because the DPC is a multifunctional signaling complex that interacts with important additional signaling molecules such as neuronal nitric oxide synthase (nNOS), Grb2 and calmodulin.
  • nNOS neuronal nitric oxide synthase
  • Grb2 calmodulin
  • utrophin Upregulation of utrophin, an autosomal paralogue of dystrophin, has been proposed as a therapy for DMD (Perkins and Davies (2002), Neuromuscul Disord, S1 : S78- S89; Khurana & Davies (2003), Nat Rev Drug Discov 2:379-390).
  • This treatment paradigm is based on the recognition that utrophin can functionally replace dystrophin in DMD muscle fibers: utrophin shares a high degree of sequence identity with dystrophin and also associates with members of the DPC.
  • utrophin upregulators referred to herein as UURs
  • UURs agents which increase utrophin activity
  • Hypertransaminasemia pathologic elevation of serum transaminase levels
  • liver disease Specifically, elevated serum levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) are associated with non-alcoholic fatty liver disease (NAFLD).
  • NAFLD encompasses a wide spectrum of conditions ranging from simple steatosis, non-alcoholic steatohepatitis (NASH) and liver cirrhosis.
  • DBMD patients may present with NAFLD, exhibiting elevated serum levels of transaminases, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (Veropalumbo et al. (201 1) JPGN 53 (4): 463- 464).
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • dystrophin function implies a role for one or more of the various dystrophin isoforms in liver function. While full-length dystrophin (muscle or M-dystrophin) is absent in hepatocytes, a 71 kDa isoform (liver or G- dystrophin) is known to be expressed in the liver and so may play a role in signalling and/or or membrane integrity in the liver analogous to that of the M-dystrophin isoform in muscle.
  • M-dystrophin muscle or M-dystrophin
  • transaminases including AST and ALT, and therefore find utility in the treatment of hypertransaminasemia and liver diseases associated therewith, including nonalcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH).
  • NAFLD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatitis
  • the increase in utrophin protein levels and/or function produced on administration of UURs can stabilize not only the dystrophin deficient sarcolemmal membrane of DBMD muscle fibres but also the cell membranes of non-muscle cells in both DBMD and non-DBMD subjects, including hepatocyte membranes.
  • UURs may be used to treat diseases associated with loss of cellular membrane integrity in non-muscle cell tissues.
  • the discovery of a ubiquitous membrane stabilizing role for utrophin also permits novel treatments for diseases caused by loss of cellular membrane integrity. Such diseases may be characterized by the presence of elevated levels of cytosolic proteins and/or enzymes in the blood.
  • the invention finds particular application in therapeutic methods for reducing the leakage of transaminases from the liver (including aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) thereby alleviating hypertransaminasemia and so providing a novel mechanism of action for the treatment of liver diseases associated with hypertransaminasemia (including NAFLD and NASH).
  • a “pharmaceutical composition” is a solid or liquid composition in a form
  • compositions are typically sterile and/or non-pyrogenic.
  • non-pyrogenic as applied to the pharmaceutical compositions of the invention defines compositions which do not elicit undesirable inflammatory responses when administered to a patient.
  • the pharmaceutical compositions of the invention preferably comprise a pharmaceutically acceptable carrier,
  • pharmaceutically acceptable excipient physiologically acceptable carrier or physiologically acceptable excipient.
  • pharmaceutically acceptable carrier pharmaceutically acceptable excipient
  • physiologically acceptable carrier pharmaceutically acceptable carrier
  • each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications,
  • the term "therapeutically effective amount” are meant to include the amount of a compound or composition that, when administered, is sufficient to prevent development of, or alleviate to some extent, one or more of the symptoms of the disorder, disease, or condition being treated.
  • the terms “treat,” “treating,” and “treatment” are meant to include preventing, reducing the incidence of, curing, alleviating or abrogating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or alleviating or eradicating the cause(s) of the disorder, disease, or condition itself.
  • disease is intended to define any disorder, disease or condition, preferably of the human body.
  • subject refers to an animal, including but not limited to, a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • primate e.g., human
  • cow, pig, sheep, goat horse
  • dog cat
  • rabbit rat
  • patient are used interchangeably herein in reference, for example, to a mammalian subject, such as a human subject, in one embodiment, a human.
  • UURs as a class upregulate utrophin.
  • This upregulation may be effected at the level of utrophin expression (for example transcriptionally or post-transcriptionally), utrophin stability (either per se or in the context of the utrophin protein complex, UPC) or at the level of the recruitment of utrophin to the UPC.
  • utrophin upregulation can stabilize cellular membranes ubiquitously, and so may be used to improve cell membrane integrity in non-muscle cells including hepatocytes.
  • any UUR may be used according to the invention, and suitable UURs include various classes of small-molecules which act at the level of utrophin gene expression. These have been extensively described in the literature, and include 2- arylbenzoxazoles, 2-arylbenzotriazoles and 2-arylindazoles. This class is exemplified by SMT C1100 (5-(ethylsulfonyl)-2-(naphthalen-2-yl)benzo[d]oxazole), a small molecule utrophin upregulator currently in Phase 1 b clinical trials. Other UURs upregulate the activity of utrophin act by protein stabilisation or enhancing translational efficiency.
  • recombinant human biglycan upregulates utrophin and can recruit it to the sarcolemma (see e.g. Amenta et al. (2011) PNAS 108(2): 762-767), while another component of the DPC, sarcospan (SSPN), improves cell surface expression of utrophin-glycoprotein complexes (Marshall and Crosbie- Watson (2013) Skeletal Muscle 3: 1).
  • URC utrophin glycoprotein complex
  • GRC utrophin glycoprotein complex
  • ADAM12 heregulin
  • L-arginine activated calcineurin-A alpha
  • N-acetylcysteine activated Akt
  • GW501516 artificial utrophin gene transcription factors (e.g. the artificial zinc finger factors UtroUp and jazz - see e.g. Onori et al. (2013) BMC Molecular Biology 2013, 14:3) and ⁇ 7 ⁇ 1 integrin.
  • UURs for use according to the invention include these proteins and compounds together with upregulators of their expression/production in vivo.
  • UURs which stimulate utrophin overexpression are agents which stimulate the overexpression of utrophin at the transcriptional level. These include any of a large number of small molecule UURs which have been extensively described in the literature, including 2-arylbenzoxazoles, 2-arylbenzotriazoles and 2-arylindazoles described in more detail below.
  • 2-arylbenzoxazole UURs include 5-(ethylsulfonyl)-2-(naphthalen-2- yl)benzo[d]oxazole (SMT C1 100), a small molecule utrophin upregulator that has the potential to be a universal treatment for DMD and is currently in Phase 1 b clinical trials:
  • Suitable UURs may also be selected from those of the general formulae:
  • WO2010/069684 W02010/086040; WO2010/1 12093; WO/2010/1 12092 and WO/2010/112091 (the contents of each of which is hereby incorporated by reference).
  • the identity of the various substituents shown in the above formulae are defined in the references provided.
  • UURs which stimulate utrophin overexpression for use according to the invention may be identified in the following predictive assay.
  • Luciferase reporter assay (murine H2K cells)
  • the cell line used for the screen is an immortalized mdx mouse H2K cell line that has been stably transfected with a plasmid containing « 8.4kb fragment of the Utrophin A promoter including the first untranslated exon linked to a luciferase reporter gene. Under conditions of low temperature and interferon containing media, the cells remain as myoblasts. These are plated into 96 well plates and cultured in the presence of compound for three days. The level of luciferase is then determined by cell lysis and reading of the light output from the expressed luciferase gene utilising a plate luminometer.
  • the H2K/mdx/Utro A reporter cell line cells were plated out into 96 well plates (Falcon 353296, white opaque) at a density of approximately 5000 cells/well in 190 ⁇ normal growth medium. The plates were then incubated at 33°C in the presence of 10% C0 2 for 24 hrs.
  • utrophin upregulation can stabilize cellular membranes ubiquitously, and so may be used to improve cell membrane integrity in non-muscle cells.
  • the invention therefore finds application in the treatment of any disease caused by impaired cellular membrane integrity in non-muscle cells and in methods for restoring non-muscle cell membrane integrity in vivo.
  • Diseases caused by impaired cellular membrane integrity in non-muscle cells which may be treated according to the invention may be identified by the presence of elevated levels of cytosolic proteins and/or enzymes in the blood.
  • the invention may be used in the treatment of hypertransaminasemia characterized by the presence of elevated serum levels of liver transaminases (including aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)).
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • the invention finds particular application in therapeutic methods for reducing the leakage of transaminases from the liver (including aspartate aminotransferase (AST) and alanine aminotransferase (ALT)) thereby alleviating
  • hypertransaminasemia and so providing a novel mechanism of action for the treatment of liver diseases associated with hypertransaminasemia (including NAFLD and NASH).
  • compositions comprising a utrophin upregulator for use in a method of restoring non-muscle cell membrane integrity, for example in the treatment of hypertransaminasemia and liver diseases associated with
  • hypertransaminasemia including for example non-alcoholic fatty liver disease
  • NAFLD non-alcoholic steatohepatitis
  • NASH non-alcoholic steatohepatitis
  • the above methods and therapeutic treatments are of general application, but may find particular application in the treatment of DBMD subjects, and in particular to the treatment of DBMD subjects exhibiting hypertransaminasemia.
  • compositions of the invention are administered in the form of a pharmaceutical composition comprising a UUR and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical compositions can be provided in solid, semisolid, or liquid dosage forms for oral administration.
  • oral administration also includes buccal, lingual, and sublingual administration.
  • Suitable oral dosage forms include, but are not limited to, tablets, fastmelts, chewable tablets, capsules, pills, strips, troches, lozenges, pastilles, cachets, pellets, medicated chewing gum, bulk powders, effervescent or non-effervescent powders or granules, oral mists, solutions, emulsions, suspensions, wafers, sprinkles, elixirs, and syrups.
  • the pharmaceutical compositions can be administered parenterally by injection, infusion, or implantation, for local or systemic administration. Parenteral
  • administration include intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical, and subcutaneous administration.
  • compositions provided herein for parenteral administration can be formulated in any dosage forms that are suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems, and solid forms suitable for solutions or suspensions in liquid prior to injection.
  • dosage forms can be prepared according to conventional methods known to those skilled in the art of pharmaceutical science (See, Remington: The Science and Practice of Pharmacy, supra).
  • the pharmaceutical compositions provided herein can be administered topically to the skin, orifices, or mucosa.
  • the topical administration includes
  • Enzyme levels of creatine phosphokinase (CPK), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were significantly elevated in the subjects.
  • CPK creatine phosphokinase
  • AST aspartate aminotransferase
  • ALT alanine aminotransferase
  • gamma-glutamyl transferase gamma-glutamyl transferase
  • 'ALK' alkaline phosphatase
  • 'ALB' albumin

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

Abstract

L'invention concerne des compositions comprenant un agent de régulation positive de l'utrophine (UUR) destinées à être utilisées dans une méthode de traitement d'une maladie associée à la perte d'intégrité de la membrane cellulaire dans des tissus cellulaires non musculaires.
PCT/GB2015/051943 2014-07-04 2015-07-02 Traitement de l'hypertransaminasémie Ceased WO2016001682A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB1412010.9A GB201412010D0 (en) 2014-07-04 2014-07-04 Treatment of hypertransaminasemia
GB1412010.9 2014-07-04

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WO2016001682A1 true WO2016001682A1 (fr) 2016-01-07

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2017168151A1 (fr) * 2016-03-30 2017-10-05 Summit (Oxford) Limited Composition pour le traitement de la myopathie de duchenne
CN109355389A (zh) * 2018-11-28 2019-02-19 陕西中医药大学 B4galnt2基因作为肝癌检测的生物标志物及应用

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CN109803641A (zh) * 2016-03-30 2019-05-24 萨米特(牛津)有限公司 用于治疗杜兴氏肌肉营养不良症的组合物
CN109355389A (zh) * 2018-11-28 2019-02-19 陕西中医药大学 B4galnt2基因作为肝癌检测的生物标志物及应用

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