WO2025078880A1 - Antioxydants ciblant les mitochondries destinés à être utilisés dans le traitement de maladies associées à la ballonisation cellulaire, comme la stéato-hépatopathie non alcoolique (nafld) et la stéatohépatite non alcoolique (nash) - Google Patents

Antioxydants ciblant les mitochondries destinés à être utilisés dans le traitement de maladies associées à la ballonisation cellulaire, comme la stéato-hépatopathie non alcoolique (nafld) et la stéatohépatite non alcoolique (nash) Download PDF

Info

Publication number
WO2025078880A1
WO2025078880A1 PCT/IB2024/000569 IB2024000569W WO2025078880A1 WO 2025078880 A1 WO2025078880 A1 WO 2025078880A1 IB 2024000569 W IB2024000569 W IB 2024000569W WO 2025078880 A1 WO2025078880 A1 WO 2025078880A1
Authority
WO
WIPO (PCT)
Prior art keywords
ballooning
group
subject
carbon atoms
increase
Prior art date
Application number
PCT/IB2024/000569
Other languages
English (en)
Inventor
Maxim Skulachev
Anton Petrov
Original Assignee
Mitotech S.A.
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 Mitotech S.A. filed Critical Mitotech S.A.
Publication of WO2025078880A1 publication Critical patent/WO2025078880A1/fr

Links

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
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • 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
    • A61K31/13—Amines
    • A61K31/14—Quaternary ammonium compounds, e.g. edrophonium, choline
    • 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
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • 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
    • A61K31/66—Phosphorus compounds
    • 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

  • Ballooning is a component and marker of severe cell injury under many pathological conditions (Clinical Hepatology: Principles and Practice of Hepatobiliary Diseases, Vol.1 , Dancygier, H. (ed.), Springer, 2010, P. 207, The Washington Manual of Surgical Pathology: Department of Pathology and Immunology, by P. A. Humphrey, L.P. Dehner, J.D. Pfeifer (eds), Washington University School of Medicine, Lippincott Williams & Wilkins, 2008, P. 209; Robbins & Cotran Pathologic Basis of Disease, 9th Edition, V. Kumar, A. Abbas, J. Aster, Elsevier, 2014).
  • Ballooned cells can undergo apoptosis and necrosis, and ballooning may cause organ disfunction, inflammation, and fibrosis, especially in the liver (Guy, C.D., et al. Hepatology, 2012, 55, 1711-172; Kleiner, D. E., et al. Hepatology, 2005. 41, 1313-1321; Lackner C, et al. J Hepatol., 2008, 48(5), 821-828).
  • MDB Mallory-Denk bodies
  • p62 oxidative stress-induced 1/p62 sequestosome
  • Recent studies demonstrate that apoptosis of hepatocytes associated with MDB can lead to an increase of CK-18 in blood plasma of patients suffering from liver diseases (Feldstain et al., Am J Gastroenterol. 2013 108:1526-31).
  • Diminution or loss of cytoplasmic K8/18 staining can be regarded as a marker for a distinguished form of hepatocellular damage that results in ballooning degeneration and eventually MDB formation, which preferentially occurs in liver diseases such as nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, chronic cholestasis, increased copper storage, or ischemia-reperfusion injury
  • liver diseases such as nonalcoholic steatohepatitis (NASH), alcoholic steatohepatitis, chronic cholestasis, increased copper storage, or ischemia-reperfusion injury
  • the present technology provides methods and compositions for treating and preventing cell ballooning and other diseases or medical conditions.
  • the diseases or medical conditions are characterized by cell degeneration or cell death as a part of the disease pathogenesis.
  • Cell ballooning involves cell swelling with loss of the usual shape of the cell and inclusions in the cytoplasm filled with fat, and sometimes with dark staining cytoplasmic structures.
  • Ballooning is a condition associated with storage of excess fat in the liver, nutritional or biochemical imbalance, damage to mitochondria, ATP depletion, or virus infection.
  • a mitochondrially targeted antioxidant compound is administered to a subject in need thereof, whereby excess fat is metabolized and burned.
  • a method to aid in treating or preventing a cell ballooning-associated disease or medical condition comprising the step of administering to a subject in need thereof therapeutically or prophylactically effective amount of a mitochondrially targeted antioxidant compound.
  • the mitochondrially targeted antioxidant is an SkQ compound of Formula II below:
  • A is hydrogen or an effector moiety, which is an antioxidant optionally having a following structure: and/or reduced forms thereof, wherein m is from 0 to 3;
  • each Y is independently selected from the group consisting of: lower alkyl (1 to 6 carbons), lower alkoxy (1 to 6 carbons); or two adjacent Y groups, together with carbon atoms to which they are attached, form a following structure: and/or reduced form thereof, wherein R1 and R2 may be the same or different and are each independently lower alkyl (1 to 6 carbon atoms) or lower alkoxy (1 to 6 carbon atoms);
  • L is a linker group, comprising: a) straight or branched hydrocarbon chain which can be optionally substituted by one or more substituents and optionally contains one or more double or triple bonds; b) a natural isoprene chain; n is the number of carbon atoms in the linker, which is an integer from 1 to 40; and
  • B is a mitochondria targeting group comprising a lipophilic cation; and a pharmacologically acceptable anion; and/or solvates, salts, isomers, or prodrugs thereof.
  • L is a linker group, comprising: a) straight or branched hydrocarbon chain which can be optionally substituted by one or more substituents and optionally contains one or more double or triple bonds; b) a natural isoprene chain; n is the number of carbon atoms in the linker, which is an integer from 1 to 40; and
  • Fig. 1A is a graph of NAFLD activity score as a function of the indicated drug administration.
  • Fig. 1B shows the amount of steatosis as a function of the indicated drug administration.
  • Fig. 1C shows the amount of inflammation as a function of the indicated drug administration.
  • Fig. 1D shows the amount of ballooning as a function of the indicated drug administration.
  • Sk+ is a lipophilic cation
  • the present technology also includes methods of manufacturing or formulating a pharmaceutical product, such as a pharmaceutical dosage form, comprising a mitochondrially targeted antioxidant, for treatment or prophylaxis of ballooning associated diseases.
  • B is a mitochondria targeting group comprising a lipophilic cation; and a pharmacologically acceptable anion; and/or solvates, salts, isomers, or prodrugs thereof.
  • Formula I may further comprise the antioxidant below:
  • the term “about” includes values close to the stated value as understood by one of ordinary skill.
  • the term “about” can refer to values within 10%, 5%, or 1%, of the stated value.
  • administering a mitochondrially targeted antioxidant can both treat and prevent hepatocellular ballooning and related conditions, including hepatic inflammation, hepatic fibrosis, hepatic collagen deposition, NASH, weight gain, fatty liver, and obesity.
  • Monitoring of the treatment or prevention of these conditions can be performed by liver biopsy, determination of body weight, hepatocyte ballooning, hepatic fibrosis or collagen content, hepatic fat content, and/or levels of systemic markers of inflammation or cell pathology, such as CK-18, ALT, TNF-alpha, or IL- 6, which can be measured in blood plasma.
  • SkQ1 stock solution was diluted 10x in saline according to the study protocol.
  • SkQ1 was administered at 2 dose levels of 0.3 or 1.7 mg/kg, twice daily.
  • mice were housed in TPX cages (CLEA Japan) with a maximum of 4 mice per cage.
  • Sterilized Paper-Clean (Japan SLC) was used for bedding and replaced once a week.
  • Sterilized solid HFD was provided ad libitum, being placed in a metal lid on the top of the cage. Pure water was provided ad libitum from a water bottle equipped with a rubber stopper and a sipper tube. Water bottles were replaced once a week, cleaned, and sterilized in an autoclave and reused.
  • mice were identified by ear punch. Each cage was labeled with a specific identification code.
  • mice were subcutaneously administered vehicle [5% propylene glycol in saline] in a volume of 5 mL/kg twice daily from 6 to 9 weeks of age.
  • NAS NAFLD activity score
  • the animals were maintained in a SPF facility under controlled conditions of temperature (23 ⁇ 2°C), humidity (45 ⁇ 10%), lighting (12-hour artificial light and dark cycles; light from 8:00 to 20:00) and air exchange. A high pressure was maintained in the experimental room to prevent contamination of the facility.
  • mice were housed in TPX cages (CLEA Japan) with a maximum of 4 mice per cage.
  • Sterilized Paper-Clean (Japan SLC) was used for bedding and replaced once a week.
  • mice were subcutaneously administered vehicle [5% propylene glycol in saline] in a volume of 5 mL/kg twice daily from 6 to 10 weeks of age.
  • mice were subcutaneously administered vehicle supplemented with SkQ1 at a dose of 3 mg/kg twice daily from 6 to 10 weeks of age.
  • Liver sections from the Vehicle group exhibited micro- and macrovesicular fat deposition, hepatocellular ballooning and inflammatory cell infiltration.
  • the SkQ1 group and Telmisartan group showed significant decreases in NAS compared with the Vehicle group. Only SkQ1 group group showed a significant decrease in ballooning score compared with the Vehicle group.
  • Liver sections from the Vehicle group showed increased collagen deposition in the pericentral region of liver lobule.
  • the SkQ1 group had significantly decreased fibrosis area (Sirius red-positive area) compared with the Vehicle group.
  • SkQ1 stock solution was diluted 10x in saline according to the study protocol.
  • mice After exposure to the high fat diet for circa 32 weeks, eight male mice were singly housed and placed on a reverse phase light/ dark cycle. Mice continued to be provided with high fat diet and filtered water ad libitum during the study.
  • SkQ1 was administered subcutaneously in a volume of 5 mL/kg.
  • mice Male C57BL/6J mice were used in the study. Animals were group housed with ad libitum access to a high fat diet and filtered tap water. The mice were housed in polypropylene cages with sawdust-coated floors, red house, red tunnel, sizzle nest and nestlet at a temperature of 22 ⁇ 2°C. Relative humidity was typically 55 ⁇ 15% with prolonged periods below 40% RH or above 70% RH avoided.
  • Body composition analysis was be performed by DEXA on mice anaesthetised with isoflurane using the Lunar PIXImus Densitometer.
  • DEXA data was analyzed by analysis of covariance with Day 1 body weight as a covariate. A log transformation and/or robust regression were used, if appropriate.

Landscapes

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

Abstract

L'invention concerne des méthodes et des compositions pour traiter et prévenir une ballonisation cellulaire et d'autres maladies ou pathologies médicales. Les maladies ou les pathologies médicales sont caractérisées par une dégénérescence cellulaire ou une mort cellulaire en tant que partie de la pathogenèse de la maladie. La ballonisation cellulaire est une pathologie associée au stockage d'excès de graisse dans le foie, à un déséquilibre nutritionnel ou biochimique, à un endommagement des mitochondries, à une déplétion d'ATP ou à une infection virale. Un composé antioxydant ciblant les mitochondries est administré à un sujet en ayant besoin, l'excès de graisse étant ainsi métabolisé.
PCT/IB2024/000569 2023-10-11 2024-10-11 Antioxydants ciblant les mitochondries destinés à être utilisés dans le traitement de maladies associées à la ballonisation cellulaire, comme la stéato-hépatopathie non alcoolique (nafld) et la stéatohépatite non alcoolique (nash) WO2025078880A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363543668P 2023-10-11 2023-10-11
US63/543,668 2023-10-11

Publications (1)

Publication Number Publication Date
WO2025078880A1 true WO2025078880A1 (fr) 2025-04-17

Family

ID=94278721

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2024/000569 WO2025078880A1 (fr) 2023-10-11 2024-10-11 Antioxydants ciblant les mitochondries destinés à être utilisés dans le traitement de maladies associées à la ballonisation cellulaire, comme la stéato-hépatopathie non alcoolique (nafld) et la stéatohépatite non alcoolique (nash)

Country Status (1)

Country Link
WO (1) WO2025078880A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012167236A1 (fr) * 2011-06-03 2012-12-06 Mitotech Sa Formulations orales d'antioxydants ciblés sur les mitochondries et leur préparation et leur utilisation
WO2013044058A1 (fr) * 2011-09-22 2013-03-28 Mitotech S.A. Antioxydants ciblant les mitochondries utilisables en vue du traitement des troubles cérébraux liés à l'âge
WO2014116591A2 (fr) * 2013-01-22 2014-07-31 Mitotech Sa Formulations pharmaceutiques contenant des antioxydants à cible mitochondriale
WO2021198786A1 (fr) * 2020-04-03 2021-10-07 Mitotech S.A. Utilisation d'antioxydants ciblant les mitochondries pour traiter des états inflammatoires graves

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012167236A1 (fr) * 2011-06-03 2012-12-06 Mitotech Sa Formulations orales d'antioxydants ciblés sur les mitochondries et leur préparation et leur utilisation
WO2013044058A1 (fr) * 2011-09-22 2013-03-28 Mitotech S.A. Antioxydants ciblant les mitochondries utilisables en vue du traitement des troubles cérébraux liés à l'âge
WO2014116591A2 (fr) * 2013-01-22 2014-07-31 Mitotech Sa Formulations pharmaceutiques contenant des antioxydants à cible mitochondriale
WO2021198786A1 (fr) * 2020-04-03 2021-10-07 Mitotech S.A. Utilisation d'antioxydants ciblant les mitochondries pour traiter des états inflammatoires graves

Non-Patent Citations (15)

* Cited by examiner, † Cited by third party
Title
"Clinical Hepatology: Principles and Practice of Hepatobiliary Diseases", vol. 1, 2010, SPRINGER, pages: 207
FELDSTAIN ET AL., AM J GASTROENTEROL., vol. 108, 2013, pages 1526 - 31
GUY, C.D. ET AL., HEPATOLOGY, vol. 55, 2012, pages 1711 - 172
KLEINER, D. E. ET AL., HEPATOLOGY, vol. 41, 2005, pages 1313 - 1321
LACKNER C ET AL., J HEPATOL., vol. 48, no. 5, 2008, pages 821 - 828
LACKNER C ET AL., J. HEPATOL., vol. 48, 2008, pages 821 - 828
MILLER, M.A.ZACHARY, J.F., PATHOLOGIC BASIS OF VETERINARY DISEASE, 2017
RANGWALA F. ET AL., J. PATHOL., vol. 224, 2011, pages 401
SANYAL AJ. ET AL., HEPATOLOGY, vol. 54, 2011, pages 344
TURKSEVEN SAADET ET AL: "Low-Dose Acetylsalicylic Acid and Mitochondria-Targeted Antioxidant Mitoquinone Attenuate Non-Alcoholic Steatohepatitis in Mice", ANTIOXIDANTS, vol. 12, no. 4, 21 April 2023 (2023-04-21), pages 971, XP093253299, ISSN: 2076-3921, DOI: 10.3390/antiox12040971 *
V. KUMARA. ABBASJ. ASTER: "Robbins & Cotran Pathologic Basis of Disease", 2014, ELSEVIER
VORONKOVA YA G ET AL: "Effect of SkQ1 on activity of the glutathione system and NADPH-generating enzymes in an experimental model of hyperglycemia", BIOCHEMISTRY (MOSCOW), PLEIADES PUBLISHING, MOSCOW, vol. 80, no. 12, 12 December 2015 (2015-12-12), pages 1614 - 1621, XP035569421, ISSN: 0006-2979, [retrieved on 20151212], DOI: 10.1134/S000629791512010X *
WANG XUE-HUI ET AL: "Jejunal epithelial barrier disruption triggered by reactive oxygen species in early SIV infected rhesus macaques", FREE RADICAL BIOLOGY & MEDICINE, ELSEVIER INC, US, vol. 177, 20 October 2021 (2021-10-20), pages 143 - 155, XP086882645, ISSN: 0891-5849, [retrieved on 20211020], DOI: 10.1016/J.FREERADBIOMED.2021.10.026 *
ZATLOUKAL K ET AL., EXP. CELL RES., vol. 313, 2007, pages 2033 - 2049
ZATLOUKAL K ET AL., J. PATHOL., vol. 204, 2004, pages 367 - 376

Similar Documents

Publication Publication Date Title
US6855340B2 (en) Copper lowering treatment of inflammatory and fibrotic diseases
Yabuki et al. Oral L-citrulline administration improves memory deficits following transient brain ischemia through cerebrovascular protection
WO2018188536A1 (fr) Médicament pour le traitement de la fibrose hépatique et méthode de traitement
AU2016325556A1 (en) Treatment and prevention of neuronal cell loss using L-ornithine in combination with at least one of phenylacetate and phenylbutyrate
Williams et al. Paraquat intoxication and associated pathological findings in three dogs in South Africa
US20180353479A1 (en) Bisamide derivative of dicarboxylic acid as an agent for stimulating tissue regeneration and recovery of diminished tissue function
Ramzan et al. Evaluation of diclofenac sodium toxicity at different concentrations in relation to time using broiler chicken model.
WO2025078880A1 (fr) Antioxydants ciblant les mitochondries destinés à être utilisés dans le traitement de maladies associées à la ballonisation cellulaire, comme la stéato-hépatopathie non alcoolique (nafld) et la stéatohépatite non alcoolique (nash)
CN115605192A (zh) 用于治疗原发性硬化性胆管炎的伊拉非布拉诺尔
US20070248689A1 (en) Copper lowering treatment of inflammatory and fibrotic diseases
TW201540297A (zh) 蛇床子素用於製備治療局部腎絲球硬化症之組合物的用途
JP2023106431A (ja) 非アルコール性脂肪性肝疾患と非アルコール性脂肪性肝炎の予防および／または処置に使用するための化合物
Miethke et al. Pharmacological inhibition of ASBT changes bile composition and blocks progression of sclerosing cholangitis in mdr2 knockout mice
CA3153784A1 (fr) Polytherapie d'elafibranor et de nitazoxanide comportant des caracteristiques antioxydantes
EP4017484A1 (fr) Composition d'acide gras mono-insaturé et son utilisation pour le traitement d'une stéatose hépatique
WO2022019235A1 (fr) Utilisation de vitamine b12 dans l'inhibition d'un trouble rénal
Lin et al. A novel nordihydroguaiaretic acid analog, compound 3a, alleviates acute lung injury by exerting antiapoptotic and antiinflammatory effects
KR20240093978A (ko) 장염과 장암을 예방 또는 치료를 위한 약물
JP7427199B2 (ja) 代謝改善剤
JPWO2017150566A1 (ja) タンパク質凝集に起因する変性症状を呈する非ヒト動物
WO2008134513A2 (fr) Traitement pour abaisser le taux de cuivre dans les maladies auto-immunes
JP2019524860A (ja) 非アルコール性脂肪肝疾患の治療法
Gut et al. Articles in PresS. Am J Physiol Renal Physiol (May 22, 2013). doi: 10.1152/ajprenal. 00514.2012
Zepeda Iriarte et al. Cardiac Tissue Injury Resistance During Myocardial Infarction at Adulthood by Developmental Exposure to Cadmium
Najim support and his help and valuable scientific knowledge which can not be forget.-Also I gratefully thank Dalia Abdul Lateef for her help during this work.-Also special thanks go to all members of the department of

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 24837444

Country of ref document: EP

Kind code of ref document: A1