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WO2018119080A1 - Composition et méthodes de traitement de troubles hépatiques - Google Patents

Composition et méthodes de traitement de troubles hépatiques Download PDF

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Publication number
WO2018119080A1
WO2018119080A1 PCT/US2017/067610 US2017067610W WO2018119080A1 WO 2018119080 A1 WO2018119080 A1 WO 2018119080A1 US 2017067610 W US2017067610 W US 2017067610W WO 2018119080 A1 WO2018119080 A1 WO 2018119080A1
Authority
WO
WIPO (PCT)
Prior art keywords
liver
hepatic
mice
apom
selective agent
Prior art date
Application number
PCT/US2017/067610
Other languages
English (en)
Inventor
Bi-Sen Ding
Timothy Hla
Original Assignee
Cornell University
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 Cornell University filed Critical Cornell University
Publication of WO2018119080A1 publication Critical patent/WO2018119080A1/fr

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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
    • A61K31/4245—Oxadiazoles
    • 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
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K31/4196—1,2,4-Triazoles
    • 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
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • 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
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers

Definitions

  • This disclosure generally relates to tissue generation and the treatment of fibrotic tissue. More specifically, this disclosure relates to methods for generating vascular tissue, ameliorating fibrosis and treating hepatic disorders by administration of certain therapeutic agents to a subject. As such, certain therapeutic methods for the treatment of hepatic disorders are disclosed.
  • the present disclosure provides novel methods for treating a subject with a hepatic disorder by administering an S1P 1 -selective agent to the subject to stimulate liver tissue development, vascularization and/or inhibit hepatic fibrosis, such that the S1P 1 -selective agent is capable of activating S1P 1 -mediated cell signaling when bound to S1P 1 on LESCs.
  • FIGS.6A-6C Development of fibrosis in hepatectomized mice lacking S1P1.
  • FIGS.10A-D SEW2871 decreases liver fibrosis in chronic liver injury hepatic disease model.
  • Chronic liver injury was induced in mice by injection of CCl 4 every three days for 10 injections. Mice were sacrificed at day 40 after first injection.
  • SEW2871 was given to mice after the third CCl 4 injection.
  • Administration of SEW2871 restored vascular perfusion and prevented liver fibrosis after repeated CCl 4 injection.
  • Vascular perfusion was tested by visualization of intravenously injected B4-isolectin (A, B) and fibrosis was determined by measuring levels of SMA (B), Collagen (C), and
  • small molecule refers to small organic compounds, including but not limited to, heterocycles, peptides, saccharides, steroids, antibodies and the like.
  • the small molecules can have a molecular weight of less than about 1500 Daltons, 1200 Daltons, 1000 Daltons, or 800 Daltons.
  • a small molecule modulator is less than 500 Daltons.
  • the small molecules can be modified to enhance efficacy, stability, pharmaceutical compatibility, and the like.
  • Some exemplary protein translation systems such as reticulocyte lysates and wheat germ extracts, use RNA as a template, whereas other exemplary systems start with DNA templates, which are transcribed into RNA then translated to form the desired S1P 1 -selective protein.
  • Cholestasis is defined by a decrease in bile flow from the liver due to impaired secretion by hepatocytes or obstruction of bile flow through intra-or extrahepatic bile ducts. Therefore, cholestasis is any condition in which substances normally excreted into bile are retained, such as biliary atresia or primary sclerosing cholangitis.
  • physiological processes that can be detected to determine treatment efficacy using the present methods can include, for example, vascularization in the liver endothelium, hepatic vascular perfusion, liver function, platelet distribution in the hepatic endothelium, fibrosis, thrombosis and Rho signaling activation.
  • compositions comprising one or more S1P 1 -selective agent can optionally be tested in one or more appropriate in vitro and/or in vivo animal models of disease, to confirm efficacy, tissue metabolism, and to determine dosages, according to methods well known in the art.
  • dosages can be initially determined by activity, stability or other suitable measures of treatment vs. non-treatment (e.g., comparison of treated vs. untreated cells or animal models), in a relevant assay.
  • bodyweight/day about 250 mg/kg of bodyweight/day, about 300 mg/kg of

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Vascular Medicine (AREA)
  • Cardiology (AREA)
  • Zoology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Immunology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Emergency Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouvelles méthodes de traitement d'un sujet atteint d'un trouble hépatique. Plus particulièrement, les méthodes comprennent l'administration d'un agent sélectif de S1P1 à un sujet afin de stimuler le développement du tissu hépatique, la vascularisation et/ou l'inhibition de la fibrose hépatique, et l'activation des cellules médiées par S1P1 dans l'endothélium hépatique.
PCT/US2017/067610 2016-12-21 2017-12-20 Composition et méthodes de traitement de troubles hépatiques WO2018119080A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201662437263P 2016-12-21 2016-12-21
US62/437,263 2016-12-21

Publications (1)

Publication Number Publication Date
WO2018119080A1 true WO2018119080A1 (fr) 2018-06-28

Family

ID=62627810

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2017/067610 WO2018119080A1 (fr) 2016-12-21 2017-12-20 Composition et méthodes de traitement de troubles hépatiques

Country Status (1)

Country Link
WO (1) WO2018119080A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111657861A (zh) * 2020-06-04 2020-09-15 浙江大学 基于双光子显微镜技术的溶栓药效评价方法
CN116459239A (zh) * 2023-06-07 2023-07-21 苏州市独墅湖医院(苏州大学附属独墅湖医院) 芬戈莫德抑制乙肝病毒复制和乙肝性肝损伤的用途

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040063667A1 (en) * 1999-07-12 2004-04-01 Ono Pharmaceutical Co., Ltd. Anti fibrotic agent containing sphingosine 1-phosphate receptor agonist or sphingosine 1-phospate as active ingredient
US20100249187A1 (en) * 2007-06-15 2010-09-30 Marc Capet Novel dicarboxylic acid derivatives as s1p1 receptor agonists
US20140193376A1 (en) * 2011-06-16 2014-07-10 Children's Medical Center Corporation Combined chemical modification of sphingosine-1-phosphate (s1p) and cxcr4 signalling pathways for hematopoietic stem cell (hsc) mobilization and engraftment
US20140303086A1 (en) * 2011-05-23 2014-10-09 Timothy Hla Endothelium protective materials and methods of use
US20150045332A1 (en) * 2012-03-26 2015-02-12 Rolf E. Swenson Novel Sphingosine 1-Phosphate Receptor Antagonists

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040063667A1 (en) * 1999-07-12 2004-04-01 Ono Pharmaceutical Co., Ltd. Anti fibrotic agent containing sphingosine 1-phosphate receptor agonist or sphingosine 1-phospate as active ingredient
US20100249187A1 (en) * 2007-06-15 2010-09-30 Marc Capet Novel dicarboxylic acid derivatives as s1p1 receptor agonists
US20140303086A1 (en) * 2011-05-23 2014-10-09 Timothy Hla Endothelium protective materials and methods of use
US20140193376A1 (en) * 2011-06-16 2014-07-10 Children's Medical Center Corporation Combined chemical modification of sphingosine-1-phosphate (s1p) and cxcr4 signalling pathways for hematopoietic stem cell (hsc) mobilization and engraftment
US20150045332A1 (en) * 2012-03-26 2015-02-12 Rolf E. Swenson Novel Sphingosine 1-Phosphate Receptor Antagonists

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
KONO ET AL.: "Sphingosine-1-phosphate receptor 1 reporter mice reveal receptor activation sites in vivo", THE JOURNAL OF CLINICAL INVESTIGATION, vol. 124, 25 March 2014 (2014-03-25), pages 2076 - 2086, XP055494843 *
PARK ET AL.: "Sphinganine-1-phosphate protects kidney and liver after hepatic ischemia and reperfusion in mice through S1P1 receptor activation", LABORATORY INVESTIGATION, vol. 90, 10 May 2010 (2010-05-10), pages 1209 - 1224, XP055494833 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN111657861A (zh) * 2020-06-04 2020-09-15 浙江大学 基于双光子显微镜技术的溶栓药效评价方法
CN111657861B (zh) * 2020-06-04 2022-02-25 浙江大学 基于双光子显微镜技术的溶栓药效评价方法
CN116459239A (zh) * 2023-06-07 2023-07-21 苏州市独墅湖医院(苏州大学附属独墅湖医院) 芬戈莫德抑制乙肝病毒复制和乙肝性肝损伤的用途

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