WO2022049168A1 - 17(s)-hdpa contre des troubles liés au syndrome métabolique - Google Patents

17(s)-hdpa contre des troubles liés au syndrome métabolique Download PDF

Info

Publication number
WO2022049168A1
WO2022049168A1 PCT/EP2021/074201 EP2021074201W WO2022049168A1 WO 2022049168 A1 WO2022049168 A1 WO 2022049168A1 EP 2021074201 W EP2021074201 W EP 2021074201W WO 2022049168 A1 WO2022049168 A1 WO 2022049168A1
Authority
WO
WIPO (PCT)
Prior art keywords
hdpa
disease
nash
human
animal
Prior art date
Application number
PCT/EP2021/074201
Other languages
English (en)
Inventor
Igor Bendik
Pascale FUCHS BOSSERT
Hubert Paul HUG
Roman IMHOF
Paul Frederick MUGFORD
Original Assignee
Dsm Ip Assets B.V.
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 Dsm Ip Assets B.V. filed Critical Dsm Ip Assets B.V.
Publication of WO2022049168A1 publication Critical patent/WO2022049168A1/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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • 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
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • 17(S)-HDPA (also called clupanodinic acid) binds to and activates the nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta, NR1C2 (nuclear receptor subfamily 1, group C, member 2)).
  • PPAR beta/delta nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • NR1C2 nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • PPAR beta/delta nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • NR1C2 nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • PPAR beta/delta nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • PPAR beta/delta nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • PPAR beta/delta is mainly expressed in muscle, brain, adipose tissue, colon, and skin. It may be involved in the development of several chronic diseases, including diabetes type II, obesity, NALFD/ NASH and atherosclerosis.
  • PPAR beta/delta expression increases during exercise, thereby resulting in increased oxidative (fat-burning) capacity and in the increase of muscle fibers.
  • 17(S)-HDPA namely all-cis-7,10,13,16,19-docosapentaenoic acid (also known as clupanodonic acid), is a hydroxylated form of an isomer of the polyunsaturated acid docosapentaenoic acid (DPA). It is an Intermediary between eicosapentaenoic acid (EPA) and docasahexanenoic acid (DHA) in the DHA pathway.
  • DPA docosapentaenoic acid
  • EPA eicosapentaenoic acid
  • DHA docasahexanenoic acid
  • 17(S)-HDPA binds to and activates the nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta, NR1C2 (nuclear receptor subfamily 1, group C, member 2)).
  • PPAR beta/delta nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • NR1C2 nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • PPAR beta/delta nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • NR1C2 nuclear transcription factor peroxisome proliferator-activated receptor-beta/delta
  • one embodiment of this invention is the use of 17(S)-HDPA to prevent, treat, and ameliorate the adverse effects of a disease/condition in an animal, including a human, selected from the group consisting of: obesity, dyslipidemia, insulin resistance/type 2 diabetes, nonalcoholic fatty liver disease (NALFD), non-alcoholic steatohepatits (NASH), and atherosclerosis.
  • a disease/condition in an animal including a human, selected from the group consisting of: obesity, dyslipidemia, insulin resistance/type 2 diabetes, nonalcoholic fatty liver disease (NALFD), non-alcoholic steatohepatits (NASH), and atherosclerosis.
  • NALFD nonalcoholic fatty liver disease
  • NASH non-alcoholic steatohepatits
  • atherosclerosis atherosclerosis
  • Another embodiment of this invention is the non-therapeutic use of 17(S)-HDPA to ameliorate a symptom associated with a disease/adverse condition in an animal, including a human, selected from the group consisting of: obesity, dyslipidemia, insulin resistance/type 2 diabetes, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatits (NASH), and atherosclerosis.
  • a disease/adverse condition in an animal, including a human, selected from the group consisting of: obesity, dyslipidemia, insulin resistance/type 2 diabetes, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatits (NASH), and atherosclerosis.
  • NALFD non-alcoholic fatty liver disease
  • NASH non-alcoholic steatohepatits
  • atherosclerosis atherosclerosis.
  • the condition is NALFD
  • the 17(S)-HDPA prevents or prolongs the time until progression to NASH.
  • Another embodiment of this invention is a method of treating, lessening the time to onset of symptoms, or lessening the severity of symptoms of a disease/condition in an animal, including a human, selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatits (NASH), and atherosclerosis comprising administering 17(S) HDPA to an animal, including a human in need thereof or, at risk of developing the disease/condition.
  • the animal including a human has or is at risk of developing NALFD, and the 17(S)-HDPA can prolong the time of progression to NASH.
  • the animal is a human.
  • Another embodiment of this invention is the use of 17(S)-HDPA in the manufacture of a medicament or nutraceutical for use in preventing, treating, and/or ameliorating the adverse effects of a disease/condition in an animal, including a human, selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease (NALFD), non-alcoholic steatohepatits (NASH), and atherosclerosis.
  • the pharmaceutical/nutraceutical is used to treat NALFD, and/or inhibit its progression to NASH.
  • the 17(S)-HDPA may be a sole active ingredient, or it may be used in addition to known therapeutic agents to treat the metabolic condition.
  • 17(S)-HDPA is an active ingredient in a medical food.
  • 17(S)-HDPA for addressing the nutritional needs of a patient suffering from a disease/condition selected from the group consisting of: obesity, dyslipidemia, insulin resistance, type 2 diabetes, non-alcoholic fatty liver disease (NALFD), nonalcoholic steatohepatits (NASH), and atherosclerosis.
  • NALFD non-alcoholic fatty liver disease
  • NASH nonalcoholic steatohepatits
  • atherosclerosis is used to address the nutritional needs of a patient suffering from NALFD or NASH.
  • PPAR beta/delta is one of three members of the PPAR family in the nuclear receptor superfamily. It is a ligand-activated transcription factor and is expressed in many tissues. Its main function is the activation of genes whose products play crucial roles in fat metabolism. In addition it leads to expression of genes with role in cell proliferation. Therefore, it has been suggested that PPAR beta/delta protects against metabolic-syndrome-related diseases, such as obesity, dyslipidemia, insulin resistance/type 2 diabetes, hepatosteatosis, and atherosclerosis.
  • NAFDL non-alcoholic liver disease
  • NAFDL non-alcoholic steatohepatitis
  • 17(S)-HDPA activates PPAR beta/delta. Therefore, 17(S)-HDPA is useful in preventing, treating, or ameliorating metabolic syndrome related disorders.
  • FIGURE 1 shows 17(S)-HDPA dose response activating the PPAR beta/delta receptor.
  • 17(S)-HDPA also includes other biologically available forms, such as its esters and its pharmaceutically acceptable salts, such as sodium salt.
  • Non-human animals including companion animals (such as dogs, cats, and horses) and animals reared for their milk production (such as dairy cows, buffalo, sheep and goats) may also exhibit symptoms of NALFD and/or NASH.
  • the recommended daily dose is the maximal dose of 17(S)-HDPA that is allowed by regulatory authorities.
  • the daily dose for humans ranges from 0.5 mg up to 10 grams per day, preferably from 5-500 mg per day, and more preferably from 100-250 mg/day.
  • the human dose is adjusted accordingly by weight of the animal.
  • composition of the present invention is preferably in the form of nutritional composition, such as fortified food, fortified feed, or fortified beverages, or in form of fortified liquid food/feed (such as drinks, or shots), pills or capsules for animals including humans.
  • nutritional composition such as fortified food, fortified feed, or fortified beverages, or in form of fortified liquid food/feed (such as drinks, or shots), pills or capsules for animals including humans.
  • the dietary and pharmaceutical compositions according to the present invention may be in any galenic form that is suitable for administering to the animal body including the human body, especially in any form that is conventional for oral administration, e.g. in solid form, such as (additives/supplements for) food or feed, food or feed premix, fortified food or feed, tablets, pills, granules, dragees, capsules, and effervescent formulations such as powders and tablets, or in liquid form such as solutions, emulsions or suspensions as e.g. beverages, pastes and oily suspensions.
  • the pastes may be encapsulated in hard or soft-shell capsules, whereby the capsules feature e.g.
  • a matrix of (fish, swine, poultry, cow) gelatin, plant proteins or lignin sulfonate examples are forms for transdermal, parenteral or injectable administration.
  • the dietary and pharmaceutical compositions may be in the form of controlled (delayed) release formulations.
  • HEK293 cells (ATCC, Molsheim, France) were used. The cells were subcultured twice a week by splitting the confluent culture 1:10. The HEK293 cells were grown in minimum essential medium (Eagle) with Earle's balanced salt solution without L-glutamine and supplemented with 10% fetal bovine serum (Sigma-Aldrich Corp., St. Gallen, Switzerland), 2 mM glutamax (Life Technologies AG, Basel, Switzerland), 0.1 mM nonessential amino acids (Life Technologies), and 1 mM sodium pyruvate (Life Technologies) in cell culture incubator at 37°C and 5% CO 2 .
  • 7.5 x 10 4 cells were plated per well (80 pl) in white 96-well cell culture plates with clear bottom (Corning, Basel, Switzerland) in minimum essential medium (Eagle) with Earle's balanced salt solution without L-glutamine and without phenol red supplemented with 10% charcoal-treated fetal bovine serum (HyClone Laboratories, Inc., Logan, UT, USA), 2 mM glutamax, 0.1 mM non-essential amino acids, and 1 mM sodium pyruvate. The cells were transiently transfected before stimulation the following day at >80% confluence using the polyethylene-imine transfection.
  • This transfection method applied 0.9 mg/ml polyethyleneimine (MW 25000, Sigma-Aldrich Corp., St. Gallen, Switzerland) reagent dissolved in water at pH 7.5.
  • the transfection mixture included per well, 100 ng of the Gal4 firefly luciferase plasmid (pFR-Luc), 5 ng of the chimeric PPAR-p/8 nuclear receptor-LBD receptor expression plasmid (pCMV-BD- PPAR-p/8-LBD) and 5 ng of the renilla control plasmid (pRL-tk renilla luciferase).
  • Compound stocks were prepared in DMSO, pre-diluted in PBS (0.45% final DMSO concentration), and added in the respective dilution 6 h after the addition of the transfection mixture onto the cells.
  • the HEK293 cells were again incubated for additional 16 h before (overnight) firefly and renilla luciferases were measured sequentially in the same cell extract using buffers according to established protocols (Promega AG, Dubendorf, Switzerland). The transfection efficiency was controlled by the co-transfection of the pRL-TK renilla luciferase reporter.
  • the ligand-binding domain of PPAR-p/8 was expressed from a GATEWAY (Invitrogen, Switzerland)-compatible version of pCMV-BD (Stratagene Corp., Santa Clara, CA, USA) as a fusion to the GAL4 DNA-binding domain (amino acids 1 to 147).
  • PPAR-p/8 ligands activated the pCMV-BD- PPAR-p/8-LBD receptor and triggered luciferase expression of the reporter plasmid pFR-Luc (Stratagene).
  • Luciferase activity after transiently transfecting HEK293 cells with PPAR beta/delta ligand binding constructs is shown in Figure 1. Concentrations of 17(S)-HDPA above 6.67 pM resulted in a significant increase of luciferase activity. Thus, dosages which would provide for at least this level would be one embodiments of this invention.

Landscapes

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

Abstract

La présente invention concerne l'utilisation de 17(S)-HDPA contre des maladies associées au syndrome métabolique comprenant NAFLD/NASH.
PCT/EP2021/074201 2020-09-04 2021-09-02 17(s)-hdpa contre des troubles liés au syndrome métabolique WO2022049168A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP20194488.1 2020-09-04
EP20194488 2020-09-04

Publications (1)

Publication Number Publication Date
WO2022049168A1 true WO2022049168A1 (fr) 2022-03-10

Family

ID=72380927

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2021/074201 WO2022049168A1 (fr) 2020-09-04 2021-09-02 17(s)-hdpa contre des troubles liés au syndrome métabolique

Country Status (1)

Country Link
WO (1) WO2022049168A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142482A2 (fr) * 2006-11-01 2008-11-27 Pronova Biopharma Norge As Composition
WO2011014261A1 (fr) * 2009-07-31 2011-02-03 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Acides gras comme agents anti-inflammatoires
WO2013170006A2 (fr) * 2012-05-10 2013-11-14 Solutex Na Llc Huiles ayant une activité anti-inflammatoire contenant des médiateurs de prorésolution spécialisés naturels et leurs précurseurs
WO2016046311A1 (fr) * 2014-09-25 2016-03-31 Astrazeneca Ab Combinaison d'un acide gras oméga-3 et d'un inhibiteur de sglt -2 pour le traitement de maladies du foie
WO2016096685A1 (fr) * 2014-12-15 2016-06-23 Dsm Ip Assets B.V. Traitement pour les stéatoses hépatiques non alcooliques

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2008142482A2 (fr) * 2006-11-01 2008-11-27 Pronova Biopharma Norge As Composition
WO2011014261A1 (fr) * 2009-07-31 2011-02-03 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Acides gras comme agents anti-inflammatoires
WO2013170006A2 (fr) * 2012-05-10 2013-11-14 Solutex Na Llc Huiles ayant une activité anti-inflammatoire contenant des médiateurs de prorésolution spécialisés naturels et leurs précurseurs
WO2016046311A1 (fr) * 2014-09-25 2016-03-31 Astrazeneca Ab Combinaison d'un acide gras oméga-3 et d'un inhibiteur de sglt -2 pour le traitement de maladies du foie
WO2016096685A1 (fr) * 2014-12-15 2016-06-23 Dsm Ip Assets B.V. Traitement pour les stéatoses hépatiques non alcooliques

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEN ET AL.: "Insights into the Role of PPAPβ/δ in NAFLD", INT J MOL SCI, vol. 19, no. 7, July 2018 (2018-07-01), pages 1893
J BRYAN SMITH: "THE PROSTANOIDS IN HEMOSTASIS AND THROMBOSIS THE PROSTANOIDS IN HEMOSTASIS AND THROMBOSIS : A REVIEW", AMERICAN JOURNAL OF PATHOLOGY., vol. 99, no. 3, 1 June 1980 (1980-06-01), US, pages 743 - 804, XP055766485, ISSN: 0002-9440 *

Similar Documents

Publication Publication Date Title
US20220072005A1 (en) Use of a ppar-delta agonist for reducing loss of muscle strength, muscle mass, or type i muscle fibers in an immobilized limb
CN103285394B (zh) 使用硝化脂质治疗脂质病症和肥胖以及与脂质和肥胖相关的病状
DE60214846T2 (de) Verwendung von mGLuR5 antagonists zur Herstellung von Medikamenten zur Behandlung von empfindlichen X Syndrome, Autismus und geistiger Zurückgebliebenheit
KR20180121983A (ko) Rxr 작용제 및 갑상선 호르몬의 조합을 사용한 근육 질환의 치료
US20220295854A1 (en) Compositions and methods using one or more autophagy-inducing amino acids to potentiate musculoskeletal effect of one or more anabolic amino acids
EP3969010A1 (fr) Compositions et méthodes destinées à traiter ou à prévenir la fatigue métabolique au moyen du composé oleuropéine ou d'un métabolite de celui-ci
Dynes et al. Elevation of feed intake in parasite-infected lambs by central administration of a cholecystokinin receptor antagonist
CN101123956A (zh) Ppar激动剂治疗反刍动物的用途
DE60220899T2 (de) Mittel gegen stressinduzierte krankheiten
JP2021510728A (ja) 脳卒中の予防又は治療用組成物
WO2022049168A1 (fr) 17(s)-hdpa contre des troubles liés au syndrome métabolique
JP2018516841A (ja) ジペノサイド７５の抗糖尿病効果
KR20190015609A (ko) 당뇨병 치료를 위한 조성물 및 치료법
DE69812010T2 (de) 4-Aminopyrrole (3,2-d) Pyrimidinen als Antagonisten des Neuropeptide Y Receptors
TWI266614B (en) Compositions comprising valine for improving lipid metabolism
DK1776956T3 (en) An agent for the prevention and / or treatment of calcium deficiency
KR102645209B1 (ko) 항스트레스, 항불안, 및 항우울 활성을 갖는 작용제 및 이를 기반으로 하는 조성물
JP7381469B2 (ja) 新生児抗痙攣薬としてのグルコースオキシダーゼ組成物
US20220023393A1 (en) Pharmaceutical composition for preventing or treating obesity or sarcopenia, containing if1 as active ingredient
US20220257550A1 (en) Reducing the viral activity of elafibranor with riboflavin or dha
KR20010051509A (ko) 아포지단백질 비 분비/미소체 삼중글리세라이드 전이단백질 저해제의 용도
EP0153471A1 (fr) Utilisation de dérivés complexés de l'inosine pour l'engraissement d'animaux
JP7503564B2 (ja) Ｔｇｒ５活性化用組成物
US20230390262A1 (en) Compositions containing nicotinamide and vitamin b6 and methods of using such compositions for treating sarcopenia and frailty
US20240189285A1 (en) Composition and method for enhancing mitochondrial biogenesis and activating pgc-1a

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: 21773483

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 21773483

Country of ref document: EP

Kind code of ref document: A1