[go: up one dir, main page]

WO2025064491A1 - Procédés de réduction de graisse - Google Patents

Procédés de réduction de graisse Download PDF

Info

Publication number
WO2025064491A1
WO2025064491A1 PCT/US2024/047190 US2024047190W WO2025064491A1 WO 2025064491 A1 WO2025064491 A1 WO 2025064491A1 US 2024047190 W US2024047190 W US 2024047190W WO 2025064491 A1 WO2025064491 A1 WO 2025064491A1
Authority
WO
WIPO (PCT)
Prior art keywords
nitro
acid
electrophilic
fatty
composition
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.)
Pending
Application number
PCT/US2024/047190
Other languages
English (en)
Inventor
Shu-Ching Hsu
Mingzi Zhang
Yu-Shao Yang
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.)
National Health Research Institutes
Original Assignee
National Health Research Institutes
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 National Health Research Institutes filed Critical National Health Research Institutes
Publication of WO2025064491A1 publication Critical patent/WO2025064491A1/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

Links

Classifications

    • 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
    • A61P3/04—Anorexiants; Antiobesity agents
    • 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
    • A61K31/201—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 one or two double bonds, e.g. oleic, linoleic acids
    • 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
    • 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
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • 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
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/5575—Eicosanoids, e.g. leukotrienes or prostaglandins having a cyclopentane, e.g. prostaglandin E2, prostaglandin F2-alpha
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

  • the present disclosure relates to a field of treatment. Particularly, the present disclosure provides a method for reducing body fat and/or treating and/or preventing obesity.
  • Background of the Invention [0002] Obesity is a burgeoning global health problem. People who are overweight or obese face increased morbidity and mortality due to serious chronic diseases including diabetes, cardiovascular diseases, stroke, dementia, metabolic syndrome and cancer. More recently, overweight and obesity have been implicated as a significant risk factors for SARS-CoV2 infection.
  • adipose tissue mass especially white adipose
  • adipogenesis mature adipocytes
  • hyperplasia Given the central role of adipocytes in adipose tissue expansion, small molecule modulators of adipocyte physiology will be invaluable both as research tools and as therapeutic agents to address obesity-linked adipocyte dysfunction and obesity-related health issues.
  • the present disclosure provides a method for inhibiting adipocyte differentiation and/or inducing adipocyte death in a subject, comprising administrating an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) to a subject in need thereof.
  • an electrophilic (unsaturated) fatty acid such as an electrophilic nitro-fatty acids
  • the present disclosure also provides a composition comprising an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) for use in a method for inhibiting adipocyte differentiation and/or inducing adipocyte death in a subject.
  • the present disclosure also provides a use of an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) in the G4590-18500PCT_20240918_Specification_TBF - 1 - PATENT Attorney Docket No.: G4590-18500PCT manufacture of a medicament for inhibiting adipocyte differentiation and/or inducing adipocyte death in a subject.
  • the present disclosure also provides a method for inducing fat tissue reduction and/or inducing cell death of adipocytes in a subject, comprising administrating an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acid) to a subject in need thereof.
  • the present disclosure also provides a composition comprising an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) for use in a method for inducing fat tissue reduction and/or inducing cell death of adipocytes in a subject.
  • the present disclosure also provides a use of an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) in the manufacture of a medicament for inducing fat tissue reduction and/or inducing cell death of adipocytes in a subject.
  • the induction of fat tissue reduction does not induce inflammation-associated side effects.
  • the nitro-fatty acids selectively induced adipocyte death.
  • the present disclosure also provides a method for treating and/or preventing inflammation, overweight, obesity and metabolic diseases associated with obesity and/or for governing chronic weight management, comprising administrating an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acid) to a subject in need thereof.
  • an electrophilic (unsaturated) fatty acid such as an electrophilic nitro-fatty acid
  • the present disclosure also provides a composition comprising an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) for use in a method for treating and/or preventing inflammation, overweight, obesity and metabolic diseases associated with obesity and/or for governing chronic weight management.
  • the present disclosure also provides a use of an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) in the G4590-18500PCT_20240918_Specification_TBF - 2 - PATENT Attorney Docket No.: G4590-18500PCT manufacture of a medicament for treating and/or preventing inflammation, overweight, obesity and metabolic diseases associated with obesity and/or for governing chronic weight management.
  • an electrophilic (unsaturated) fatty acid such as an electrophilic nitro-fatty acids
  • the metabolic diseases associated with obesity include, but are not limited to, ectopic fat accumulation, lipomas, insulin resistance, gastroesophageal reflux disease, cellulite, proteus syndrome, obesity caused by phosphatase and tensin homolog (PTEN) mutation(s), Dercum's disease, Gardner syndrome, submental fat, cardiometabolic disease, hyperuricemia, hepatic steatosis, nonalcoholic steatohepatitis, cardiovascular disease, prediabetes, osteoarthritis, obstructive sleep apnea, hepatic steatosis, type 2 diabetes, cardiovascular diseases, high blood pressure, high LDL cholesterol, low HDL cholesterol, high levels of triglycerides (dyslipidermia), coronary heart disease, gallbladder disease, osteoarthritis, stroke, sleep apnea and breathing problems and cancers.
  • PTEN tensin homolog
  • the present disclosure also provides a method for treating, preventing and/or alleviating obesity-associated liver, pancreas and kidney pathologies induced by high-fat diets, comprising administrating an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro- fatty acid) to a subject in need thereof.
  • an electrophilic (unsaturated) fatty acid such as an electrophilic nitro-fatty acid
  • the present disclosure also provides a composition comprising an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) for use in a method for treating, preventing and/or alleviating obesity-associated liver, pancreas and kidney pathologies induced by high-fat diets.
  • the present disclosure also provides a use of an electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids) in the G4590-18500PCT_20240918_Specification_TBF - 3 - PATENT Attorney Docket No.: G4590-18500PCT manufacture of a medicament for treating, preventing and/or alleviating obesity-associated liver, pancreas and kidney pathologies induced by high-fat diets.
  • the treatment, prevention and/or alleviation of obesity-associated liver, pancreas and kidney pathologies induced by high-fat diets does not induce inflammation- associated side effects.
  • examples of the nitro-fatty acid described herein include, but are not limited to, nitro-oleic acid, (NO 2 -OA), nitro-palmitoleic acid (NO 2 -POA), nitro linolenic acid (NO 2 -LNA), nitro-arachidonic acid (NO 2 -AA), nitro eicosapentaenoic acid (NO 2 -EPA), nitro-docosahexaenoic acid (NO 2 -Dha), nitro-hydroxy acid, and nitro-allyl fatty acid and any combination thereof.
  • the nitro-fatty acid described herein is 9-nitro-oleic acid (9N-OA), 10-nitro-oleic acid (10N-OA), 12-nitro-oleic acid (12N-OA), 9-nitro-9-cis- octadecenoic acid, 10-nitro-9-cis-octadecenoic acid, 9-nitro-9,12-octadecadienoic acid, 10-nitro- 9,12-octadecadienoic acid, 12-nitro-9,12- octadecadienoic acid, 13-nitro-9,12-octadecadienoic acid, 9-nitrolinoleic acid, 10-nitrolinoleic acid, 12-nitrolinoleic acid, 13-nitrolinoleic acid, 5- nitro-5,8,11,14-eicosatetraenoic acid, 6-nitro-5,8,11,14-eicosatetraenoic acid, 8-nitro-5,8,11,14- eicos
  • the nitro-fatty acid described herein is 9-nitro-oleic acid (9N-OA) or 10-nitro-oleic acid (10N-OA) or a combination thereof.
  • the electrophilic (unsaturated) fatty acids can be administered separately, concurrently or subsequently with a second agent selected from anti-cholesterol drug, antidiabetic drug and anti-obesity drug.
  • the electrophilic fatty acids described herein include, but are not limited to, nitro-fatty acids (NO 2 -FA) and oxo-fatty acids.
  • US 9750725B2 is incorporated as reference.
  • the electrophilis fatty acid has the following formula: R 1 is a heterocyclyl; is an optional double bond; W is —OH, —C(O)H, —C(O), —C(O)R p , —COOH, —COOR p , —Cl, —Br, —I, —CF 3 , — CN, —SO 3 , —SO 2 R p , —SO 3 H, —NH 3 + , —NH 2 R p+ , —NR p R q R t , —NO 2 , ⁇ O, ⁇ NR p , ⁇ CF 2 , or —CHF; each V is, independently —CH or —C
  • W is —H, ⁇ O or ⁇ NR p ; V is —CH— and W is —H; V is — C— and W is ⁇ O; or c is 1, V is —C—, and W is ⁇ O.
  • R b and R b′ are each, independently, —H, —OH, —CN, or — NO 2; or R b and R b′ are each —H.
  • a is 3.
  • R 1 is a heteroaryl or a heterocycloalkyl.
  • the electrophilic fatty acid iucludes but is not limited to 13-oxo-(7Z,10Z,14A,16Z,19Z)-docosa-7,10,14,16,19-pentanoic acid, 17-oxo- (7Z,10Z,13Z,15A,19Z)-docosa-7,10,13,15,19-pentanoic acid, 13-oxo- (4Z,7Z,10Z,14A,16Z,19Z)-docosa-4,7,10,14,16,19-hexanoic acid and 17-oxo- (4Z,7Z,10Z,13Z,15A,19Z)-docosa-4,7,10,13,15,19-hexanoic acid, where A indicates either E or Z configuration, and any combination thereof.
  • Figures 1 (A) to (C) show that nitro-oleate/fatty acids selectively kill hMSCs-derived adipocytes.
  • (A) Proportion of live MSCs (left panel) or MSCs-derived adipocytes (right panel) after 48 h treatment with different concentrations of the indicated lipids. Error bars, S.E.M. *p ⁇ 0.05, **p ⁇ 0.01. n 3.
  • Figures 2 (A) and (B) show viability assay of (A) DCA-treated hMSCs and MDAs (B) FA and N-OA-treated hMSCs-derived osteoblasts.
  • Figures 3 (A) to (D) show that nitro-oleate-mediated adipocyte killing does not induce inflammation.
  • A) Production of pro-inflammatory cytokines (IL-6, IL-1 ⁇ , and TNF ⁇ ) by hMSCs-derived adipocytes after 48 h treatment with 5 ⁇ M of indicated lipids or 20 ⁇ M of DCA. Error bars, S.E.M. *p ⁇ 0.05, **p ⁇ 0.01, n 3.
  • FIGS 5 (A) to (E) show that intraperitoneally administered N-OA ameliorates HFD-induced liver, pancreas, and kidney abnormalities.
  • FIG. 6 Representative H&E images of the liver tissue (C), pancreatic tissue (D), and kidney tissue (E) from vehicle or N-OA-treated mice fed with the indicated diets. Blue asterisks, HFD- induced abnormality in pancreas islet. Black arrow, HFD-induced abnormality in the kidney glomerulus. Red arrow, HFD-induced abnormality abnormality in the renal tubule. Scale bars in (C), 50 ⁇ m. Scale bars in (D) and (E), 25 ⁇ m. [0027] Figures 6 (A) to (F) show N-OA induced fat reduction of local fat tissue through intra-fat injection. (A) Schematic graph for the lipid treatment through intra-fat injection in HFD- fed mice.
  • FIG. 7 (A) to (F) show intra-fat administration of N-OA harbors systematical effects in reducing fat accumulation in the liver, pancreas, and kidney.
  • A, B Biochemical analyses of total cholesterol, triglyceride, GOT (AST), and GPT (ALT) levels in the plasma of mice with the indicated treatments.
  • n 3, ns, not significant, *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 (two-sided unpaired t-test)
  • C Representative livers from the mice after sacrifice.
  • D-F The liver (D), pancreas (E), and kidney (F) from mice treated with the indicated lipids were sectioned and stained with hematoxylin & eosin (top panels) or with a combination of DPAI (DNA, blue) and BODIPY (lipid droplet, green) (bottom panels). Black scale bars, 50 ⁇ m. White scale bars, 25 ⁇ m.
  • the present disclosure shows that in addition to inhibiting adipocyte differentiation, nitro-fatty acids selectively induced the cell death of human mesenchymal stem cells (hMSCs)- derived adipocytes.
  • hMSCs human mesenchymal stem cells
  • the present disclosure demonstrates that nitro-oleate (N-OA) directly reduced fat tissue by triggering adipocyte death, while exerting beneficial systemic effects in alleviating obesity-associated liver, pancreas and kidney pathologies induced by high-fat diets.
  • N-OA nitro-oleate
  • the present disclosure shows that the adipocyte death and fat tissue reduction induced by N-OA does not induce obvious inflammation-associated side effects normally observed for deoxycholic acid (DCA).
  • DCA deoxycholic acid
  • N-OA is an improved therapeutic agent for fat-reduction compared to FDA-approved drugs (such as DCA).
  • DCA FDA-approved drugs
  • the present disclosure provides insights into the biological roles and applications of nitro-fatty acids as chemical modulators of the adipose tissue and obesity-related metabolic disorders.
  • Small molecule modulators of adipocyte differentiation or viability are viewed as a way to manage obesity and obesity-related diseases.
  • G4590-18500PCT and synthetic compounds are shown to inhibit adipogenic differentiation and lipogenesis, and/or induce apoptosis in terminally differentiated mature adipocytes.
  • Some of these compounds require particularly high (>100 ⁇ M) concentrations to achieve the reported effects in vitro, usually in murine 3T3-L1 preadipocytes and adipocytes. Even fewer compounds have been shown to work on primary or human adipocytes or in vivo.
  • DCA deoxycholic acid
  • electrophilic nitro-fatty acids confer beneficial anti-inflammatory and cytoprotective effects in disease models characterized by dysfunctional metabolism. While nitro-fatty acids have been shown to accumulate and be metabolized in adipose tissues in vivo, the effects of nitro-fatty acids on the physiology of adipocytes and adipose tissue, which are central to our systemic metabolism, remains unclear and to be determined.
  • the present disclosure demonstrates the selective killing effects of nitro-fatty acids or electrophilic fatty acids on adipocytes in vitro and in vivo.
  • the present disclosure shows that nitro-fatty acids or electrophilic fatty acids selectively induced cell death of adipocytes via a different mechanism from FDA-approved fat-reducing agent DCA.
  • the present disclosure demonstrates that nitro-oleate (N-OA) or electrophilic fatty acids directly reduced fat tissue by inducing adipocyte death, while exerting beneficial systemic effects in alleviating obesity-associated liver, pancreas and kidney pathologies induced by high-fat diets.
  • the present disclosure shows that N-OA- or electrophilic fatty acid-induced adipocyte death and fat tissue reduction did not induce the G4590-18500PCT_20240918_Specification_TBF - 10 - PATENT Attorney Docket No.: G4590-18500PCT obvious inflammation-associated side effects normally observed for DCA, highlighting the possibility of N-OA or electrophilic fatty acids being an improved therapeutic agent for fat- reduction.
  • the present disclosure provides a novel application of nitro-fatty acids or electrophilic fatty acids and informs the design of small molecule modulators of the adipose tissue for therapeutic intervention of obesity and related diseases.
  • Electrophilic fatty acid nitroalkenes are products of nitric oxide and nitrite- mediated unsaturated fatty acid nitration. These electrophilic products induce pleiotropic signaling actions that modulate metabolic and inflammatory responses in cell and animal models.
  • Nitro fatty acids is a class of compounds that are formed by the reaction of unsaturated fatty acids (UFAs) (such as oleic (OA), linoleic (LA), etc.) with secondary products of nitrogen monoxide (NO.) and nitrite anions (NO 2 ⁇ ).
  • nitro fatty acids include, but are not limited to, In some embodiments, examples of the nitro-fatty acid described herein include, but are not limited to, nitro-oleic acid, (NO 2 -OA), nitro-palmitoleic acid (NO 2 -POA), nitro linolenic acid (NO 2 -LNA), nitro-arachidonic acid (NO 2 -AA), nitro eicosapentaenoic acid (NO 2 -EPA), nitro-docosahexaenoic acid (NO 2 -Dha), nitro-hydroxy acid, and nitro-allyl fatty acid and any combination thereof.
  • NO 2 -OA nitro-oleic acid
  • NO 2 -POA nitro-palmitoleic acid
  • NO 2 -LNA nitro linolenic acid
  • NO 2 -AA nitro-arachidonic acid
  • NO 2 -AA nitro eicosapentaenoic acid
  • Examples of the electrophilic fatty acids include, but are not limited to, those disclosed in US 9750725B2 that is incorporated into reference. US 9750725B2 demonstrates the following compounds: G4590-18500PCT_20240918_Specification_TBF - 11 - PATENT Attorney Docket No.: G4590-18500PCT
  • X is selected from the group consisting of —CH 2 —, —OH, —S, —OR t and — NR p R q
  • Y is selected from the group consisting of —C(O)—, O, —S—, and —NR p R q
  • W is selected from the group consisting of —OH, —H, ⁇ S, —SR p , —C(O)H, —C(O), —C(O)R p , — COOH, —COOR p , —Cl, —Br, —I,
  • indices a, b, c, d, e, and f independently are integers between 0 and 15 inclusive.
  • c is 0 when d is not 0.
  • d is 0 when c is not 0; such that the sums (a+b+c+e+f) and (a+b+d+e+f) independently are equal to an integer that conforms to the formula 2n or 2n+1, wherein n is an integer between 3 and 15 inclusive.
  • Substituents —R p , —R q and —R t are independently selected from H, (C 1 -C 8 )alkyl and (C 1 - C 8 )haloalkyl.
  • —R a , —R a′ , —R b , —R b′ , —R c , —R c′ are independently selected from the group consisting of —H, —OH, —C(O)H, —C(O), —C(O)R p , —COOH, —COOR p , —Cl, —Br, — I, —F, —CF 3 , —CHF 2 , —CH 2 F, —CN, —SO 3 , —SO 2 R p , —SO 3 H, —NH 3 + , —NH 2 R p+ , — NR p R q R t and NO 2 .
  • —R a and —R a′ do not simultaneously represent non-hydrogen groups; —R b and — R b do not simultaneously represent non-hydrogen groups; and, similarly, —R c and —R c′ do not simultaneously represent non-hydrogen groups.
  • the representative compounds include, but are not limited to, 13-oxo- (7Z,10Z,14A,16Z,19Z)-docosa-7,10,14,16,19-pentanoic acid, 17-oxo-(7Z,10Z,13Z,15A,19Z)- docosa-7,10,13,15,19-pentanoic acid, 13-oxo-(4Z,7Z,10Z,14A,16Z,19Z)-docosa- 4,7,10,14,16,19-hexanoic acid, 17-oxo-(4Z,7Z,10Z,13Z,15A,19Z)-docosa-4,7,10,13,15,19- hexanoic acid, where A indicates either E or Z configuration.
  • the electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids), or its composition as described herein can be can be formulated with a suitable carrier in various forms, such as solids, solutions, powders, fluid emulsions, fluid suspensions, semi-solids, and dry powders containing an effective amount of the electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids).
  • formulations may also include pharmaceutically acceptable diluents, fillers, disintegrants, binders, lubricants, surfactants, hydrophobic vehicles, water soluble vehicles, emulsifiers, buffers, humectants, moisturizers, solubilizers, antioxidants, preservatives, and similar ingredients.
  • the means and methods for administration are well- known in the art, and guidance can be found in various pharmacologic references.
  • the electrophilic (unsaturated) fatty acid such as an electrophilic nitro-fatty acids
  • Formulations for injection can be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions or G4590-18500PCT_20240918_Specification_TBF - 13 - PATENT Attorney Docket No.: G4590-18500PCT emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent.
  • the sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic diluent or solvent suitable for injection, such as a solution in 1,3- butanediol. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile fixed oils are commonly used as a solvent or suspending medium. Any mild fixed oil can be used, including synthetic mono- or diglycerides. Fatty acid diluents like oleic acid are also used in injectable preparations.
  • fatty acid diluents that may be useful include stearic acid, metallic stearate, sodium stearyl fumarate, fatty acid, fatty alcohol, fatty acid ester, glyceryl behenate, mineral oil, vegetable oil, paraffin, leucine, silica, silicic acid, talc, propylene glycol fatty acid ester, polyethoxylated castor oil, polyethylene glycol, polypropylene glycol, polyalkylene glycol, polyoxyethylene-glycerol fatty ester, polyoxyethylene fatty alcohol ether, polyethoxylated sterol, polyethoxylated castor oil, polyethoxylated vegetable oil, and similar substances.
  • the formulations are solid dosage forms for oral administration including capsules, tablets, pills, powders, and granules.
  • the electrophilic (unsaturated) fatty acid such as an electrophilic nitro-fatty acids
  • the electrophilic fatty acid such as an electrophilic nitro-fatty acids
  • Such dosage forms may also comprise, as in normal practice, additional substances other than inert diluents, e.g., G4590-18500PCT_20240918_Specification_TBF - 14 - PATENT Attorney Docket No.: G4590-18500PCT lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents and can additionally be prepared with enteric coatings.
  • Additional embodiments that could be beneficial for administering the the electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty), or its composition orally include liquid forms of dosage.
  • a liquid dosage could consist of a pharmaceutically acceptable emulsion, solution, suspension, syrup, or elixir containing inert diluents commonly used in the field, such as water.
  • These compositions may also contain adjuvants, such as wetting agents, emulsifying and suspending agents, as well as sweetening, flavoring, and perfuming agents.
  • the electrophilic (unsaturated) fatty acid (such as an electrophilic nitro-fatty acids), or its composition as described herein can be administered through various conventional methods and routes where they are effective. Administration can be either systemic or local, such as parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, oral, buccal, ocular, intravaginal, inhalation, depot injections, or implants. In some cases, the administration may be parenteral or intravenous, with or without stabilizing additives to enhance systemic uptake, tissue half-life, and intracellular delivery.
  • the electrophilic (unsaturated) fatty acid such as an electrophilic nitro-fatty acids
  • the electrophilic (unsaturated) fatty acids selectively induced adipocyte death while impairing adipogenesis in vitro using G4590-18500PCT_20240918_Specification_TBF - 15 - PATENT Attorney Docket No.: G4590-18500PCT MDAs.
  • lipid droplet-containing cells expressing the relevant adipocyte markers.
  • MDAs provide an excellent model system to study the effects of chemical compounds on adipogenesis and adipocyte physiology.
  • Treatment of hMSCs and MDAs with different lipids revealed that nitro-linoleic acid and nitro-oleate (N-OA) rapidly and selectively induced the death of MDAs at low micromolar concentrations (Table 1).
  • N-OA nitro-linoleic acid and nitro-oleate
  • nitro-fatty acids The induction of cell death by nitro-fatty acids is specific to MDAs as these nitro-fatty acids did not affect the viability of MSCs ( Figure 1A) and hMSC-derived osteoblasts (Figure 2B).
  • This killing effect is independent of the peroxisome proliferator- activated receptor ⁇ (PPAR ⁇ ) agonist effect reported for nitro-fatty acids,30,31 since high- affinity PPAR ⁇ ligand rosiglitazone did not affect MDAs survival.
  • PPAR ⁇ peroxisome proliferator- activated receptor ⁇
  • the electrophilic nitro moiety is required since killing of MDAs was not observed with oleate (OA) and linoleate ( Figure 1A).
  • nitro-fatty acids Molecular recognition of the nitro-fatty acids is also important since MDAs viability was unaffected by another electrophilic lipid, 15-deoxy- ⁇ -12,14-prostaglandin J2 (15d- G4590-18500PCT_20240918_Specification_TBF - 16 - PATENT Attorney Docket No.: G4590-18500PCT PGJ2). 15d-PGJ2 also covalently modifies nucleophilic amino acid residues of cellular proteins via Michael addition, including a number of proteins also targeted by nitro-fatty acids such as KEAP1 and p65 subunit of NF- ⁇ B.
  • N-OA a bile acid that induces non-specific cell lysis for localized fat reduction
  • N-OA showed significantly increased killing of MDAs within 36 h at much lower CC50 values (Figure 2A, Table 1).
  • Table 1 CC 50 values of indicated compounds in the hMSCs, MDAs and osteoblasts.
  • N-OA in vivo as an anti-obesity medication for weight loss and fat reduction.
  • Intraperitoneally administrated N-OA showed significant weight loss in HFD mice while the weight of N-OA treated NCD remains unchanged.
  • the inguinal fat tissue as well as adipocytes size were smaller HFD than in NCD mice treated with N-OA.
  • N-OA harbored fat-targeting (or obese-targeting) capability in vivo, which is consistent with our in vitro results.
  • N-OA also has systemic anti- obesity effects in HFD mice, including reduced blood cholesterol, HFD-induced fatty liver, and HFD-induced abnormalities in the pancreas and kidney.
  • N-OA may be a superior alternative to DCA for fat reduction in the clinic.
  • Direct injection of N-OA into the inguinal fat pads of HFD mice resulted in strikingly smaller fat pads without noticeable side effects.
  • the significantly more pronounced fat loss in N- OA-treated fat pads than vehicle-treated contralateral fat pads supported the direct effects of N- OA on fat reduction. Additionally, systemic effects of N-OA were also observed.
  • N-OA Systemic effects such as downregulation of blood cholesterol, GOT, and GPT, and reduced HFD- associated fat accumulation in multiple organs were observed in HFD mice receiving intra-fat injections of N-OA. These beneficial systemic effects are unique to N-OA as these effects were not seen in animals with pronounced fat loss as a result of intra-fat DCA injections. [0063] Overall, our results suggested that administration of N-OA for body weight control can help alleviate metabolic disorders and diseases linked to high-cholesterol, including cardiovascular disease, diabetes, and high blood pressure, as well as fatty liver, fatty pancreas, and fatty kidney. In addition, N-OA could also be used topically to locally reduce adipose tissue with potentially fewer adverse effects than the currently used agent (DCA) in the clinic.
  • DCA currently used agent

Landscapes

  • Health & Medical Sciences (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)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Child & Adolescent Psychology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

La présente divulgation concerne une méthode d'inhibition de la différenciation adipocytaire et/ou d'induction de la mort des adipocytes chez un sujet, consistant à administrer un acide gras électrophile (insaturé) (tel qu'un acide gras nitro électrophile) à un sujet en ayant besoin.
PCT/US2024/047190 2023-09-18 2024-09-18 Procédés de réduction de graisse Pending WO2025064491A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US202363583431P 2023-09-18 2023-09-18
US63/583,431 2023-09-18

Publications (1)

Publication Number Publication Date
WO2025064491A1 true WO2025064491A1 (fr) 2025-03-27

Family

ID=95072061

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2024/047190 Pending WO2025064491A1 (fr) 2023-09-18 2024-09-18 Procédés de réduction de graisse

Country Status (2)

Country Link
TW (1) TW202519236A (fr)
WO (1) WO2025064491A1 (fr)

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014261A1 (fr) * 2009-07-31 2011-02-03 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Acides gras comme agents anti-inflammatoires
US20150018417A1 (en) * 2012-02-03 2015-01-15 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Fatty acids as anti-inflammatory agents
US10966954B2 (en) * 2016-05-16 2021-04-06 Global Biolife Inc. Electrophilically enhanced phenolic compounds for treating inflammatory related diseases and disorders

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011014261A1 (fr) * 2009-07-31 2011-02-03 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Acides gras comme agents anti-inflammatoires
US20150018417A1 (en) * 2012-02-03 2015-01-15 University Of Pittsburgh - Of The Commonwealth System Of Higher Education Fatty acids as anti-inflammatory agents
US10966954B2 (en) * 2016-05-16 2021-04-06 Global Biolife Inc. Electrophilically enhanced phenolic compounds for treating inflammatory related diseases and disorders

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
FAZZARI MARCO, KHOO NICHOLASK.H., WOODCOCK STEVEN R., JORKASKY DIANE K., LI LIHUA, SCHOPFER FRANCISCO J., FREEMAN BRUCE A.: "Nitro-fatty acid pharmacokinetics in the adipose tissue compartment", JOURNAL OF LIPID RESEARCH, vol. 58, no. 2, 1 February 2017 (2017-02-01), US , pages 375 - 385, XP093293138, ISSN: 0022-2275, DOI: 10.1194/jlr.M072058 *
KHOO NICHOLAS K.H., FAZZARI MARCO, CHARTOUMPEKIS DIONYSIOS V., LI LIHUA, GUIMARAES DANIELLE APARECIDA, ARTEEL GAVIN E., SHIVA SRUT: "Electrophilic nitro-oleic acid reverses obesity-induced hepatic steatosis", REDOX BIOLOGY, vol. 22, 1 April 2019 (2019-04-01), NL , pages 1 - 9, XP093293130, ISSN: 2213-2317, DOI: 10.1016/j.redox.2019.101132 *

Also Published As

Publication number Publication date
TW202519236A (zh) 2025-05-16

Similar Documents

Publication Publication Date Title
US7807711B2 (en) Medicinal acidic cannabinoids
AU2011322255A1 (en) Inflammatory disease
KR102164567B1 (ko) 염증 질환의 예방 및 치료
JP2004531468A (ja) スタチン副作用の処置
KR20140108630A (ko) 체지방 및 지방세포를 감소시키는 방법 및 조성물
EP3187178B1 (fr) Composition et produits pharmaceutiques pour réduire les dépôts de graisse locaux et le poids corporel et leurs utilisation associée
US11149014B2 (en) Method for treating pain or associated condition or symptom
KR20180098222A (ko) 활성화된 지방산의 치료학적 유효량을 이용한 질환의 예방, 치료 및 역행
KR20110117257A (ko) 트리에틸아세틸기-3-히드록실기페닐기아데노신 및 혈지조절에 대한 용도
CA2572796A1 (fr) Conjugues d'acides gras et amines et leur procedes d'utilisation
JP2006070032A (ja) 抗血管形成薬剤組成物
US20220313626A1 (en) Small molecule inhibitors for treating cancer in a subject having tumors with high interstitial pressure
JPS6036408A (ja) 抗炎症性デポー剤
WO2025064491A1 (fr) Procédés de réduction de graisse
JP2002543125A (ja) リンパ増殖性および自己免疫症状の治療のための、ボスウェリアセラータ（Ｂｏｓｗｅｌｌｉａｓｅｒｒａｔａ）ゴム樹脂由来ボスウェリン酸の組成物
CN113244405B (zh) 佛司可林/异佛司可林与五环三萜类化合物的药物组合物及其应用
US20160354333A1 (en) Compositions of polyunsaturated fatty acids and methods of use thereof
JP6761347B2 (ja) 脂質異常症治療剤
KR20120099366A (ko) 장기간 ｎｓａｉｄ 사용을 위한 약제
JP2000297036A (ja) 外用消炎鎮痛剤
EP4501331A1 (fr) Agent d?induction de prolifération ou de différenciation de chondrocyte
JPH11322603A (ja) 抗腫瘍作用増強剤
CA3217719A1 (fr) Derives d'acide phenoxyalkylcarboxylique et leur utilisation pour abaisser les taux de triglycerides
TW202517244A (zh) 提高活性成分之生體可用率的組成物與方法
JPH01294619A (ja) グリチルリチン製剤

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: 24869054

Country of ref document: EP

Kind code of ref document: A1