WO2017031392A1 - Composés lipidiques pour le traitement de l'obésité, de l'hypertension et du syndrome métabolique - Google Patents

Composés lipidiques pour le traitement de l'obésité, de l'hypertension et du syndrome métabolique Download PDF

Info

Publication number
WO2017031392A1
WO2017031392A1 PCT/US2016/047681 US2016047681W WO2017031392A1 WO 2017031392 A1 WO2017031392 A1 WO 2017031392A1 US 2016047681 W US2016047681 W US 2016047681W WO 2017031392 A1 WO2017031392 A1 WO 2017031392A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbon
aliphatic
hydrogen atoms
iii
branch points
Prior art date
Application number
PCT/US2016/047681
Other languages
English (en)
Inventor
Stanislav I. Svetlov
Original Assignee
University Of Florida Research Foundation, Incorporated
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 University Of Florida Research Foundation, Incorporated filed Critical University Of Florida Research Foundation, Incorporated
Publication of WO2017031392A1 publication Critical patent/WO2017031392A1/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
    • A61K31/13—Amines
    • A61K31/131—Amines acyclic
    • 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
    • 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
    • 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

  • Metabolic syndrome is a constellation of disorders manifested as a combination of dyslipidemia, hyperglycemia and obesity commonly accompanied by fatty liver disease, atherosclerosis and hypertension.
  • the metabolic syndrome and obesity is often complicated by life-threatening diseases such as cardiovascular/cerebrovascular insults, type 2 diabetes, hepatobiliary and GI cancers (Chaiteerakij et al., 2013), the most frequent causes of death worldwide (O'Neill, 2015) (Chillaron, 2014; Medina-Santillan, 2013; Fan, 2013; Luo, 2015; Karagozian, 2014).
  • Heterogeneity of metabolic syndrome and obesity regarding molecular mechanisms of its initiation and progression highlights the need to modulate multiple "targets" for its correction and especially prevention of co-morbidities, including diabetes type 2, fatty liver disease and hepatobiliary and GI tumors.
  • multifaceted agents, nontoxic for normal cells, including liver and GI cells are needed to overcome molecular diversity of metabolic syndrome and its complications.
  • AIPs affect multiple targets in vitro and in vivo.
  • the instant application discloses that oral administration of AIPs significantly reduced weight in high fat fed obese mice.
  • AIPs represent a novel class of non-toxic, orally administered endogenous- like fatty acid analogs, which can be used for correction of metabolic syndrome, hypertension and obesity.
  • the present invention provides compounds, or pharmaceutically acceptable salts or analogs thereof, useful for the treatment of obesity, hypertension and metabolic syndrome.
  • a subject e.g., a human or non-human animal
  • the invention provides a method for reducing obesity in a subject reducing hypertension in a subject or treating metabolic syndrome in a subject such that improvement in the overall health of the subject is improved.
  • FIG. 1 Chemical structure of AIP prototype and hydrochloride salts of three analogs.
  • AIPs are natural fatty acids linked via ether bond to isopropylamino propanol polar head. The structures were verified by nuclear magnetic resonance (MR) and mass- spectroscopy.
  • Figures 4A-4B Lack of AIP toxic effect on normal human hepatocytes.
  • Human donor hepatocytes were obtained from LONZA, Inc. and cultured according to manufacturer's instructions.
  • AIP-1 and AIP-2 were added at different concentrations and incubated overnight, following addition of MTS for additional 2 hours.
  • OD450 nm was counted and data shown as percent of control values (Figure 4B). Phase contrast microphotographs are shown in Figure 4A.
  • AIPs reduce metabolic fatty acid synthase in human liver cells.
  • HUH-7 cells were cultured under standard conditions as described previously. AIPs were added at final concentration of 10 mM and incubated overnight at 37 °C. Representative immunoblot with FASN antibody is shown out of 3 with similar results.
  • AIP-1 up-regulates GPR40 expression in human liver cells.
  • the incubations, conditions and AIP concentrations are the same as in autophagy experiments.
  • AIP2 has no effect on GPR40 induction in HUH-7 cells.
  • FIG. 7 AIPs induce autophagy in human liver cells. Cultured HUH-7 cells were incubated with 10 mM of AIP overnight. The cell extract was immunoblotted with LCI and LC3 antibody. A representative western blot out of 3 performed with similar results is shown.
  • AIPs inhibit beta-2 and beta-3 adrenoreceptors in CHO cells overexpressing adrenoreceptors.
  • AIP1 and AIP-2 stimulate GPR40 receptor signaling in CHO overexpressing the receptor.
  • the term “about” or “approximately” means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, “about” can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, “about” can mean a range of up to 0-20%, 0 to 10%, 0 to 5%, or up to 1% of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.
  • Treatment “Treatment”, “treating”, “palliating” and “ameliorating” (and grammatical variants of these terms), as used herein, are used interchangeably. These terms refer to an approach for obtaining beneficial or desired results including but not limited to therapeutic benefit. A therapeutic benefit is achieved with the eradication or amelioration of one or more of the physiological symptoms associated with the underlying disorder such that an improvement is observed in the patient, notwithstanding that the patient may still be afflicted with the underlying disorder.
  • an effective amount or “therapeutically effective amount” refers to that amount of an inhibitor described herein that is sufficient to effect the intended application including but not limited to disease treatment.
  • the therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art.
  • pharmaceutically acceptable salt refers to salts derived from a variety of organic and inorganic counter ions well known in the art. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids.
  • Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like.
  • Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases.
  • Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like.
  • Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine.
  • the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts.
  • “Pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient” includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions of the invention is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Subject refers to an animal, such as a mammal, for example a human.
  • the methods described herein can be useful in both pre-clinical human therapeutics and veterinary applications.
  • the subject is a mammal (such as an animal model of disease), and in some embodiments, the subject is human.
  • the terms “subject” and “patient” can be used interchangeably.
  • the subject invention pertains to compounds capable of treating obesity, hypertension and metabolic syndrome.
  • the subject invention concerns a pharmaceutical composition comprising compounds of Formula I or a pharmaceutically acceptable salt thereof.
  • R 1 and R 2 are aliphatic (including, in some embodiments, alicyclic).
  • R 1 is Ci-C 30 , and R 1 can have 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 carbon atoms.
  • R 1 contains no cyclic moieties. In other embodiments, R 1 is straight-chain. In yet other embodiments, R 1 is branched-chain or a non-aromatic cyclic.
  • R 2 can contain in some embodiments, no cyclic moieties. In certain other embodiments, R 2 is straight-chain or branched-chain. Yet other embodiments provide R 2 as a non-aromatic cyclic.
  • m and n are independently 0-3, and each substituent R 3 that is present can independently contain 1-10 non-hydrogen atoms along with 0 or more hydrogen atoms.
  • the atom belonging to R 3 that is directly bonded to R 2 must be (a) a carbon that is itself directly bonded to a heteroatom in R 3 , for example a carbonyl carbon; (b) a heteroatom, for example halogen, O, S, P, or N; or (c) a carbon that is a ring atom in an aryl or heteroaryl ring.
  • the compound of the invention is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl
  • compositions and methods of the invention a combination of any two of these compounds may be used, or a combination of three of all four of the compounds may be used.
  • a combination of the salts could be used.
  • each depicted, above may exist in more than one stereoisomeric form, including E and Z configurations at double bonds and isomers in which any given chiral center may be (R) or (S), and it is contemplated that any single isomer may be used or any mixture or combination thereof can be used for the treatment of obesity, hypertension and metabolic syndrome.
  • the compounds disclosed herein may contain chiral centers. Such chiral centers may be of either the (R) or (S) configuration, or may be a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, or be stereoisomeric or diastereomeric mixtures. It is understood that the disclosure of a compound herein encompasses any racemic, optically active, polymorphic, or stereoisomeric form, or mixtures thereof, which preferably possesses the useful properties described herein, it being well known in the art how to prepare optically active forms and how to determine activity using the standard tests described herein, or using other similar tests which are well known in the art.
  • the subject invention concerns a method of treating obesity, hypertension and metabolic syndrome in a subject by the administration of an effective amount of a compound of the invention or a pharmaceutical composition comprising a compound of the invention.
  • an effective amount of a pure or isolated compound is administered.
  • the method of the subject invention is useful in treating obesity, hypertension and metabolic syndrome.
  • Treatment of obesity, hypertension and metabolic syndrome involves a beneficial change in one or more symptoms associated with the obesity, hypertension and metabolic syndrome.
  • a beneficial change for a subject treated for obesity is a reduction in body mass index (BMI).
  • subject treated for hypertension observe a reduction in systolic, diastolic or both systolic and diastolic blood pressure.
  • beneficial changes include a decrease in blood pressure following treatment with the disclosed compounds, reduction in blood sugar levels, reduction in cholesterol levels, reduction in excess body fat around the waist or any combination of such beneficial effects in a subject to whom the disclosed compounds are administered.
  • the subject has a BMI of at least 20.
  • BMI a BMI of at least 20.
  • one embodiment for the treatment of obesity provides for the treatment of individuals with BMI values of at least 25.
  • Another embodiment for the treatment of obesity provides for the treatment of individuals with BMI values of at least 30.
  • Yet another embodiment provides for the treatment of individuals with BMI values of at least 40.
  • metabolic syndrome is a cluster of conditions selected from increased blood pressure, a high blood sugar level, excess body fat around the waist and abnormal cholesterol levels that occur together. The development of these conditions increase the risk of heart disease, stroke and diabetes in subjects having metabolic syndrome.
  • a substituted amino-propanol compound, or a pharmaceutically acceptable salt or analog thereof is administered to a subject in an effective amount to treat the obesity, hypertension or metabolic syndrome.
  • the precise dosage will depend on a number of clinical factors, for example, the type of subject (such as human, non-human mammal, or other animal) and age of the subject. A person having ordinary skill in the art would readily be able to determine, without undue experimentation, the appropriate dosages required to achieve the appropriate clinical effect.
  • a “subject” refers to a human, non-human mammal, or other animal in which the administration of a compound, as disclosed herein, would have a beneficial effect.
  • the term "treatment” includes amelioration or alleviation of a pathological condition associated with obesity, hypertension or metabolic syndrome. These include, for obesity, a reduction in body mass index (BMI) for the subject when treated with the disclosed compounds; for hypertension, an observed reduction in the measured systolic, diastolic or both systolic and diastolic blood pressure of the subject after treatment with the disclosed compounds; and for metabolic syndrome, a decrease in blood pressure following treatment with the disclosed compounds, a reduction in blood sugar levels following treatment with the disclosed compounds, a reduction in cholesterol levels following treatment with the disclosed compounds, a reduction in excess body fat around the waist following treatment with the disclosed compounds or any combination of these effects on a subject to whom the disclosed compounds are administered.
  • BMI body mass index
  • the reduction in BMI or systolic, diastolic and/or both systolic and diastolic blood pressure can be at least 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 39, 30, 31, 32 or 33% from the originally measured value for a subject.
  • substituted amino-propanol compounds of the subject invention including the compounds disclosed above, with their associated stereoisomers, and analogs or derivatives of the foregoing, can be obtained through a variety of methods known in the art.
  • Derivatives of the subject invention can be synthesized using methods of organic synthesis known to those of ordinary skill in the art.
  • substituted amino-propanol compound can be administered as an isolated compound, it may be preferred to administer these compounds as a pharmaceutical composition.
  • the subject invention thus further provides pharmaceutical compositions comprising a substituted amino-propanol compound, as an active agent, or physiologically acceptable salt(s) thereof, in association with at least one pharmaceutically acceptable carrier or diluent.
  • the pharmaceutical composition can be adapted for various routes of administration, such as enteral, parenteral, intravenous, intramuscular, topical, subcutaneous, and so forth. Administration can be continuous or at distinct intervals, as can be determined by a person of ordinary skill in the art.
  • administration may be at a frequency of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times every 1, 2, 3, 4, 5, or 6 months; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times every 1, 2, 3, 4, 5, or 6 weeks; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times every 1, 2, 3, 4, 5, or 6 days; 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 times every 1, 2, 3, 4, 5, or 6 hours; or at similar frequencies.
  • the compounds of the subject invention can be formulated according to known methods for preparing pharmaceutically useful compositions.
  • Formulations are described in a number of sources which are well known and readily available to those skilled in the art.
  • Remington 's Pharmaceutical Science (Martin E.W., Easton Pennsylvania, Mack Publishing Company, 19 th ed., 1995) describes formulations which can be used in connection with the subject invention.
  • Formulations suitable for administration include, for example, aqueous sterile injection solutions, which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and nonaqueous sterile suspensions which may include suspending agents and thickening agents.
  • the formulations may be presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the condition of the sterile liquid carrier, for example, water for injections, prior to use.
  • sterile liquid carrier for example, water for injections, prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powder, granules, tablets, etc. It should be understood that in addition to the ingredients particularly mentioned above, the formulations of the subject invention can include other agents conventional in the art having regard to the type of formulation in question.
  • the substituted amino-propanol compounds of the present invention include all hydrates and salts that can be prepared by those of skill in the art. Under conditions where the compounds of the present invention are sufficiently basic or acidic to form stable nontoxic acid or base salts, administration of the compounds as salts may be appropriate.
  • pharmaceutically acceptable salts are organic acid addition salts formed with acids which form a physiologically acceptable anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartarate, succinate, benzoate, ascorbate, alpha- ketoglutarate, and alpha-glycerophosphate.
  • Suitable inorganic salts may also be formed, including chloride, sulfate, nitrate, bicarbonate, and carbonate salts.
  • Pharmaceutically acceptable salts may be obtained by using standard procedures well known in the art, for example by reacting a basic group such as an amine with an acid affording a physiologically acceptable anion or by reacting an acidic group such as a carboxylic acid with a base affording a physiologically acceptable cation.
  • alkali metal e.g., lithium, sodium, potassium
  • alkaline earth metal e.g., magnesium, calcium
  • the compounds of the present invention can be formulated as pharmaceutical compositions and administered to a subject, such as a human or veterinary subject, in a variety of forms adapted to the chosen route of administration, i.e., orally or parenterally, by intravenous, intramuscular, topical or subcutaneous routes.
  • the present compounds may be systemically administered, e.g., orally, in combination with a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into tablets, or may be incorporated directly with the food of the subject's diet.
  • a pharmaceutically acceptable vehicle such as an inert diluent or an assimilable edible carrier.
  • the active compound may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
  • compositions and preparations may contain less than 0.01%, 0.01-0.05%, 0.05-0.1%, 0.1-0.5%, 0.5-1.0%, 1.0-5.0%, 5-10%, 10- 20%, 20-30%, 30-40%, 40-50%, or greater than 50% active ingredient by weight, or any combination of such ranges.
  • the amount of the active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
  • the tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid and the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
  • a liquid carrier such as vegetable oil or a polyethylene glycol.
  • any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
  • the active compound may be incorporated into sustained-release preparations and devices.
  • the active agent i.e., substituted amino-propanol compound or pharmaceutically acceptable salts thereof
  • Dispersions and/or solutions of the active agent or its salts can be prepared in water, preferably mixed with a nontoxic surfactant, in oils, or in glycerol, liquid polyethylene glycols, triacetin, and in mixtures thereof. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
  • the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating compounds of the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
  • the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
  • the present invention includes a pharmaceutical composition comprising substituted amino-propanol compound or pharmaceutically acceptable salts thereof, as described herein, or pharmaceutically acceptable salts thereof, in combination with a pharmaceutically acceptable carrier.
  • compositions adapted for oral, topical or parenteral administration comprising an amount of substituted amino-propanol compound, or a pharmaceutically acceptable salt thereof, constitute a preferred embodiment of the invention.
  • the dose administered to a subject, particularly a human, in the context of the present invention should be sufficient to effect a therapeutic response in the subject over a reasonable time frame.
  • Mammalian species which benefit from the disclosed methods include, but are not limited to, primates, such as apes, chimpanzees, orangutans, humans, monkeys; domesticated animals (e.g., pets) such as dogs, cats, guinea pigs, hamsters, Vietnamese pot-bellied pigs, rabbits, and ferrets; domesticated farm animals such as cows, buffalo, bison, horses, donkey, swine, sheep, and goats; exotic animals typically found in zoos, such as bear, lions, tigers, panthers, elephants, hippopotamus, rhinoceros, giraffes, antelopes, sloth, gazelles, zebras, wildebeests, prairie dogs, koala bears, kangaroo, opossums, raccoons, pandas, hyena, seals, sea lions, elephant seals, otters, porpoises,
  • a substituted amino-propanol compound or a pharmaceutically acceptable salt or derivative thereof can be administered to a subject by itself, or co-administered with one or more other compounds, including one or more other substituted amino-propanol compounds, or a pharmaceutically acceptable salt or analog thereof.
  • co-administration encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the subject at the same time.
  • Coadministration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present.
  • Co-administered agents may be in the same formulation.
  • Co-administered agents may also be in different formulations.
  • the substituted amino- propanol compound, or a pharmaceutically acceptable salt or analog thereof can be administered to a subject as adjunctive therapy.
  • a substituted amino-propanol compound, or a pharmaceutically acceptable salt or analog thereof can be administered to a subject in conjunction with various approved treatments for obesity, hypertension or metabolic syndrome.
  • the disclosed compounds can be co-administered with thiazide diuretics, such as hydrochlorothiazide (Microzide), chlorthalidone and others; beta blockers, such as propranolol (Inderal), acebutolol (Sectral ), atenolol (Tenormin) and others; angiotensin-converting enzyme (ACE) inhibitors, such as lisinopril (Zestril), benazepril (Lotensin), captopril (Capoten) and others; angiotensin 11 receptor blockers (ARBs), such as candesartan (Atacand), losartan (Cozaar) and others; calcium channel blockers, such as amlodipine (Norvasc), diltiazem (Cardizem or Tiazac); and iRenin inhibitors (e.g., Aliskiren (Tekturna)); alpha blockers, such as doxazo, such
  • AIPs analogs with C16:0 (AIP-1), C18: l (AIP-2)and C8:0 (AIP-3) fatty acids were prepared, purified and tested as previously described by us in detail (Cao et al, 2013).
  • the chemical structures of AIPs were verified by mass-spectrometry (MS) and Nuclear Magnetic Resonance (NMR), and hydrochloride salts obtained as described previously (Cao et al, 2013).
  • MS mass-spectrometry
  • NMR Nuclear Magnetic Resonance
  • hydrochloride salts obtained as described previously (Cao et al, 2013).
  • AIPs will be solubilized ex tempora in sterile saline/1% low molecular weight polyvinylpyrrolidone at 1.0 and 5.0 mg/ml, heated and kept at 40°C during the procedure.
  • high-fat diet 20% of energy is from carbohydrates, 20% from protein and 60% from fat.
  • the standard low-fat diet supplies 60% of energy from carbohydrates, 26%) from protein and 14% from fat.
  • the body weight and food intake was measured using a digital weighing scale every other day at which time urine was collected from lightly anesthetized mice by massaging the lower abdominal part of the body, while a drop of blood was collected twice a week to measure glucose and lipids by glucose monitor and lipid assay micro-method.
  • AIPs or vehicle Treatment with AIPs or vehicle began 8 weeks after initiation of high fat diet, when body weight increase in obese mice attains about 45% over normal diet animals.
  • AIP hydrochloride salts were be solubilized in sterile saline/1.0%) low molecular weight polyvinylpyrrolidone at 1.0 and 5 mg/ml, heated and maintained at 40° C throughout the procedure.
  • AIPs were administered at 5 and 25 mg/kg of each ADM, AIP -2 and AIP-3 every other day for 3 weeks.
  • Group 7 received a vehicle (saline/1%) PVP).
  • AIP-1 administration in obese mice for 2 weeks decreased body mass by nearly 9% compared to untreated obese mice (Fig. 2).
  • Blood glucose levels varied substantially during the whole observation period in both normal diet mice and high fat diet group.
  • Ten weeks after initiation of high fat diet and beginning the treatment with AIP-1 blood glucose levels were higher in obese mice vs. normal dietl68.6+6.5 mg/dL vs. 143. 7+3.4 mg/dL.
  • Two weeks treatment with AIP-1 reduced weight (Fig. 2) and showed a trend to decrease blood glucose, but not in a consistently significant fashion: 148.1 ⁇ 7.2 mg/dL 7 days after beginning of AIP-1 treatment and 153.2+4.9 mg/dL at 14 day of treatment. (Fig. 3).
  • Human pre-adipocytes and adipocyte differentiation Kits were obtained from ATCC. The cells will be analyzed by FACS, induced to differentiate to mature adipocytes as described according to manufacturer's instructions and adapted from Church et al. (2014). The effect of AIPs (1-25 uM) on adipocyte precursors was assessed using Sca-1 and CD34 markers during time-course of incubation. At defined times, media aliquots were removed and cytotoxicity assessed by LDH activity. At the end of incubations, MTS tests were conducted to assess cell survival/proliferation.
  • AIP-1 and particularly AIP-3, but not AIP-2 substantially down-regulated FASN expression in human liver cell line HUH-7 upon overnight treatment (Fig. 5).
  • AIP-1 significantly up-regulated GPR40 in these cells in a dose-dependent fashion (Fig. 6).
  • AIP-1 and AIP-2 stimulated autophagy as indicated by up-regulation of LC3 isoform 1 and 2 (Fig. 7).
  • AIP-1 and AIP-2 (10 uM) induced Ca 2+ mobilization as assessed by fluorescent FLIPR assay, while in the cells expressing adrenoreceptors, AIPs (10 ⁇ ), particularly AIP- 3, suppressed agonist-induced calcium fluxes (FLIPR assay, Millipore, Inc., Fig. 8).

Landscapes

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

Abstract

La présente invention concerne des composés, ou des sels ou analogues de qualité pharmaceutique de ces derniers pour le traitement de l'obésité, de l'hypertension et/ou de troubles métaboliques.
PCT/US2016/047681 2015-08-20 2016-08-19 Composés lipidiques pour le traitement de l'obésité, de l'hypertension et du syndrome métabolique WO2017031392A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201562207503P 2015-08-20 2015-08-20
US62/207,503 2015-08-20

Publications (1)

Publication Number Publication Date
WO2017031392A1 true WO2017031392A1 (fr) 2017-02-23

Family

ID=58051774

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2016/047681 WO2017031392A1 (fr) 2015-08-20 2016-08-19 Composés lipidiques pour le traitement de l'obésité, de l'hypertension et du syndrome métabolique

Country Status (1)

Country Link
WO (1) WO2017031392A1 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019018785A3 (fr) * 2017-07-20 2019-04-18 University Of Florida Research Foundation, Inc. Compositions et méthodes pour le traitement de tumeurs du système nerveux central
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030073631A1 (en) * 2000-02-29 2003-04-17 Rie Igarashi Modified bdnf
US20090087406A1 (en) * 2004-11-02 2009-04-02 Jean-Claude Maurel Reverse micelles based on phytosterols and acylglycerols and therapeutic uses thereof
US20110177108A1 (en) * 2008-08-08 2011-07-21 University Of Florida Research Foundation Inc. Lipid compounds for supression of tumorigenesis

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030073631A1 (en) * 2000-02-29 2003-04-17 Rie Igarashi Modified bdnf
US20090087406A1 (en) * 2004-11-02 2009-04-02 Jean-Claude Maurel Reverse micelles based on phytosterols and acylglycerols and therapeutic uses thereof
US20110177108A1 (en) * 2008-08-08 2011-07-21 University Of Florida Research Foundation Inc. Lipid compounds for supression of tumorigenesis

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019018785A3 (fr) * 2017-07-20 2019-04-18 University Of Florida Research Foundation, Inc. Compositions et méthodes pour le traitement de tumeurs du système nerveux central
EP3654959A4 (fr) * 2017-07-20 2021-03-31 University of Florida Research Foundation, Inc. Compositions et méthodes pour le traitement de tumeurs du système nerveux central
US11434195B2 (en) 2017-07-20 2022-09-06 University Of Florida Research Foundation, Inc. Compositions and methods for treatment of central nervous system tumors
US10710986B2 (en) 2018-02-13 2020-07-14 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11555029B2 (en) 2018-02-13 2023-01-17 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10899735B2 (en) 2018-04-19 2021-01-26 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US10774071B2 (en) 2018-07-13 2020-09-15 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors
US11236085B2 (en) 2018-10-24 2022-02-01 Gilead Sciences, Inc. PD-1/PD-L1 inhibitors

Similar Documents

Publication Publication Date Title
WO2017031392A1 (fr) Composés lipidiques pour le traitement de l'obésité, de l'hypertension et du syndrome métabolique
EP1177197B1 (fr) Polyamines et leur utilisation en therapie
JP2009539780A (ja) ２０（ｓ）−プロトパナキサジオールの抗うつ薬製造への使用
CN118453559A (zh) 炎症性疾病或骨病的预防或治疗剂及医药组合物
US9850199B2 (en) Metabolites of (1R-trans)-N-[[2-(2,3-dihydro-4-benzofuranyl)cyclopropyl]methyl]propanamide
US20070105937A1 (en) Indole-3-propionamide and derivatives thereof
AU2007273809A1 (en) Combination methods of treating cancer
US7632863B2 (en) 3,4,5,4′-tetramethoxyl-α,β-diphenylethane-3′-O-sodium sulphate and its use
CA3237988A1 (fr) Psilocybine et o-acetylpsilocine, leurs sels et formes a l'etat solide
US20150044293A1 (en) Radioprotector compounds
US6423744B2 (en) Method of diminishing the adverse effects of interleukin-2
WO2017076332A1 (fr) Composé de triterpénoïde pentacyclique produisant un effet régulateur de la protéine acc1, et utilisations du composé
US11629121B2 (en) Benzylideneacetone derivative and use thereof
JP2011530539A (ja) 腫瘍形成を抑制する脂質化合物
KR102114197B1 (ko) 신규한 벤질리덴아세톤 유도체 및 이의 용도
EP3750904A1 (fr) Médicament thérapeutique pour maladie neurodégénérative et son application
EP0146920A2 (fr) Composés à usage oral à effet inotrope
JP2015134732A (ja) 血管透過性亢進抑制剤
WO2023160112A1 (fr) Composé azaphilone et son utilisation dans la préparation de médicaments antitumoraux
JP2019178129A (ja) 血液脳関門保護剤
WO2008105872A1 (fr) Combinaisons de médicament pour traiter des tumeurs résistant aux médicaments
CN117797134A (zh) 一种4-tmap治疗或缓解抑郁症的用途
US20110287116A1 (en) Use of jasmonates for treating heart failure and related cardiac disorders
US20210052537A1 (en) Colitis ameliorating agent
AU2007203426B8 (en) Methods for treating neuropsychiatric disorders with NMDA receptor antagonists

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: 16837885

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: 16837885

Country of ref document: EP

Kind code of ref document: A1