WO2016126662A1 - Composés destinés à prévenir et à traiter une maladie cardiovasculaire - Google Patents

Composés destinés à prévenir et à traiter une maladie cardiovasculaire Download PDF

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WO2016126662A1
WO2016126662A1 PCT/US2016/016100 US2016016100W WO2016126662A1 WO 2016126662 A1 WO2016126662 A1 WO 2016126662A1 US 2016016100 W US2016016100 W US 2016016100W WO 2016126662 A1 WO2016126662 A1 WO 2016126662A1
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formula
composition
treating
disease
viii
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PCT/US2016/016100
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Josefino B. Tunac
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Kardiatonos, Inc.
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    • 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
    • A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
    • A61K31/385—Heterocyclic compounds having sulfur as a ring hetero atom having two or more sulfur atoms in the same ring
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • 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
    • A61K31/4406—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 3, e.g. zimeldine
    • 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
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/498—Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
    • 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

Definitions

  • the present invention relates to the treatment of vascular diseases or thromboembolism. More specifically, the present invention relates to compounds used to prevent and treat vascular diseases or thromboembolism.
  • infectious disease e.g., tetanus, pneumonia, typhoid, dysentery, tuberculosis, malaria, etc.
  • infectious disease e.g., tetanus, pneumonia, typhoid, dysentery, tuberculosis, malaria, etc.
  • Treatment options included 'blue powder' (mixture of mercury and chalk) given to soldiers with intestinal complaints; opium, morphine, whiskey, cod-liver oil, cinnamon and bark extracts for the other diseases. It was only towards the 1930s that microorganisms were realized as the common cause of infectious diseases, and the discovery of antibiotics offered an effective treatment.
  • thromboembolic disease is a blood vessel or vascular abnormality common to both arteries and veins. It involves formation of blood clots, which can subsequently dislodge to form a thrombus or embolus that flows downstream in the blood vessel tree and impairs blood flow: a process called thrombosis.
  • Thromboembolic disease is the leading cause of morbidity and mortality in the developed world with arterial thromboses as the most common underlying cause of coronary heart disease (CHD), acute myocardial infarction (Ml), stroke, hypertension, atrial fibrillation, congestive heart failure (CHF), congenital heart condition, and peripheral arterial disease (PAD); and venous thromboses, which include chronic venous insufficiency (CVI) and deep venous thrombosis (DVT) affect approximately two million Americans annually, and pulmonary embolism (PE) which accounts for 60,000 annual deaths in the United States.
  • CVI chronic venous insufficiency
  • DVT deep venous thrombosis
  • PE pulmonary embolism
  • CHD The most prominent member of the family of thromboembolic diseases is CHD; CHD was identified throughout the industrialized world during the 1920s and became the major cause of premature death in the 1940s and continuing to the present. In 1950, cholesterol was hypothesized as the culprit and gained acceptance the following year when pathologists dissecting dead US soldiers in the Korean War unexpectedly found deposits of fibrous, fatty material sticking to the artery wall, with cholesterol being one of the components. Meanwhile, dietician Ancel Keys (U Minnesota) endorsed the 'cholesterol hypothesis' because he learned that low-cholesterol Mediterranean diets correlated with low incidence of CHD. Subsequently, Ancel Keys joined the Board of the American Heart Association (AHA), and in 1977 lobbied Congress the legislation of the "War on Cholesterol".
  • AHA American Heart Association
  • Stagnant blood flow concentrates blood contaminants (bacterial infections, pollutants, etc.), which attracts monocytes and white blood cells (WBC), subsequently provoking an inflammatory response with the release of inflammatory cytokines and free radicals or reactive oxygen species (ROS).
  • WBC white blood cells
  • ROS reactive oxygen species
  • chronic inflammation disrupts the protective endothelial glycocalyx lining, and creates 'gaps' and an osmotic imbalance in the blood vessel, resulting in edema and infiltration of blood debris, e.g., dead cells, chemicals, calcium, etc.
  • the denuded endothelium produces a sticky or adhesive material called e-selectin, causing activated macrophages to accumulate to form sticky 'foam cells', which mature into plaque.
  • the processes leading to plaque build-up or atheroma generally begin in the early years of life, as young as 5 years old, but the symptoms generally do not become apparent until after the age of 40 years.
  • the endothelial glycocalyx offers a 'nest' for protective enzymes including anticoagulant anti-thrombin (AT-III), anti-oxidant (SOD), and anti-high blood viscosity lipoprotein lipase (LpL).
  • the loss of endothelial glycocalyx results in a build up of fibrin, a suppression of fibrinolysis and the promotion of clot formation.
  • Further inflammation predisposes the plaque to rupture, and ruptured plaque triggers clots formation: this clot can be exacerbated by the seed clot formed by Roleaux cells thus becoming a significant thrombus.
  • Loose thrombi can wedge on a rigid vessel narrowed by plaque, particularly in individuals who already have atherosclerosis, causing a stroke (clogged artery to the brain), heart attack (clogged artery to the heart), or PAD (clogged artery to the arms or legs).
  • the straight vessel segment with high blood flow has high shear stress, which is important in maintaining a thick protective endothelial glycocalyx layer.
  • the venous system returns 'used' blood to the heart by means of the skeletal pump.
  • the mechanism involves the contraction-relaxation motion of muscles surrounding the veins (relaxation, draws blood from superficial veins; contraction, propels blood to heart) pushing blood through the one-way valve system (preventing back-flow). Poor muscle contraction or dysfunctional valve system, due to inactivity or muscle degeneration, create stagnation and blood pooling. Concentration of blood cells is the main mechanism for clot formation, although injury to vein wall may trigger formation of blood clot as well. A loose clot becomes an embolus, which travels to the lung or heart causing a DVT.
  • antithrombotics There are several treatments available for blood clots, i.e. antithrombotics. These treatments fall into two classes, anticoagulants (that slow down clotting) and antiplatelets (that prevent clumping of platelets and clot formation).
  • Heparin is an anticoagulant that is commonly used and administered before surgery in order to prevent clots forming. Heparin has the side effect of causing excessive bleeding and bruising and cannot be used on a long term basis.
  • Dicumarol, and its derivative warfarin are other anticoagulants that act as a vitamin K depleter and prevent the formation of coagulant enzymes.
  • Fondaparinux is a synthetic anticoagulant related to low molecular weight heparin that is indicated for deep vein thrombosis and can be given daily.
  • Bivalirudin is a synthetic anticoagulant that is a specific and reversible direct thrombin inhibitor and is indicated for patients with unstable angina undergoing percutaneous transluminal coronary angioplasty or percutaneous coronary intervention.
  • Aspirin is an antiplatelet and widely used in low doses to reduce the risk of stroke and heart attack.
  • Clopidogrel is an antiplatelet that irreversibly inhibits P2Y12 receptor on platelet cell membranes and can be administered along with or instead of aspirin in preventing heart disease.
  • Dipyridamole is an antiplatelet that inhibits thrombus formation, and is also administered along with aspirin to prevent stroke and heart attack.
  • Abciximab is another antiplatelet administered to patients undergoing percutaneous coronary intervention. While each of these antithrombotics are useful in different situations, there are still side effects and there remains a need for more effective therapeutics.
  • the present invention provides for a combination drug formulation for treating and preventing cardiovascular disease, comprising the compositions of
  • the present invention provides for a composition for treating or preventing disease, especially vascular disease, comprising a composition chosen from the group consisting of FORMULA I
  • FORMULA VIII ligands thereof, analogs thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof.
  • the present invention provides for a method of treating or preventing disease, by administering a pharmaceutically effective amount of at least one of
  • FORMULA VIII a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject.
  • the present invention provides for a method of treating or preventing vascular disease, by administering a pharmaceutically effective amount of a
  • FORMULA VIII a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject, and minimizing or preventing clot formation in the vascular system of the subject.
  • the present invention provides for a method of treating or preventing arthritis, by administering a pharmaceutically effective amount of a composition FORMULA V
  • FORMULA VII I a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject suffering from arthritis.
  • the present invention provides for a method of treating or preventing metastatic cancer, by administering a pharmaceutically effective amount of a
  • FORMULA VII I a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject suffering from metastatic cancer.
  • the present invention provides for a method of treating or preventing diabetes, by administering a pharmaceutically effective amount of a composition
  • FORMULA VII I a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject suffering from diabetes.
  • FIGURE 1 is a table of the treatment schedule of EXAMPLE 1 ;
  • FIGURE 2 is a representation of a thromboembolism cascade and drug targets
  • FIGURE 3 is a table of the treatment schedule
  • [00028] is a graph of HAS-1 levels
  • FIGURES 4A-4C are photographs of fibrous fat deposits and plaques: for the animal control group (fed with high fat diet and treated with PCB), 4A (10X magnification), 4B (40X magnification), and for the negative control group (normal diet) 4C;
  • FIGURE 5 is a table of ratings of drug combinations
  • FIGURES 6A-6H are photographs of 'therapeutic' and 'preventive' histopathology of arterial vessels in compounds B, F, I, and K;
  • FIGURE 7 is a table of statistical significance for drugs
  • FIGURE 8 is a graph of hyaluronan synthase 1 levels
  • FIGURE 9 is a graph of heparan sulfate levels
  • FIGURE 10 is a graph of graph of PAI-1 levels.
  • FIGURE 1 1 is a graph of SDC1 levels.
  • the present invention is directed to compositions and methods for treating or preventing the onset of various diseases, including vascular diseases.
  • Vascular disease refers to any disease affecting the circulatory system of arteries, veins, capillaries, and lymph vessels in the body.
  • Vascular disease can include, but is not limited to, peripheral artery disease, aneurysms, renal artery disease, Raynaud's disease, Buerger's disease, peripheral venous disease, varicose veins, blood clots (thromboembolism), blood clotting disorders, lymphedema.
  • Thromboembolism refers to a family of vascular diseases including coronary heart disease (CHD), acute myocardial infarction (Ml), stroke, hypertension, atrial fibrillation, congestive heart failure (CHF), congenital heart condition, peripheral arterial disease (PAD), chronic venous insufficiency (CVI), deep venous thrombosis (DVT), and pulmonary embolism (PE).
  • CHD coronary heart disease
  • Ml acute myocardial infarction
  • stroke hypertension
  • atrial fibrillation congestive heart failure
  • CHF congestive heart failure
  • PED peripheral arterial disease
  • CVI chronic venous insufficiency
  • DVT deep venous thrombosis
  • PE pulmonary embolism
  • composition can be melatonin ⁇ , ⁇ -D xyloside (FTX214-1 ), shown in FORMULA I.
  • composition in FORMULA I stimulates chondroitin sulfate synthesis, the second most common glycosaminoglycan (GAG) in the endothelial cell glycocalyx.
  • GAG glycosaminoglycan
  • ⁇ -D-Xylosides act as primers for GAG chain initiation and compete with the xylosilated core protein, which adds galactose to a xylose residue on the core protein.
  • the composition acts to stimulate antioxidative enzymes including superoxide dismutase, glutathione peroxidase and glutathione reductase as well as acting as a direct reactive oxygen species (ROS) scavenger: it neutralizes the highly toxic hydroxyl radical hydrogen peroxide, singlet oxygen, peroxynitrite anion, nitric oxide and hypochlorous acid as well as stimulates several antioxidative enzymes which increase its efficiency as an antioxidant.
  • ROS direct reactive oxygen species
  • composition of the present invention can also be compounds with the base functionality of 6-N-oxide ribose-phenazinol as exemplified in FORMULA II (FTX 216-4).
  • composition in FORMULA II stimulates chondroitin sulfate synthesis, the second most common glycosaminoglycan (GAG) in the endothelial cell glycocalyx.
  • GAG glycosaminoglycan
  • ⁇ -D-Xylosides act as primers for GAG chain initiation and compete with the xylosilated core protein, which adds galactose to a xylose residue on the core protein.
  • Xyloside activity varies with the aglycone (since primers compete with endogenous substrates and inhibits proteoglycan (PG) and glycoprotein synthesis, type of aglycone is critical).
  • the composition is a broad spectrum antimicrobial agent.
  • composition of the present invention can also be lipoate- cysteine-glutamic tripeptide exemplified by FORMULA III (FTX219-1 ).
  • composition in FORMULA III acts to stimulate glycoprotein synthesis in which the peptide portion of the molecule is synthesized first, then the sugar moieties are incorporated. Attachment of the peptide portion to the surface appears to be by association between a region of repeated amino acids and components of the endothelial glycocalyx.
  • composition of the present invention can also be that shown in FORMULA IV (FTX224-2: Di Oxide isothiocyanate indole), which was designed to inhibit blood clotting. (FORMULA IV)
  • composition of FORMULA IV acts as an anti-inflammation agent, an antiproliferation agent, and an antiangiogenesis agent and is known to prevent glutathione depletion in the liver.
  • composition of the present invention can also be a piperidine ribose as exemplified in FORMULA V (FTX226-4)
  • composition of FORMULA V inhibits production of two important proinflammatory mediators, IL6 and PGE2 (triggers pain) and enhances drug bioavailability by inhibiting drug metabolism or by increasing absorption.
  • This composition can be useful in combination treatments with other drugs by improving therapeutic effect or lowering the dose requirements of other drugs when administrated with disease-modifiying antirheumatic drugs (DMARDs) as a therapeutic drug or dietary supplement.
  • DMARDs disease-modifiying antirheumatic drugs
  • the composition is an antihypertensive as it inhibits platelet aggregation, and stabilizes and increases activity of eNOS which leads to decreased blood pressure.
  • composition can also be the compound lipoate-choline as exemplified in FORMULA VI (FTX218).
  • Lipoic acid is an organosulfur derived from octanoic acid. It contains two sulfur atoms (at C6 and C8) connected by a disulfide bond and is thus considered to be oxidized. Lipoic regenerates glutathione and glutamic. LA is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects. Choline and its metabolites serve three physiological functions: structural integrity and signaling roles for cell membranes, and cholinergic neurotransmission.
  • a cholinergic compound regenerates glutathione and glutamic and reduced glutathione (GSH) is the most abundant non-protein thiol in mammalian cells and the preferred substrate for several enzymes in xenobiotic metabolism and antioxidant defense. Glutathione is the most powerful antioxidant and has even been called “the master antioxidant.”
  • the composition can also be nicotinyl choline as exemplified in
  • nicotinic acid receptor GPR109A After the discovery of the nicotinic acid receptor GPR109A on adipocytes and immune cells, novel direct immunomodulatory properties of nicotinic acid have been identified including the release of inflammatory mediators from adipose tissue, direct anti-inflammatory activities of nicotinic acid in other cells previously indicated as key players in atherogenesis (such as hepatocytes andendothelial and vascular cells), nicotinic acid keeps macrophages from entering the atherosclerotic vascular wall by activating its receptor, thereby halting chronic inflammation.
  • choline serves various functions in mammalian bodies: structure of cell membranes, protecting the liver from accumulating fat, as the precursor molecule for the neurotransmitter acetylcholine, and more.
  • Choline via its metabolite, trimethylglycine (betaine) is a major source for methyl groups that participates in the S-adenosylmethionine synthesis pathways, used in treating hepatitis, glaucoma, atherosclerosis, and, possible, neurological disorders.
  • the composition can also be the an ammonium lipoate as exemplified in FORMULA VIII (FTX230).
  • GSH Reduced glutathione
  • Computer programs for use in rational drug design include but are not limited to AMBER (available from University of California, San Francisco), CHARMM (Chemistry at HARvard Molecular Mechanics, available from Harvard University), MM2, SYBYL (Trypos Inc.), CHEMX (Chemical Design), MACROMODEL, GRID (Molecular Discovery Ltd), and Insight II (Accelry).
  • AMBER available from University of California, San Francisco
  • CHARMM Choemistry at HARvard Molecular Mechanics, available from Harvard University
  • MM2 SYBYL (Trypos Inc.)
  • CHEMX Chemical Design
  • MACROMODEL MACROMODEL
  • GRID Molecular Discovery Ltd
  • Insight II Insight II
  • Such programs are contemplated as being useful for the determination of the chemical interaction between two molecules, either isolated, or surrounded by solvent molecules, such as water molecules, or using calculations that approximate the effect of solvating the interacting molecules.
  • the ligands or analogs of compounds of the above FORMULAS thus identified or designed can be subsequently tested for their ability to treat and/or prevent vascular diseases.
  • the computer-based methods discussed above are used.
  • the compounds are tested for their ability to treat and/or prevent vascular diseases.
  • Lead compounds identified during these screens can serve as the basis for the synthesis of more active analogs.
  • Lead compounds and/or active analogs generated therefrom can be formulated into pharmaceutical compositions effective in treating and/or preventing autoimmune diseases or inflammatory diseases.
  • compositions of the present invention can be administered together to target specific aspects of disease, especially vascular disease.
  • Any combination of the compounds of the above FORMULAS and especially FORMULAS l-VIII can be used.
  • the compositions can be in a single dosage form or in multiple dosage forms, and each composition can be tailored to provide different release profiles as needed or desired for a particular individual, such as, but not limited to, sustained release, prolonged release, or immediate release. Therefore, the present invention also provides for a composition for treating or preventing disease, especially vascular disease, including a composition of at least two of FORMULAS l-VIII, ligands thereof, analogs thereof, pharmaceutically acceptable salts thereof, solvates thereof, esters thereof, or tautomers thereof.
  • compositions of FORMULA I, FORMULA III, and FORMULA VI are particularly useful combinations. Therefore, the present invention provides for a combination drug formulation for treating and preventing cardiovascular disease, including the compositions of FORMULA I, FORMULA III, and FORMULA VI.
  • compositions of the present invention can be delivered alone or in combination with additional agents.
  • the compositions can be combined with other agents that treat vascular diseases.
  • the compositions can be combined with statins that lower cholesterol levels in blood and prevent heart attacks and strokes, such as, but not limited to, atorvastatin, cerivastatin, fluvastain, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, or simvastatin.
  • compositions can be combined with lipid-lowering antibodies, such as, but not limited to, anti-PCSK9 MAb (monoclonal antibody), any antibody that interacts with PCSK9 to lower LDL levels, brococizumab (Pfizer RN316), or any other suitable antibody.
  • lipid-lowering antibodies such as, but not limited to, anti-PCSK9 MAb (monoclonal antibody), any antibody that interacts with PCSK9 to lower LDL levels, brococizumab (Pfizer RN316), or any other suitable antibody.
  • the agent can be non-steroidal anti-inflammatory drugs (NSAIDS) such as, but not limited to, acetaminophen, salicylates (aspirin, diflunisal, salsalate), acetic acid derivatives (indomethacin, ketorolac, sulindac etodolac, diclofenac, nabumetone), propionic acid derivatives (ibuprofen, naproxen, flurbiprofen, ketoprofen, oxaprozin, fenoprofen, loxoprofen), fenamic acid derivatives (meclofenamic acid, mefenamic acid, flufenamic acid, tolfenamic acid), oxicam (enolic acid) derivatives (piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam), arylalkanoic acid derivatives (tolmetin); or selective COX-2 inhibitors (celec
  • the agent can also be generally from the classes antihistamines, anti-infective agents, antineoplastic agents, autonomic drugs, blood derivatives, blood formation agents, coagulation agents, thrombosis agents, cardiovascular drugs, cellular therapy, central nervous system agents, contraceptives, dental agents, diagnostic agents, disinfectants, electrolytic, caloric, and water balance, enzymes, respiratory tract agents, eye, ear, nose, and throat preparations, gold compounds, heavy metal antagonists, hormones and synthetic substitutes, oxytocics, radioactive agents, serums, toxoids, and vaccines, skin and mucous membrane agents, smooth muscle relaxants, and vitamins.
  • compositions including the molecules described above, where the molecule is preferably any of the FORMULAS describe above and especially FORMULAS l-VIII as described in detail above, together with one or more pharmaceutically acceptable excipients or vehicles, and optionally other therapeutic and/or prophylactic ingredients.
  • excipients include liquids such as water, saline, glycerol, polyethyleneglycol, hyaluronic acid, ethanol, etc. Suitable excipients for non-liquid formulations are also known to those of skill in the art.
  • compositions of the present invention include, for example, mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like; and the salts of organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • mineral acid salts such as hydrochlorides, hydrobromides, phosphates, sulfates, and the like
  • organic acids such as acetates, propionates, malonates, benzoates, and the like.
  • a biological buffer can be any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i.e., a pH in the physiologically acceptable range.
  • buffer solutions include saline, phosphate buffered saline, and Tris buffered saline, Hank's buffered saline, and the like.
  • the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, may include other pharmaceutical agents, adjuvants, diluents, buffers, etc.
  • the invention includes a pharmaceutical composition including a compound of the present invention including isomers, racemic or non-racemic mixtures of isomers, or pharmaceutically acceptable salts or solvates thereof together with one or more pharmaceutically acceptable carriers, and optionally other therapeutic and/or prophylactic ingredients.
  • the compounds of this invention are administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compounds of this invention for a given disease.
  • the compounds of this invention can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • oral including buccal and sub-lingual
  • rectal including nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • parenteral including intramuscular, intraarterial, intrathecal, subcutaneous and intravenous administration or in a form suitable for administration by inhalation or insufflation.
  • the preferred manner of administration is intravenous or oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered may also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, etc.
  • the composition will generally take the form of a tablet, capsule, and a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • the compounds of the invention can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl callulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • capsules can be prepared by conventional procedures so that the dosage unit is 100 mg of the compounds of the invention, 100 mg of cellulose and 10 mg of magnesium stearate.
  • a large number of unit capsules may also prepared by filling standard two-piece hard gelatin capsules each with 100 mg of powdered active ingredient, 150 mg of lactose, 50 mg of cellulose, and 10 mg magnesium stearate.
  • tablets may be prepared by conventional procedures so that the dosage unit is 100 mg of the compounds of the invention, 150 mg of lactose, 50 mg of cellulose and 10 mg of magnesium stearate.
  • a large number of tablets may also be prepared by conventional procedures such that the dosage unit was 100 mg of the compounds of the invention, and other ingredients can be 0.2 mg of colloidal silicon dioxide, 5 mg of magnesium stearate, 250 mg of microcrystalline cellulose, 10 mg of starch and 100 mg of lactose. Appropriate coatings may be applied to increase palatability or delay absorption.
  • the active agent can be combined with any oral, non-toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents may be added as well.
  • suitable inert carrier such as ethanol, glycerol, water, and the like
  • flavoring, coloring and/or sweetening agents may be added as well.
  • Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
  • Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation may also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration may involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • aqueous and non-aqueous, isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Administration via certain parenteral routes can involve introducing the formulations of the present invention into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
  • a formulation provided by the present invention can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
  • the formulations can optionally contain an isotonicity agent.
  • the formulations preferably contain an isotonicity agent, and glycerin is the most preferred isotonicity agent.
  • concentration of glycerin, when it is used, is in the range known in the art, such as, for example, about 1 mg/mL to about 20 mg/mL.
  • the pH of the parenteral formulations can be controlled by a buffering agent, such as phosphate, acetate, TRIS or L-arginine.
  • concentration of the buffering agent is preferably adequate to provide buffering of the pH during storage to maintain the pH at a target pH ⁇ 0.2 pH units.
  • the preferred pH is between about 7 and about 8 when measured at room temperature.
  • additives such as a pharmaceutically acceptable solubilizers like Tween 20® (polyoxyethylene (20) sorbitan monolaurate), Tween 40® (polyoxyethylene (20) sorbitan monopalmitate), Tween 80® (polyoxyethylene (20) sorbitan monooleate), Pluronic F68® (polyoxyethylene polyoxypropylene block copolymers), and PEG (polyethylene glycol) can optionally be added to the formulation, and may be useful if the formulations will contact plastic materials.
  • the parenteral formulations can contain various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • Sterile injectable solutions are prepared by incorporating one or more of the compounds of the invention in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum- drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1 .5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • the pharmaceutical compositions of the invention can be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable nonirritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • compositions of the invention can also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
  • Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives.
  • Creams containing the selected active agent are, as known in the art, viscous liquid or semisolid emulsions, either oil- in-water or water-in-oil.
  • Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • the specific ointment or cream base to be used is one that will provide for optimum drug delivery.
  • an ointment base should be inert, stable, nonirritating and nonsensitizing.
  • Formulations for buccal administration include tablets, lozenges, gels and the like.
  • buccal administration can be effected using a transmucosal delivery system as known to those skilled in the art.
  • the compounds of the invention may also be delivered through the skin or muscosal tissue using conventional transdermal drug delivery systems, i.e., transdermal "patches" wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface.
  • the drug composition is typically contained in a layer, or "reservoir,” underlying an upper backing layer.
  • the laminated device may contain a single reservoir, or it may contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
  • the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above or it may be a liquid or gel reservoir, or may take some other form.
  • the backing layer in these laminates which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility.
  • the material selected for the backing layer should be substantially impermeable to the active agent and any other materials that are present.
  • the compounds of the present invention can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size may be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, tnchlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol may conveniently also contain a surfactant such as lecithin.
  • the dose of drug may be controlled by a metered valve.
  • the active ingredients may be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrolidine (PVP).
  • the powder carrier will form a gel in the nasal cavity.
  • the powder composition may be presented in unit dose form for example in capsules or cartridges of e.g., gelatin or blister packs from which the powder may be administered by means of an inhaler.
  • a pharmaceutically or therapeutically effective amount of the composition will be delivered to the subject.
  • the precise effective amount will vary from subject to subject and will depend upon the species, age, the subject's size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration.
  • the subject can be human or animal.
  • the effective amount for a given situation can be determined by routine experimentation.
  • a therapeutic amount will be in the range of about 0.01 mg/kg to about 40 mg/kg body weight, more preferably about 0.1 mg/kg to about 10 mg/kg, in at least one dose.
  • the indicated daily dosage can be from about 1 mg to 300 mg, one or more times per day, more preferably in the range of about 10 mg to 200 mg.
  • the subject can be administered as many doses as is required to reduce and/or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system.
  • One preferable dosing range is 200 to 1000 mg/kg for each of the compositions of FORMULAS l-VIII.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • the present invention provides for a method of treating or preventing disease, by administering a pharmaceutically effective amount of at least one of the compositions of FORMULAS I - VIII, a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, or tautomer thereof to a subject.
  • compositions can be used to treat diseases such as, but not limited to, vascular diseases, hyperlipidemia, coronary heart disease (CHD), stroke, hypertension, peripheral arterial disease (PAD), pulmonary embolism (PE), inflammation diseases, metabolic syndrome, dyslipidemia, disorders of the peripheral and central nervous system, hematological diseases, cancer, respiratory diseases, gastroenterological diseases, diabetes, or non-alcoholic fatty liver disease.
  • diseases such as, but not limited to, vascular diseases, hyperlipidemia, coronary heart disease (CHD), stroke, hypertension, peripheral arterial disease (PAD), pulmonary embolism (PE), inflammation diseases, metabolic syndrome, dyslipidemia, disorders of the peripheral and central nervous system, hematological diseases, cancer, respiratory diseases, gastroenterological diseases, diabetes, or non-alcoholic fatty liver disease.
  • CHD coronary heart disease
  • PDA peripheral arterial disease
  • PE pulmonary embolism
  • inflammation diseases such as, but not limited to, vascular diseases, hyperlipidemia, coronary heart disease (CHD), stroke, hypertension, peripheral arterial disease (PA
  • a single composition can be administered, or combinations of any of the compositions can be administered as described above.
  • different mechanisms of action can be present. Several of these mechanisms are shown in FIGURE 2.
  • chondroitin sulfate synthesis can be stimulated, antioxidative enzymes can be stimulated such as superoxide dismutase, glutathione peroxidase and glutathione reductase, and the composition can act as a direct ROS scavenger.
  • chondroitin sulfate can be synthesized, and antimicrobial effects can be induced.
  • compositions of FORMULA III glycoprotein synthesis can be stimulated.
  • composition of FORMULA IV anti-inflammation, antiproliferation, and antiangiogenesis effects can be induced, and glutathione depletion in the liver can be prevented.
  • composition of FORMULA V the production of IL6 and PGE2 can be inhibited, drug bioavailability can be enhanced, and antihypertensive effects can be induced.
  • antioxidant effects can be induced, and hepatitis, glaucoma, atherosclerosis, and neurological disorders can be treated.
  • composition of FORMULA VII immunomodulatory effects can be induced.
  • compositions of FORMULA VIII antioxidant effects can be induced.
  • Different compositions can be combined to arrive at a specific mechanism of action profile for different diseases, and especially for vascular disease.
  • the present invention provides for a method of treating or preventing vascular disease, by administering a pharmaceutically effective amount of a composition of FORMULAS I - VIII, a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject.
  • the compositions act to prevent or minimize clot formation in the vascular system.
  • the present invention provides for a method of treating or preventing arthritis, by administering a pharmaceutically effective amount of a composition of FORMULAS I - VIII, a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject suffering from arthritis.
  • Osteoarthritis is characterized by cartilage erosion, proteolysis of aggrecan and collagen, and disturbed synthesis rates of aggrecan and hyaluronan by chondrocytes.
  • An autoimmune and inflammatory response to cartilage proteoglycans is an important element of the pathology of rheumatoid arthritis.
  • the autocrine/paracrine activities of TNF- and IL- 1 in articular cartilage can play important roles in cartilage matrix degradation in OA patients.
  • One preferred combination of compositions in the method of treating arthritis is FORMULA I, FORMULA III, and FORMULA VI.
  • composition of FORMULA I achieves stabilization and repair of cartilage via stimulation of chondroitin sulfate synthesis, generating a glycosaminoglycan (GAG) which is a critical component of the proteoglycan molecule.
  • GAG glycosaminoglycan
  • the composition of FORMULA III acts to stimulate glycoprotein synthesis and therefore repairs and stabilizes hyaline cartilage.
  • the composition of FORMULA VI blocks the activity of pro-inflammatory cytokines that are key aspects of the pathology of damage to the cartilage and surrounding joint tissues in both rheumatoid arthritis and osteoarthritis.
  • the present invention provides for a method of treating or preventing metastatic cancer, by administering a pharmaceutically effective amount of a composition of FORMULAS I - VIII, a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject suffering from metastatic cancer.
  • Cancer metastasis begins with detachment of metastatic cells from the primary tumor, travel of the cells to different sites through blood/lymphatic vessels, settlement, and growth of the cells at a distal site. During the process, metastatic cells go through detachment, migration, invasion, and adhesion.
  • the tumor microenvironment including extracellular matrix structure, growth factors, chemokines, and matrix metalloproteinases plays a significant role in cancer metastasis.
  • Tumor cell adhesion to the microvessel wall is a critical step during tumor metastasis.
  • Aberrant glycosylation of cell surface glycoproteins acquired during malignant progression is a common characteristic of human cancer cells. Damage to the endothelial glycocalyx is likely to increase microvessel permeability and tumor cell adhesion.
  • One preferred combination of compositions in the method of treating metastatic cancer is FORMULA I, FORMULA III, and FORMULA VI.
  • the composition of FORMULA I achieves stabilization and repair of the endothelial glycocalyx via stimulation of chondroitin sulfate synthesis, generating a glycosaminoglycan (GAG) which is a critical component of blood vessel proteoglycan molecules.
  • GAG glycosaminoglycan
  • the composition of FORMULA III acts to stimulate glycoprotein synthesis and therefore repairs and stabilizes the endothelial glycocalyx, thus deterring metastases.
  • An increase in TNF- expression promotes tumor metastasis and induces the endothelial dysfunction in many related pathophysiological conditions.
  • the composition of FORMULA VI blocks the activity of this pro-inflammatory cytokine in metastasis.
  • the present invention provides for a method of treating or preventing diabetes, by administering a pharmaceutically effective amount of a composition of FORMULAS I - VIII, a ligand thereof, an analog thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, an ester thereof, a tautomer thereof, or combinations thereof to a subject suffering from diabetes.
  • Damage to the endothelial glycocalyx alters the permeability of multiple capillary beds that in the glomerulus will clinically result as albuminuria.
  • Glomerular endothelial dysfunction, and in particular damage to its glycocalyx, represents the most likely initiating step in diabetic microalbuminuria.
  • Hypertension and shear stress, inflammation, and other diabetes-associated are some of the prevalent risk factors of endothelial dysfunction in chronic kidney disease.
  • endothelial dysfunction and atherosclerosis are almost universal, as well as cardiovascular complications.
  • Microvascular alterations including changes in microvessel distribution and loss of the glycocalyx, can be detected in children with type 1 diabetes mellitus before clinically apparent vascular complications.
  • One preferred combination of compositions in the method of treating diabetes is FORMULA I, FORMULA III, and FORMULA VI.
  • the composition of FORMULA I achieves stabilization and repair of the glomerular endothelial surface layer (ESL) via stimulation of chondroitin sulfate synthesis, generating a glycosaminoglycan (GAG) which is a critical component of the ESL.
  • the composition of FORMULA III acts to stimulate glycoprotein synthesis and therefore repairs and stabilizes the glomerular endothelial surface layer.
  • the composition of FORMULA VI blocks the activity of pro-inflammatory cytokines such as tumor necrosis factor-a (TNF-a) that are key aspects of the pathology of endothelial dysfunction in type 2 diabetes.
  • TNF-a tumor necrosis factor-a
  • mice Eighty-four (84) ten week old male C57/BI6 mice were obtained from Jackson Laboratories. Three mice were raised from 6 weeks on a regular diet and served as controls, and the remaining mice were raised on a 60% fat diet (D12451 , DIO series diet, Opensource Diets).
  • PCB-77 3,3',4,4'-Tetrachlorobiphenyl (PCB-77) was obtained from Neosyn Laboratories. The dry chemical was suspended in 15.22 ml of corn oil to deliver 200 ⁇ /kg in 0.2 ml by gavage per mouse according to the treatment schedule as illustrated in FIGURE 1 . Drugs were suspended in 8 ml carboxymethylcellulose and 0.2 ml/mouse was delivered by gavage. Another detailed treatment schedule is shown in FIGURE 3
  • HAS-1 Heparan Sulfate ELISA and Hyaluronan Synthase 1
  • PAI-1 Total Plasminogen Activation lnhibitor-1
  • SDC1 Syndecan 1
  • mice were sacrificed on days 4, 1 1 , or 18 according to the experimental plan (three each from groups).
  • the animals were anesthetized by intraperitoneal injection of 90 mg/kg Ketamine and 8 mg/kg Xylazine, and Isoflurane gas anesthesia.
  • Blood was collected by retro-orbital bleeding or from the heart and mixed with 50 mg/ml heparin to prevent clotting.
  • the thorax was opened to expose the heart, and saline was injected into the left ventricle, with the right atrium opened to allow the drainage of blood and saline.
  • the heart was perfused with at least 5 ml of saline and until no blood was observed in the drainage from the atrium.
  • the heart was carefully dissected and frozen for histological sectioning. Plasma was collected from the blood samples by centrifuging at 1000 rpm for 15 minutes, and collecting the supernatant. The samples were stored at -80°C until analysis.
  • Typical hallmarks of cardiovascular disease pathologies include fibrous fat deposits and plaques, which are illustrated in the animal control group (fed with high fat diet and treated with PCB), FIGURE 4A (10X magnification) and FIGURE 4B (40X magnification).
  • the negative control group normal diet
  • FIGURE 4C Typical features of a normal arterial wall
  • the three biomarkers that were found highly correlative to plaque production include Hyaluronan Synthase (HY), Heparan Sulfate (HS). And Plasminogen Activation lnhibitor-1 (PA); Syndecan 1 (SD) was not predictive.
  • these 3 biomarkers (HY, HS, PA) were used to rate the activities of the different drug combos, particularly 'preventive' or 'therapeutic' of plaques.
  • the ratings of the 1 1 drug combos, summarized in FIGURE 5 are varied. For example, Combos A & C, were therapeutic but not preventive. On the other hand, combo drug G was preventive but not therapeutic.
  • HAS-1 Hyaluronan Synthase 1
  • HAS-1 Hyaluronan Synthase 1
  • FIGURE 8 The results for Hyaluronan Synthase 1 (HAS-1 ) are shown in FIGURE 8. It was observed that the highest HAS-1 levels occurred in the mice on the high fat diet treated with PCB on Day 1 and 3 and sacrificed at Day 4, which was the comparison control for the Therapeutic groups.
  • the comparative control for the Preventative groups were mice on the high fat diet treated with PCB on Day 7 and 9 and sacrificed on Day 1 1 . Reductions in HAS-1 levels were observed in mice treated with: Compounds G, K, and I in the Preventative Protocol, and Compounds A, B, C, F, I, J, and K in the Therapeutic Protocol.
  • Heparin Sulfate The results for Heparin Sulfate (Hep) are shown in FIGURE 9. It was observed that the highest Hep levels occurred in the mice on the high fat diet treated with Compounds A and E in the Preventative Protocol, although high levels were also seen in mice on the high fat diet treated with PCB on Day 7 and 9 and sacrificed on Day 1 1 , the comparative control for the Preventative groups. Hep levels were not noticeably higher in mice on the high fat diet treated with PCB on Day 1 and 3 and sacrificed at Day 4, which was the comparison control for the Therapeutic groups.
  • Plasminogen Activation Inhibitor- 1 (PAI-1 ).
  • PAI-1 Total Plasminogen Activation lnhibitor-1
  • FIGURE 10 The results for Total Plasminogen Activation lnhibitor-1 (PAI-1 ) are shown in FIGURE 10. It was observed that high PAI-1 levels occurred in the control mice for both the Preventative Protocol and the Therapeutic Protocol. Reductions in PAI-1 levels were observed in mice treated with Compounds B, D, E, F, H, I, J and K in the Preventative Protocol, and all Compounds except F and J in the Therapeutic Protocol. ANOVA statistics for the comparison of levels revealed significant changes in the Preventative Protocol, with decrease due to Compounds B, D, E, F, H, I, J and L ranging from p ⁇ 0.02 to p ⁇ 0.001 . Statistical differences were observed for all Compounds except F and J in the Therapeutic Protocol and were typically p ⁇ 0.001 (FIGURE 7).
  • FIGURE 1 1 The results for Syndecan 1 (SDC1 ) are shown in FIGURE 1 1 . It was observed that high SDC1 levels occurred in mice treated with Compounds A and E in the Preventative Protocol, while the control mice for both the Preventative Protocol and the Therapeutic Protocol did not show notable elevations of SDC1 . No significant reductions in SDC1 levels were observed in mice treated with and Compounds in either the Preventative or Therapeutic Protocol (FIGURE 7)

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Abstract

L'invention concerne une composition destinée à traiter ou à prévenir une maladie, notamment une maladie vasculaire, y compris une composition choisie parmi les FORMULES I-VIII, des ligands, des analogues, un sel pharmaceutiquement acceptable, un solvate, un ester, un tautomère associés ou des combinaisons de ceux-ci. Une formulation médicamenteuse combinée destinée à traiter et à prévenir une maladie cardiovasculaire, y compris les compositions représentées par la FORMULE I, la FORMULE III et la FORMULE VI. L'invention concerne une méthode de traitement ou de prévention d'une maladie qui consiste à administrer à un sujet une quantité pharmaceutiquement efficace d'au moins une des compositions représentées par les FORMULES I-VIII, ou d'un ligand, d'un analogue, d'un sel pharmaceutiquement acceptable, d'un solvate, d'un ester, d'un tautomère associés ou de combinaisons de ceux-ci. L'invention concerne également des méthodes de traitement ou de prévention d'une maladie vasculaire, de l'arthrite, d'un cancer métastatique et du diabète.
PCT/US2016/016100 2015-02-03 2016-02-02 Composés destinés à prévenir et à traiter une maladie cardiovasculaire WO2016126662A1 (fr)

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US11143659B2 (en) 2015-01-27 2021-10-12 Arterez, Inc. Biomarkers of vascular disease
US11821905B2 (en) 2015-01-27 2023-11-21 Arterez, Inc. Biomarkers of vascular disease
CN107540605A (zh) * 2016-12-28 2018-01-05 李明霞 用于头发或头皮护理的胆碱酯类化合物
CN107540605B (zh) * 2016-12-28 2020-03-06 宁波见睿新材料有限公司 用于头发或头皮护理的胆碱酯类化合物
EP4034164A4 (fr) * 2019-09-27 2024-01-24 Arterez, Inc. Traitement médicamenteux et panel de biomarqueurs ciblant des maladies dues à l'ontologie multifactorielle de l'interruption de la glycocalyx
US11135239B1 (en) 2020-03-13 2021-10-05 Novartis Ag Pharmaceutical compositions of lipoic acid choline ester salts and methods of treatment using same
US11590158B2 (en) 2020-03-13 2023-02-28 Novartis Ag Pharmaceutical compositions of lipoic acid choline ester salts and methods of treatment using same

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