EP2424541A2 - Analogues de pyrone phosphorylés et phosphonés comme agents therapeutiques - Google Patents

Analogues de pyrone phosphorylés et phosphonés comme agents therapeutiques

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Publication number
EP2424541A2
EP2424541A2 EP10714412A EP10714412A EP2424541A2 EP 2424541 A2 EP2424541 A2 EP 2424541A2 EP 10714412 A EP10714412 A EP 10714412A EP 10714412 A EP10714412 A EP 10714412A EP 2424541 A2 EP2424541 A2 EP 2424541A2
Authority
EP
European Patent Office
Prior art keywords
phosphonated
pyrone analog
quercetin
fisetin
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP10714412A
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German (de)
English (en)
Inventor
May Dean-Ming Lee
Ving Lee
Wendye Robbins
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Limerick Biopharma Inc
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Limerick Biopharma Inc
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Publication date
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Publication of EP2424541A2 publication Critical patent/EP2424541A2/fr
Withdrawn legal-status Critical Current

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    • A61K31/66—Phosphorus compounds
    • A61K31/665—Phosphorus compounds having oxygen as a ring hetero atom, e.g. fosfomycin
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    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
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    • A61K31/66—Phosphorus compounds
    • A61K31/661—Phosphorus acids or esters thereof not having P—C bonds, e.g. fosfosal, dichlorvos, malathion or mevinphos
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    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/655—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms
    • C07F9/6552—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring
    • C07F9/65522—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having oxygen atoms, with or without sulfur, selenium, or tellurium atoms, as the only ring hetero atoms the oxygen atom being part of a six-membered ring condensed with carbocyclic rings or carbocyclic ring systems

Definitions

  • polyphenols such as flavonoids have been shown to have beneficial health effects
  • polyphenols can provide beneficial effects by lowering the side effects of co-administered therapeutic agents, in some cases acting as tissue transport protein modulators
  • blood tissue barrier (BTB) structures such as the blood-brain barrier (BBB), blood pancreas barrier, blood kidney barrier, and blood-placenta barrier
  • BBB blood-brain barrier
  • BBB blood-brain barrier
  • BB blood-brain barrier
  • blood pancreas barrier blood pancreas barrier
  • blood kidney barrier blood-placenta barrier
  • blood-placenta barrier function as an obstacle to isolate tissues from the systemic blood circulation
  • some pharmaceutical agents such as anesthetic and pharmaceutical agents, cross tissues selectively causing tissue specific toxicity or side-effects rather than a desired localized action
  • blood tissue barriers may be compromised by disease states and therapeutic treatments, causing barrier laxity and then permitting unwanted agents to cross the barrier and adversely affect tissue structures
  • co-adrrunistered therapeutic agents
  • Diabetes mellitus has become one of the most prevalent diseases in industrialized countries In the United States alone, about 23 6 million people (about 8% of the population) have diabetes with an additional 57 million people at ⁇ sk Because of such a large prevalence and impact upon the health and economy of a society, diabetes is a subject of intense interest by academics and pharmaceutical industry
  • Insulin is a hormone that is produced by beta cells of the islets of Langerhans in the pancreas, and functions to facilitate glucose uptake in the cells
  • beta cells are destroyed and rendered nonfunctional by autoimmune inflammation resulting in no insulin production T ⁇ ggers for the autoimmune response are not yet known, but it has been contemplated that viruses and environmental factors in genetically susceptible individuals play a factor
  • Type 2 diabetes is characterized by the onset of insulin resistance or reduced sensitivity in pe ⁇ pheral tissues in combination with impaired insulin secretion
  • the impaired insulin secretion results from progressive degeneration and dysfunction of pancreatic alpha and beta cells as well as a significant reduction in cell mass, and is typically associated with obese conditions
  • Obesity is now a world wide epidemic, and is one of the most se ⁇ ous cont ⁇ butors to increased morbidity and mortality
  • Obesity which is an excess of body fat relative to lean body mass, is a chronic disease
  • Obesity is also a multiple etiology problem
  • the prevalence of obesity has ⁇ sen significantly in the past decade in the United States and many other developed count ⁇ es (Fiegal et al, Int J Obesity 22 39-47 ( 1998), Mokdad et al, JAMA 282 1519- 1522 (1999))
  • Obesity is associated not only with a social stigma, but also with decreased life span and numerous medical problems, including adverse psychological development, stroke, hyperhpidemia, some cancers, type 2 diabetes, coronary heart disease, hypertension, numerous other major illnesses, and overall mortality from all causes (see, e g , Nishina, et al , Metab 43 554-558, 1994, Grundy and Barnett, Dis Mon 36 641-731 ( 1990), Rissanen, et al , British Medical Journal, 301 835-837 ( 1990), Must et al, JAMA 282 1523- 1529 ( 1999), Calle et al, N Engl J Med
  • the invention encompasses compositions comprising a phosphonated pyrone analog or a pharmaceutically or vete ⁇ nary acceptable salt, glycoside, ester, or prodrug thereof
  • the invention encompasses methods of treating an animal comp ⁇ sing administering to an animal in need of treatment, a composition comp ⁇ sing a phosphonated pyrone analog or a pharmaceutically or vete ⁇ nary acceptable salt, glycoside, ester, or prodrug thereof, and a pharmaceutically acceptable excipient
  • kits comprising (a) a therapeutic agent or a pharmaceutically or vete ⁇ nary acceptable salt, glycoside, ester, or prodrug thereof, and (b) a phosphonated pyrone analog or a pharmaceutically or vete ⁇ nary acceptable salt, glycoside, ester, or prodrug thereof
  • the invention encompasses methods of treating an animal comp ⁇ sing administe ⁇ ng to an animal in need of treatment, (a) a therapeutic agent or a pharmaceutically or vete ⁇ nary acceptable salt, glycoside, ester, or prodrug thereof, and (b) a phosphonated pyrone analog or a pharmaceutically or vete ⁇ nary acceptable salt, glycoside, ester, or prodrug thereof
  • the invention encompasses methods of maintaining cellular physiological conditions for cell survival, comp ⁇ sing adrruniste ⁇ ng to a subject an effective amount of a phosphonated pyrone analog that modulates activity of a cellular transporter
  • the invention encompasses methods of treating a disease, comp ⁇ sing administe ⁇ ng to a subject an effective amount of a phosphonated pyrone analog, wherein the phosphonated pyrone analog modulates activity of a cell surface transporter
  • the invention encompasses methods of modulating transport of a lipophilic molecule, the method comp ⁇ sing administe ⁇ ng an effective amount of a phosphonated pyrone analog to a subject, wherein the phosphonated pyrone analog modulates activity of a cellular transporter
  • the invention encompasses methods of modulating a lipid, cholesterol, triglyce ⁇ de, insulin or glucose level in a subject, the method comprising administe ⁇ ng an effective amount of a phosphonated pyrone analog to the subject, wherein the phosphonated pyrone analog modulates activity of a cellular transporter
  • the invention encompasses methods of assessing a cellular protective effect in a pancreatic islet cell, comprising i) selecting a patient for treatment based on one or more biomolecule levels in a sample compared to a control sample, ⁇ ) administe ⁇ ng an effective amount of a phosphonated pyrone analog to the patient, and in) monitoring said one or more biomolecule levels in the patient
  • the invention encompasses methods of treating pancreatic cell stress or injury comp ⁇ sing administe ⁇ ng to a subject an effective amount of at least one phosphonated pyrone analog, wherein at least one effect of stress or injury is improved in one or more cell types of the subject INCORPORATION BY REFERENCE
  • Figure 1 shows that pyrone analogs LIM-0705 and LIM-0741 have little impact on weight gain of ZDF rats over 6 weeks of daily treatment
  • FIG. 2 shows that pyrone analogs LIM-0705 (high dose) and LIM-0741 impact glucose levels in ZDF rats over 6 weeks of daily treatment
  • FIG. 3 shows that pyrone analogs LIM 0705 and LIM-0741 impact glucose levels in produces elevated insulin levels in ZDF rodents Bars from left to ⁇ ght at each day of measurement are as follows V/V, V/C, Rosy,
  • LIM-0705 high dose HD
  • LIM-0705 low dose LD
  • FIG. 4 shows that pyrone analogs LIM-0705 and LIM-0741 impact glycated hemoglobin levels (%
  • HbA Ic HbA Ic
  • Figure 5 shows that pyrone analogs LIM-0705 and LIM-0741 impact insulin levels in ZDF rats following 5 and 6 weeks of daily treatment
  • Figure 6 shows the effect of pyrone analogs LIM-0705 and LIM-0741 on cholesterol levels in ZDF rats over 6 weeks of daily treatment
  • Figure 7 illustrates cholesterol levels at days 0, 7 and 14
  • Figure 8 shows the effect of pyrone analogs LIM-0705 and LIM-0741 on triglyceride levels in ZDF rats over 6 weeks of daily treatment
  • Figure 9 shows the effect of pyrone analogs on triglyceride levels
  • Figure 10 shows that pyrone analogs LIM-0705 and LIM-0741 impact adiponectin levels in ZDF rats following 6 weeks of daily treatment
  • Figure 11 shows that pyrone analogs LIM-0705 and LIM-0741 impact glucagon levels in ZDF rats following 6 weeks of daily treatment
  • Figure 12 shows AST levels in ZDF rodents at 14 weeks of age
  • Figure 13 shows ALT levels in ZDF rodents at 14 weeks of age
  • Figure 14 shows that liver weight is not effected in response to LIM-0705 and LIM-0741 in ZDF rodents
  • Figure 15 shows that kjdney weight is not effected in response to LIM-0705 and LIM-0741 in ZDF rodents
  • Figure 16 shows that pyrone analogs LIM-0705 and LIM-0741 impact fat weight in ZDF rats following 6 weeks of daily treatment
  • Figure 17 shows the effect of pyrone analog LIM-0742 on glucose levels in aging ZDF rats du ⁇ ng 6 weeks of daily treatment
  • Figure 18 shows the effect of pyrone analog LIM 0742 on fad insulin levels in aging ZDF rats du ⁇ ng 6 weeks of daily treatment
  • Figure 19 shows the effect of pyrone analog LIM-0742 on circulating triglyceride levels in aging ZDF rats during 6 weeks of daily treatment
  • Figure 20 shows the effect of pyrone analog LIM-0742 on weight gain in ZDF rats du ⁇ ng 6 weeks of daily treatment
  • Figure 21 shows the effect of pyrone analog LIM 0742 on plasma glucose following oral glucose load
  • Figure 22 shows the effect of pyrone analog LlM 0742 on insulin production following oral glucose load
  • Figure 23 shows the effect of pyrone analog LIM 0742 on total plasma cholesterol du ⁇ ng 6 weeks of daily treatment
  • Figure 24 shows that pyrone analogs LIM-0705 and LIM-0741 have little impact on weight gain of ZDF rats over 2 weeks of daily treatment
  • Figure 25 shows the effect of pyrone analogs LIM-0705 and LIM-0741 on cholesterol levels in ZDF rats over 2 weeks of daily treatment
  • Figure 26 shows that pyrone analogs LIM-0705 (high dose) and LIM-0741 impact glucose levels in ZDF rats over 2 weeks of daily treatment
  • Figure 27 shows that phosphonated pyrone analogs compound 2 and compound 3 impact plasma glucose levels in ZDF rats over four weeks of daily treatment
  • Figure 28 shows that phosphonated pyrone analogs compound 2 and compound 3 impact plasma insulin levels in ZDF rats over four weeks of daily treatment
  • Figure 29 shows that phosphonated pyrone analogs compound 2 and compound 3 impact glycated hemoglobin levels (% HbA Ic levels) in ZDF rats following four weeks of daily treatment
  • Figure 30 shows that phosphonated pyrone analogs compound 2 and compound 3 impact t ⁇ glyce ⁇ de levels in ZDF rats
  • Figure 31 shows that phosphonated pyrone analogs compound 2 and compound 3 protect against hyperglycemia du ⁇ ng oral glucose tolerance test (OGTT) in ZDF rats following four weeks of daily treatment
  • OGTT oral glucose tolerance test
  • Figure 32 shows that phosphonated pyrone analog compound 3 raises insulin output in response to oral glucose tolerance test (OGTT) in ZDF rats following four weeks of daily treatment
  • OGTT oral glucose tolerance test
  • Figure 33 shows that phosphonated pyrone analogs compound 2 and compound 3 decrease pancreatic inflammation (by 60% and 35% inhibition respectively) in ZDF rats following four weeks of daily treatment
  • Figure 34 shows that phosphonated pyrone analogs compound 2 and compound 3 decrease pancreatic islet vacuolar degeneration (by 43% for both compounds) in ZDF rats following four weeks of daily treatment
  • Figure 35 shows that phosphonated pyrone analogs compound 2 and compound 3 decrease islet cell apoptosis in ZDF rats following four weeks of daily treatment
  • Figure 36 demonstrates that following four weeks of daily treatment, phosphonated pyrone analog compound 3 improves response to IP glucose load in diet-induced obese mice [0056]
  • Figure 37 demonstrates that less insulin output is required to lower plasma glucose in response to IP glucose load in compound 3-treaied diet-induced obese mice
  • Figure 38 demonstrates that following four weeks of daily treatment, phosphonated pyrone analog compound 3 enhances glucose uptake in diet-induced obese mice
  • Figure 39 demonstrates that following four weeks of daily treatment, phosphonated pyrone analog compound 3 reduces hepatic glucose output in diet-induced obese mice
  • Figure 40 demonstrates that following four weeks of daily treatment, phosphonated pyrone analog compound 3 reduces basal glucose in diet-induced obese mice
  • Figure 41 shows that phosphonated pyrone analog compound 1 reduces fed plasma glucose levels in ZDF rats over four weeks of daily treatment
  • Figure 42 shows that phosphonated pyrone analog compound 1 improves glucose tolerance in ZDF rats following four weeks of daily treatment
  • Figure 43 shows that phosphonated pyrone analog compound 1 maintains higher fed and fasting insulin level following four weeks of daily treatment
  • Figure 44 shows that phosphonated pyrone analog compound 1 reduces glycated hemoglobin levels (%
  • Figure 45 shows that effective doses of phosphonated pyrone analog compound 1 increases pancreatic insulin levels following four weeks of daily treatment
  • Figure 46 shows that phosphonated pyrone analog compound 1 does not increase terminal liver triglyceride following four weeks of daily treatment, contrary to Rosightazone
  • Figure 47 shows that phosphonated pyrone analog compound 1 reduces plasma glucose levels in cyclospo ⁇ n treated Wistar rats over two weeks of daily treatment
  • Figure 48 shows that phosphonated pyrone analog compound 1 improves glucose tolerance in cyclosporin treated Wistar rats following two weeks of daily treatment
  • Figure 49 shows that phosphonated pyrone analog compound 1 reduces cyclosporne induced islet cell injury in cyclospo ⁇ n treated Wistar rats following two weeks of daily treatment
  • Figure 50 shows that phosphonated pyrone analog compound 1 reduces cyclospo ⁇ ne induced islet cell apoptosis in cyclosporin treated Wistar rats following two weeks of daily treatment
  • Figure 51 shows that phosphonated pyrone analog compound 1 reduces plasma glucose levels in tacrolimus treated Wistar rats over two weeks of daily treatment
  • Figure 52 shows that phosphonated pyrone analog compound 1 improves glucose tolerance in tacrolimus treated Wistar rats following two weeks of daily treatment
  • Figure 53 shows that phosphonated pyrone analog compound 1 increases insulin level in tacrolimus treated
  • Wistar rats (during oral glucose tolerance test) following two weeks of daily treatment
  • Figure 54 shows that phosphonated pyrone analog compound 3 reduces plasma t ⁇ glyce ⁇ de levels in
  • Figure 55 shows that phosphonated pyrone analog compound 3 reduces liver t ⁇ glyce ⁇ de levels in
  • Figure 56 shows that phosphonated pyrone analog compound 3 reduces plasma glucose levels in db/db mice over 4 weeks of daily treatment
  • Figure 57 shows that phosphonated pyrone analog compound 3 reduces plasma t ⁇ glyce ⁇ de levels in db/db mice over 4 weeks of daily treatment
  • Figure 58 shows that phosphonated pyrone analog compound 3 reduces plasma cholesterol levels in db/db mice over 4 weeks of daily treatment
  • Figure 59 shows that phosphonated pyrone analog compound 3 reduces liver t ⁇ glyce ⁇ de levels in db/db mice over 4 weeks of daily treatment
  • Figure 60 shows that phosphonated pyrone analog compound 3 does not produce excessive body weight gain in db/db mice over 4 weeks of daily treatment
  • an "average” as used herein is preferably calculated in a set of normal subjects, this set being at least about 3 subjects, at least about 5 subjects, at least about 10 subjects, at least about 25 subjects, or at least about 50 subjects
  • the terms "effective amount” or “pharmaceutically effective amount” refer to a nontoxic but sufficient amount of the agent to provide the desired biological, therapeutic, and/or prophylactic result That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system
  • an "effective amount” for therapeutic uses is the amount of a pyrone analog as disclosed herein per se or a composition comp ⁇ sing the pyrone analog required to provide a therapeutically significant decrease in a disease
  • An approp ⁇ ate effective amount in any individual case may be determined by one of ordinary skill in the art using routine expenmentation
  • pharmaceutically acceptable or “pharmacologically acceptable” is meant a mate ⁇ al which is not biologically or otherwise undesirable, i e , the material may be administered to an individual without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained
  • treating and its grammatical equivalents as used herein include achieving a therapeutic benefit and/or a prophylactic benefit
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated Treating also refers to obtaining a desired pharmacologic and/or physiologic effect
  • the effect may be prophylactic in terms of completely or partially preventing a condition or disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a condition or disease and/or adverse affect attributable to the condition or disease
  • “Treatment” covers any treatment of a condition or disease in a mammal, particularly in a human, and includes (a) preventing the condition or disease from occurring in a subject which may be predisposed to the condition or disease but has not yet been diagnosed as having it, (b) inhibiting the condition or disease, such as, arresting its development, and (c) relieving, alleviating or ameliorating the condition or disease, such as, for example, causing regression of the condition or disease
  • co-administration encompass administration of two or more agents to a subject so that both agents and/or their metabolites are present in the animal at the same time
  • Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present
  • composition refers to a biologically active compound, optionally mixed with at least one pharmaceutically acceptable chemical component, such as, though not limited to earners, stabilizers, diluents, dispersing agents, suspending agents, thickening agents, and/or excipients [0089]
  • agent refers to relatively nontoxic chemical compounds or agents that facilitate the incorporation of the compound into cells or tissues
  • pharmaceutically acceptable excipient includes vehicles, adjuvants, or diluents or other auxiliary substances, such as those conventional in the art, which are readily available to the public
  • pharmaceutically acceptable auxiliary substances include pH adjusting and buffering agents, tonicity adjusting agents, stabilizers, wetting agents and the like
  • metabolite refers to a derivative of the compound which is formed when the compound is metabolized
  • active metabolite refers to a biologically active de ⁇ vative of the compound that is formed when the compound is metabolized
  • metabolized refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism Thus, enzymes may produce specific structural alterations to the compound Further information on metabolism may be obtained from The Pharmacological Basis of Therapeutics, 9th Edition, McGraw-Hill (1996)
  • unit dosage form refers to physically discrete units suitable as unitary dosages for human and animal subjects, each unit containing a predetermined quantity of API calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, earner or vehicle
  • the specifications for the novel unit dosage forms of the present compounds depend on the particular compound employed and the effect to be achieved, and the pharmacodynamics associated with each compound in the host [00
  • a "substantially pu ⁇ fied" compound in reference to the pyrone analogs or de ⁇ vatives thereof is one that is substantially free of mate ⁇ als that are not the pyrone analogs or de ⁇ vatives thereof
  • substantially free is meant at least about 50% free of non-pyrone analog mate ⁇ als, at least about 70%, at least about 80%, at least about 90% free or at least about 95% free of non-pyrone analog matenals I. PYRONE ANALOGS
  • pyrone analogs One class of compounds useful in the compositions and methods descnbed herein are pyrone analogs
  • the pyrone analog is phosphorylated or phosphonated
  • a phosphorylated or phosphonated pyrone analog may be converted in vivo to metabolites that have diffe ⁇ ng activities in the modulation of one or more cholesterol, glucose, lipid and/or triglyce ⁇ de transporters, and these metabolites are also encompassed by the compositions and methods descnbed herein [0099]
  • the phosphorylated pyrone analogs descnbed herein comprise polyphosphate de ⁇ vatives
  • Polyphosphate de ⁇ vatives are those in which more than one phosphate is connected in a linear chain
  • Suitable polyphosphate de ⁇ vatives include, for example, diphosphates (pyrophosphates), and t ⁇ phosphates
  • the phosphonated polyphenols of the invention comprise polyphosphonate derivatives
  • Polyphosphonate de ⁇ vatives are those in which more than one phosphonate is connected in a linear chain
  • Suitable polyphosphonate de ⁇ vatives include, for example, diphosphonates (pyrophosphonates), and
  • Alkylaryl refers to an (alkyl)aryl- radical, where alkyl and aryl are as defined herein
  • Alkyl refers to an (aryl)alkyl — radical where aryl and alkyl are as defined herein
  • Alkoxy refers to a (alkyl)O-radical, where alkyl is as described herein and contains 1 to 10 carbons (e g , C
  • Alkyl refers to a straight or branched hydrocarbon chain radical, having from one to ten carbon atoms (e g , C
  • an alkenyl group is optionally substituted by one or more substituents which independently are halo, cyano, nitro, oxo, thioxo, t ⁇ methylsilanyl, -OR a , -SR", -OC(O)-R 3 , -N(R a ) 2 , -C(O)R", -C(O)OR", -C(O)N(R a ) 2 , -N(R")C(O)OR a , -N(R")C(0)R", -N(R°)S(O),R a (where t is 1 or 2), -S(O) 1 OR" (where t is 1 or 2),-S(O),N(R a ) 2 (where t is 1 or 2), -PO 3 WY ( where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun) or- PO
  • Alkynyl refers to a straight or branched hydrocarbon chain radical group, containing at least one t ⁇ ple bond, having from two to ten carbon atoms (i e , C 2 -Ci 0 alkynyl) Whenever it appears herein, a numerical range such as “2 to 10" refers to each integer in the given range, e g , "2 to 10 carbon atoms” means that the alkynyl group may consist of 2 carbon atoms, 3 carbon atoms, etc , up to and including 10 carbon atoms In certain embodiments, an alkynyl comp ⁇ ses two to eight carbon atoms In other embodiments, an alkynyl has two to four carbon atoms The alkynyl is attached to the rest of the molecule by a single bond, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like Unless stated otherwise specifically
  • Amine refers to a -N(R a ) 2 radical group, where R" is independently hydrogen, alkyl, fluoroalkyl, carbocyclyl, carbocyclylalkyl, aryl, aralkyl, heterocyclyl, heterocyclylalkyl, heteroaryl or heteroarylalkyl Unless stated otherwise specifically in the specification, an amino group is optionally substituted by one or more substituents which independently are halo, cyano, nitro, oxo, thioxo, t ⁇ methylsilanyl, -OR", -SR", -OC(O)-R", -N(R") 2 , -C(O)R", -C(O)OR", -C(0)N(R") 2 , -N(R a )C(O)OR a , -N(R a )C(O)OR a , -N(R a )C(O)R", -N(R")
  • An "amide” refers to a chemical moiety with formula -C(O)NR a R b or -NR"C(0)R b , where R a or R b is independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ⁇ ng carbon) and heterocyclic (bonded through a ⁇ ng carbon)
  • An amide may be an amino acid or a peptide molecule attached to a compound of Formula I, thereby forming a prodrug Any amine or carboxyl side chain on the compounds desc ⁇ bed herein can be amidified
  • the procedures and specific groups to make such amides are known to those of skill in the art and can readily be found in reference sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 sup rd Ed , John Wiley & Sons, New York, N Y , 1999, which is incorporated herein by reference in its entirety
  • Aromatic or "aryl” refers to an aromatic radical with six to fourteen ⁇ ng carbon atoms (e g , C 6 -C 14 aromatic or C 6 -Cu aryl)
  • the term includes monocyclic or fused- ⁇ ng polycyclic (i e , ⁇ ngs which share adjacent pairs of ⁇ ng atoms) groups It has at least one ⁇ ng having a conjugated pi electron system Whenever it appears herein, a numerical range such as “6 to 14" refers to each integer in the given range, e g , "6 to 14 ⁇ ng atoms" means that the aryl group may consist of 6 ⁇ ng atoms, 7 ⁇ ng atoms, etc , up to and including 14 ⁇ ng atoms Unless stated otherwise specifically in the specification, an aryl moiety is optionally substituted by one or more substituents which are independently hydroxyl, carboxaldehyde, amine, C
  • Carbohydrate as used herein, includes, but not limited to, monosaccharides, disaccha ⁇ des, oligosaccharides, or polysaccharides
  • Monosaccha ⁇ de for example includes, but not limited to, aldot ⁇ oses such as glyceraldehyde, ketot ⁇ oses such as dihydroxyacetone, aldotetroses such as erythrose and threose, ketotetroses such as erythrulose, aldopentoses such as arabinose, lyxose, ⁇ bose and xylose, ketopentoses such as ⁇ bulose and xylulose, aldohexoses such as allose, altrose, galactose, glucose, gulose, idose, mannose and talose, ketohexoses such as fructose, psicose, sorbose and tagatose, heptoses such as manno
  • a compound of Formula I having a carbohydrate moiety can be referred to as the pyrone analog glycoside or the pyrone analog saccha ⁇ de
  • carbohydrate further encompasses the glucuronic as well as the glycosidic de ⁇ vative of compounds of Formula I Where the phosphorylated pyrone analog has no carbohydrate moiety, it can be referred to as the aglycone
  • the carbohydrate moiety is referred to as a glycosyl residue
  • a carbohydrate group is optionally substituted by one or more substituents which are independently halo, cyano, nitro, oxo, thioxo, tnmethylsilanyl, -OR", -SR a , -OC(O)-R ⁇ -N(R a ) 2 , -C(O)R", -C
  • Cycloalkyl or “carbocyclyl” refers to a monocyclic or polycyclic non-aromatic radical that contains 3 to 10 ⁇ ng carbon atoms (ie C 3 -Ci 0 cycloalkyl) It may be saturated or unsaturated Whenever it appears herein, a numerical range such as “3 to 10" refers to each integer in the given range, e g , "3 to 10 carbon atoms” means that the cycloalkyl group may consist of 3 carbon atoms, etc , up to and including 10 carbon atoms Illustrative examples of cycloalkyl groups include, but are not limited to the following moieties cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloseptyl, cyclooctyl, cyclononyl, cyclodecyl, norbornyl, and the like Unless stated otherwise specifically in the specification,
  • Ester refers to a chemical radical of formula -COOR, where R is selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ⁇ ng carbon) and heterocyclic (bonded through a ⁇ ng carbon) Any hydroxy, or carboxyl side chain on the compounds desc ⁇ bed herein can be este ⁇ fied
  • the procedures and specific groups to make such esters are known to those of skill in the art and can readily be found in reference 'sources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 sup rd Ed , John Wiley & Sons, New York, N Y , 1999, which is incorporated herein by reference in its entirety Unless stated otherwise specifically in the specification, an ester group is optionally substituted by one or more substituents which are independently halo, cyano, nitro, oxo, thioxo, trimelhylsilanyl, -OR", -SR",
  • Fluoroalkyl refers to an alkyl radical, as defined above, that is substituted by one or more fluoro radicals, for example, t ⁇ fluoromethyl, difluoromethyl, 2,2,2-t ⁇ fluoroethyl, l-fluoromethyl-2-fluoroethyl, and the like
  • the alkyl part of the fluoroalkyl radical may be optionally substituted as defined above for an alkyl group
  • Halo means fluoro, chloro, bromo or iodo
  • haloalkyl alkenyl
  • fluoroalkyl and fluoroalkoxy are included in
  • Heteroaryl or, alternatively, “heteroaromatic” refers to a 5- to 18-membered aryl group that includes one or more ⁇ ng heteroatoms selected from nitrogen, oxygen and sulfur, and which may be a monocyclic, bicyclic, tricyclic or tetracyclic fused ring system Whenever it appears herein, a nume ⁇ cal range such as “5 to 18" refers to each integer in the given range, e g , "5 to 18 ⁇ ng atoms” means that the heteroaryl group may consist of 5 ⁇ ng atoms, 6 ⁇ ng atoms, etc , up to and including 18 ⁇ ng atoms
  • An "N-containing heteroaromatic” or “N-containing heteroaryl” moiety refers to an aromatic group in which at least one of the skeletal atoms of the ⁇ ng is a nitrogen atom
  • the heteroatom(s) in the heteroaryl radical is optionally oxidized One or more nitrogen atoms, if present,
  • a heteroaryl moiety is optionally substituted by one or more substituents which are independently hydroxyl, carboxaldehyde, amine, Ci-C
  • Heterocyclyl refers to a stable 3- to 18-membered non-aromatic ⁇ ng radical that comprises one to six heteroatoms selected from nitrogen, oxygen and sulfur Whenever it appears herein, a numerical range such as “3 to 18" refers to each integer in the given range, e g , "3 to 18 ⁇ ng atoms” means that the heteroaryl group may consist of 3 ⁇ ng atoms, 4 ⁇ ng atoms, etc , up to and including 18 ⁇ ng atoms In some embodiments, it is a C 5 -Ci 0 heterocyclyl In some embodiments, it is a C 4 -C] 0 heterocyclyl In some embodiments, it is a C 3 -Ci 0 heterocyclyl Unless stated otherwise specifically in the specification, the heterocyclyl radical is a monocyclic, bicyclic, t ⁇ cyclic or tetracyclic ⁇ ng system, which may include fused or
  • Mercapto refers to a (alkyl)S- or (H)S- radical
  • Phosphorylated compound refers to compounds comprising at least one phosphate group
  • a phosphate group includes but not limited to the groups -OCH 2 OPO 3 WY (also known as - OCH 2 PO 4 WY) , or -OCH 2 OPO 3 Z (also known as -OCH 2 PO 4 Z), -OPO 3 WY, or -OPO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, and wherein Z is a multivalent cation
  • Phosphorylated compounds include compounds having a phosphate group on polyphenol, hydroxylated or polyhdroxylated aromatic compound, or phosphorylated pyrone analog
  • a phosphorylated compound would include a compound with an inositol phosphate group
  • Examples of phosphorylated compounds are, but in no way limited to, phosphorylated compounds are, but in no way limited to, phosphorylated
  • Phosphonated compound or “phosphonate” "refers to compounds comprising at least one phosphonate group
  • a phosphonate group includes the groups -PO 3 WY, -OCH 2 PO 3 WY, -OCH 2 PO 3 Z, -OLPO 3 WY, -OLPO 3 Z or - PO 3 Z, wherein the group is attached to a carbon atom, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, L is methyl, ethyl, alkyl or a carbohydate and wherein Z is a multivalent cation
  • Phosphonated compounds include compounds having a phosphonate group on polyphenol, polyhdroxylated aromatic compund, or flavonoid
  • a phosphonated compound would include a compound with an inositol phosphonate group Examples of phosphonated compounds are, but in no way limited to,
  • Prodrug refers to a derivative of an active compound (drug) that undergoes a transformation under the conditions of use, such as within the body, to release an active drug or an active metabolite thereof
  • Prodrugs are frequently, but not necessa ⁇ ly, pharmacologically inactive until converted into the active drug or an active metabolite thereof
  • Prodrugs are typically obtained by masking one or more functional groups in the drug believed to be in part required for activity with a prodrug group to form a prodrug moiety which undergoes a transformation, such as cleavage, under the specified conditions of use to release the functional group, and hence the active drug
  • the cleavage of the prodrug moiety may proceed spontaneously, such as by way of a hydrolysis reaction, or it may be catalyzed or induced by another agent, such as by an enzyme, by light, by acid, or by a change of or exposure to a
  • a wide va ⁇ ety of prodrug groups, as well as the resultant prodrug moieties, suitable for masking functional groups in active compounds to yield prodrugs are well-known in the art
  • a hydroxyl functional group may be masked as a sulfonate, ester or carbonate prodrug moiety, which may be hydrolyzed in vitro to provide the hydroxyl group
  • An amino functional group may be masked as an amide, imine, or sulfenyl promoiety, which may be hydrolyzed in vivo to provide the amino group
  • a carboxyl group may be masked as an ester (including silyl esters and thioesters), amide or hydrazide prodrug moiety, which may be hydrolyzed in vivo to provide the carboxyl group
  • ester including silyl esters and thioesters
  • amide or hydrazide prodrug moiety which may be hydrolyzed in vivo to provide the carboxy
  • Substituted means that the referenced group may be substituted with one or more additional group(s) individually and independently selected from acyl, alkyl, alkylaryl, cycloalkyl, aralkyl, aryl, carbohydrate, heteroaryl, heterocyclic, hydroxy, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, ester, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, phosphate, silyl, sulfinyl, sulfonyl, sulfonamidyl, sulfoxyl, sulfonate, and amino, including mono- and di-substituted amino groups, and the protected denvatives thereof
  • the subsituents themselves may be substituted, for example
  • methylphosphonate and “methyl phosphonic acid” are used interchangeably herein to refer to the group “-CH 2 -P(O)(OH) 2 "
  • the compounds presented herein may possess one or more crura! centers and each center may exist in the R or S configuration
  • the compounds presented herein include all diastereome ⁇ c, enantiomeric, and epime ⁇ c forms as well as the appropriate mixtures thereof Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns
  • the methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula I, as well as active metabolites of these compounds having the same type of activity
  • the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like
  • pharmaceutically acceptable solvents such as water, ethanol, and the like
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein
  • a pyrone analog of Formula I and its pharmaceutically/vete ⁇ na ⁇ ly acceptable salt or esters is provided herein
  • X is O, S, or NR' wherein R' is hydrogen, C,-C 10 alkyl, C 2 -Ci 0 alkynyl, C 2 -C] 0 alkenyl, Ci-Ci 0 aliphatic acyl, C 6 -Ci 0 aromatic acyl, Ce-Ci 0 aralkyl acyl, C 6 -Ci 0 alkylary I acyl, aryl, C 3 -Ci 0 heterocyclyl, heteroaryl, or C 3 -Ci 0 cycloalkyl,
  • Ri, and R 2 are independently hydrogen, hydroxyl, Ci-Ci O alkyl, C 2 -Ci 0 alkynyl, C 2 -Ci 0 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-Ci 0 aliphatic acyl, C 6 -Ci 0 aromatic acyl, C 6 -Ci 0 aralkyl acyl, C 6 -Ci 0 alkylaryl acyl, alkoxy, amine, aryl, C 4 -Ci 0 heterocyclyl, heteroaryl, C 3 -C
  • R 3 and R 4 are independently hydrogen, hydroxyl, Ci-C
  • W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, and Z is a multivalent cation, and
  • L is methyl, ethyl, alkyl or a carbohydate
  • W is potassium In va ⁇ ous embodiments
  • W is sodium In various embodiments
  • W is lithium In va ⁇ ous embodiments
  • Y is potassium In va ⁇ ous embodiments
  • Y is sodium In va ⁇ ous embodiments
  • Y is lithium
  • Z is calcium In va ⁇ ous embodiments, Z is magnesium In va ⁇ ous embodiments, Z is iron
  • L is methyl or ethyl
  • the 2,3 bond may be saturated or unsaturated in the compounds of Formula I
  • the pyrone analog of Formula I is of Formula II ,
  • Xi, X 2 , X 3 , and X 4 are independently CR 5 , O, S, or N,
  • R 5 is independently hydrogen, hydroxy!, carboxaldehyde, amino, C
  • R ]6 is hydrogen, C
  • Rn is hydrogen, hydroxy, carboxaldehyde, amine, Ci-C
  • R ⁇ 8 and R 2 are independently hydrogen, hydroxyl, carboxaldehyde, amine, Ci-Ci 0 alky!, C 2 -C 10 alkynyl, C 2 -Ci 0 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Cj -C
  • R 19 Is hydrogen, Ci-Ci 0 alky], C 2 -Ci 0 alkynyl, C 2 -Ci 0 alkenyl, carbohydrate, C]-Ci 0 aliphatic acyl, C 6 -C, 0 aromatic acyl, C 6 -Ci 0 aralkyl acyl, C 6 -Ci 0 alkylaryl acyl, aryl, C 3 -Ci 0 heterocyclyl, heteroaryl, optionally substituted CrCocycloalkyl, -CH 2 OPO 3 WY, -CH 2 OPO 3 Z, -PO 3 WY, -PO 3 Z-OLPO 3 WY, or -OLPO 3 Z, s is an integer of O, 1 , 2, or 3, and n is an integer of O, 1 , 2, 3, or 4
  • W and Y are independently potassium, sodium, or lithium
  • Z is calcium, magnesium or iron
  • the pyrone analog is of Formulae III, IV, V, or VI as illustrated in Scheme 1
  • R 6 , R 7 , R 8 , and R 9 are independently hydrogen, hydroxyl, carboxaldehyde, amino, C 1 -C 10 alky], C 2 -C 10 alkynyl, C 2 -C 10 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen]
  • the pyrone analog of Formula III is of Formula VIl:
  • the pyrone analog of Formula III is of Formula IX
  • R 6 , R 7 , R 8 , and R 9 are independently hydrogen, carboxaldehyde, amino, CpCio alkyl, C 2 -Cio alkynyl, C 2 - C
  • none of R 6 -R 9 is OH [00181] In this
  • R 2 , Ri 6 , Ris and Ri ⁇ are as defined in Formula II and R 6 , R 7 and R 9 are as defined in Formula Hl
  • compounds of the following Formulae VlII-A, Vi ⁇ -B, and VlII-C are useful in the embodiments desc ⁇ bed herein, where R c and R d are independently hydrogen,-CH 2 OPO 3 WY, -CH 2 OPO 3 Z, - PO 3 WY, -PO 3 Z, -OLPO 3 WY, or -OLPO 3 Z, where W and Y are hydrogen, methyl, ethyl, alkyl, carbohydrate, lithium, sodium or potassiun, Z is calcium, magnesium or iron, and L is methyl, ethyl, alkyl or a carbohydate, and wherein at least one of the R 0 or R d is a phosphate or phosphonate
  • R c is -PO 3 WY and R d is hydrogen In some embodiments, R c is -PO 3 WY and R d is -PO 3 WY In some embodiments, R c is a mixture of hydrogen and -PO 3 WY and R d is -PO 3 WY In some embodiments, R c is hydrogen and R d is a mixture of hydrogen and -PO 3 WY In some embodiments, R c is -PO 3 Z and R d is hydrogen In some embodiments, R c is -PO 3 Z and R d is -PO 3 Z In some embodiments, R c is a mixture of hydrogen and -PO 3 Z and R d is -PO 3 Z In some embodiments, R c is hydrogen and R d is a mixture of hydrogen and -PO 3 Z In some embodiments, R c is hydrogen and R d is a mixture of hydrogen and -PO 3 Z In some embodiments, R c is hydrogen and R d is a mixture of hydrogen and -PO 3 Z In
  • Rc and Rd are hydrogen
  • R c is -LPO 3 WY and R d is hydrogen
  • R c is a mixture of hydrogen and -LPO 3 WY and R d is -LPO 3 WY
  • R 0 is hydrogen and R d is a mixture of hydrogen and
  • Formula XIV wherein R 18 R
  • the pyrone analog of Formula III is of Formula XV
  • R 20 is hydrogen, C r C
  • W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, Z is a multivalent cation, and L is methyl, ethyl, alkyl or a carbohydate
  • the pyrone analog of Formula III is of Formula XVII
  • R 20 is hydrogen, C r C
  • the pyrone analog of Formula III is of Formula XVlU
  • n, Ri 8 and R 19 are as defined in Formula II, wherein R 22 is independently hydrogen, hydroxyl, carboxaldehyde, amine, Ci-Ci 0 alkyl, C 2 -Ci 0 alkynyl, C 2 - C
  • n, R 18 and R 19 are as defined in Formula U, wherein R 22 is independently hydrogen, hydroxyl, carboxaldehyde, amine, Ci-Ci 0 alkyl, C 2 -Ci 0 alkynyl, C 2 - Cio alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, C, -Ci 0 aliphatic acyl, C 6 -Ci 0 aromatic acyl, C 6 -Ci 0 aralkyl acyl, C 6 -Ci 0 alkylaryl acyl, alkoxy, alkyl, phosphate, aryl, heteroaryl, heterocyclic, C 3 -C
  • the pyrone analog of Formula III is of Formula XXI
  • R 20 is hydrogen, Ci-C
  • the pyrone analog of Formula Hl is of Formula XXII
  • R 23 is independently hydrogen, C
  • the pyrone analog of Formula III is of Formula XXIII
  • R 20 is hydrogen, Ci-C [O alkyl, C 2 -Ci 0 alkynyl, C 2 -Ci 0 alkenyl, carbohydrate, Ci-Ci 0 aliphatic acyl, C 6 -Ci 0 aromatic acyl, C 6 -Ci 0 aralkyl acyl, C 6 -Ci 0 alkylaryl acyl, aryl, C 3 -Ci 0 heterocyclyl, heteroaryl, optionally substituted C 3 -Ci 0 cycloalkyl, -PO 3 WY, -CH 2 OPO 3 WY, -CH 2 OPO 3 Z, -PO 3 Z, -LPO 3 WY, or -LPO 3 Z,
  • Het is a 3 to 10 membered optionally substituted monocyclic or bicyclic heteroaromatic or heterocyclic ⁇ ng system containing 1 , 2, 3, 4, or 5 heteroatoms selected from the group of O, S, and N, with the proviso that no two adjacent ⁇ ng atoms are O or S, wherein the ⁇ ng system is unsaturated, partially unsaturated or saturated, wherein any number of the ⁇ ng atoms have substituents as valency permits which are hydrogen, hydroxyl, carboxyaldehyde, alkylcarboxaldehyde, imino, C 1 -C 10 alkyl, C 2 -Ci 0 alkynyl, C 2 -Ci 0 alkenyl, carboxyl, carbohydrate, acyloxy, nitro, halogen, Ci-Ci O ahphatic acyl, C 5 -Ci 0 aromatic acyl, C 6 -C
  • W and Y are independently hydrogen, methyl, ethyl, alkyl, carbohydrate, or a cation, Z is a multivalent cation, and L is methyl, ethyl, alkyl or a carbohydate [00197]
  • Het is one of the following formulae
  • R, 8 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C
  • the pyrone analog of Formula II is of Formula IV
  • Rio and Rn are independently hydrogen, hydroxyl, carboxaldehyde, amino, C r C
  • the pyrone analog of Formula IV is
  • Formula XXIV Formula XXV wherein R 18 , Ri 9 , and n are as defined in Formula II [00200]
  • the pyrone analog of Formula IV is of Formula XXVl or Formula XXVII
  • R 16 is hydrogen, -CH 2 OPO 3 WY, -CH 2 OPO 3 Z, -PO 3 WY, -PO 3 Z, -OLPO 3 WY, or -OLPO 3 Z, wherein Ri 8 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C
  • n is an integer of O, 1 , 2, 3, or 4
  • the pyrone analog of Formula IV is of Formula XXVIlI
  • Ri 6 is hydrogen, -CH 2 OPO 3 WY, -CH 2 OPO 3 Z, -PO 3 WY or -PO 3 Z , wherein R ! 8 is independently hydrogen, hydroxyl, carboxaldehyde, amine, C
  • the pyrone analog of Formula II is of Formula V
  • R ⁇ 2 and R !3 are independently hydrogen, hydroxyl, carboxaldehyde, amino, Ci-Ci 0 alkyl, C 2 -Ci 0 alkynyl, C 2 -Ci 0 alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, Ci-Ci O aliphatic acyl, C 6 -Ci 0 aromatic acyl, C 6 - C
  • the pyrone analog of Formula V is of Formula XXIX or Formula XXX wherein the compound comprises at least one phosphate group Formula XXIX Formula XXX wherein R 2 , R 5 , R
  • Formula XXXI wherein R 2 R !8 and n are as defined for Formula Il and R 12 and R n are as defined for Formula V, and R 16 is hydrogen, -CH 2 OPO 3 WY, -CH 2 OPO 3 Z, -PO 3 WY, -PO 3 Z, -LPO 3 WY, or -LPO 3 Z [00205]
  • the pyrone analog of Formula 11 is of Formula VI
  • R H and Ri 5 are independently hydrogen, hydroxyl, carboxaldehyde, amino, CpC 1O alkyl, C 2 -Ci 0 alkynyl, C 2 -C 1O alkenyl, carboxyl, carbohydrate, ester, acyloxy, nitro, halogen, CpC 1O aliphatic acyl, C 6 -C 10 aromatic acyl, C 6 - C lo aralkyl acyl, C 6 -C 10 alkylaryl acyl, alkoxy, amine, aryl, C 3 -C 10 heterocyclyl, heteroaryl, C 3 -C 10 cycloalkyl, - OCH 2 OPO 3 WY, -OCH 2 OPO 3 Z, -OPO 3 WY, -OPO 3 Z, -OLPO 3 WY, or -OLPO 3 Z [00206]
  • the pyrone analog of Formula VI is of Formula XXXIl or Formula XXX
  • Formula XXXII Formula XXIII wherein R 2 , R 5 , Ri 8 , and n are as defined for Formula Il and R 14 and R 15 are as defined for Formula VI, and R 16 is hydrogen, -CH 2 OPO 3 WY, -CH 2 OPO 3 Z, -PO 3 WY, -PO 3 Z, -LPO 3 WY, or -LPO 3 Z [00207]
  • the pyrone analog of Formula VI is of Formula XXXIV
  • Formula XXXIV wherein R 2 , R
  • a useful class of pyrone analogs is the flavonoids Flavonoids, the most abundant polyphenols in the diet, can be classified into subgroups based on differences in their chemical structures
  • the basic flavonoid structure is shown below as Formula XXXV
  • Compounds useful in the invention include phosphorylated compounds of the basic flavonoid structure, also shown below as Formula XXXV, and its pharmaceutically acceptable salts, esters, prodrugs, analogs, isomers, stereoisomers or tautomers thereof
  • Formula XXXV wherein the 2,3 bond may be saturated or unsaturated, and wherein R 24 , R25, R 26 , R 2 7, R 28 , R29. R 3 O. R31. R32. and R 33 can be independently selected from the group consisting of hydrogen, halogen, hydroxyl, amine, thiol, C 1 - Cio alkyl, C 2 -Ci 0 alkynyl, C 2 -Ci 0 alkenyl, aryl, heteroaryl, C 3 -Ci 0 cycloalkyl, heterocycloalkyl, C 1 -Ci 0 aliphatic acyl, C 6 -C 10 aromatic acyl, t ⁇ alkylsilyl, ether, carbohydrate, -OPO 3 WY, -OPO 3 Z, -OLPO 3 WY, and -OLPO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbo
  • a flavonoid is utilized where the molecule is planar In some embodiments, a flavonoid is utilized where the 2,3 bond is unsaturated In some embodiments, a flavonoid is utilized where the 3- position is hydroxylated, phosphorylated, or phosphonated In some embodiments, a flavonoid is utilized where the 2-3 bond is unsaturated and the 3-position is hydroxylated, phosphorylated, or phosphonated (e g , flavonols) [00210] In some embodiments, a phosphorylated flavonoid is utilized where the molecule is planar In some embodiments, a phosphorylated flavonoid is utilized where the 2,3 bond is unsaturated In some embodiments, a phosphorylated flavonoid is utilized where the 3-position is hydroxylated or phosphorylated In some embodiments, a phosphorylated flavonoid is utilized where the 2-3 bond is unsaturated and the 3-position is hydroxylated or phospho
  • Flavonoids include, but are not limited to, quercetin, isoquercetin, fiavone, chrysm, apigenin, rhoifolin, diosmin, galangin, fisetin, mo ⁇ n, rutin, kaempferol, my ⁇ cetin, taxifohn, na ⁇ ngenin, na ⁇ ngin, hesperetin, hespe ⁇ din, chalcone, phloretin, phlo ⁇ zdin, gemstein, biochanin A, catechin, epicatechin, and a mixture (combination) thereof
  • one or more flavonoids utilized in the methods desc ⁇ bed herein include, but are not limited to, apigenin, rhoifolin, galangin, fisetin, monn, rutin, kaempferol, my ⁇ cetin, na ⁇ ngenin, hesperetin, phloretin, gemstein
  • Phosphorylated flavonoids include, but are not limited to, phosphorylated quercetin, phosphorylated isoquercetin, phosphorylated fisetin, phosphorylated fiavone, phosphorylated chrysin, phosphorylated apigenin, phosphorylated rhoifohn, phosphorylated diosmin, phosphorylated galangin, phosphorylated mo ⁇ n, phosphorylated rutin, phosphorylated kaempferol, phosphorylated my ⁇ cetin, phosphorylated taxifohn, phosphorylated na ⁇ ngenin, phosphorylated na ⁇ ngin, phosphorylated hesperetin, phosphorylated hespe ⁇ din, phosphorylated chalcone, phosphorylated phloretin, phosphorylated phlo ⁇ zdin,
  • Phosphonated flavonoids include, but are not limited to, phosphonated quercetin, phosphonated isoquercetin, phosphonated fisetin, phosphonated fiavone, phosphonated chrysin, phosphonated apigenin, phosphonated rhoifolin, phosphonated diosmin, phosphonated galangin, phosphonated mo ⁇ n, phosphonated rutin, phosphonated kaempferol, phosphonated my ⁇ cetin, phosphonated taxifohn, phosphonated na ⁇ ngenin, phosphonated na ⁇ ngin, phosphonated hesperetin, phosphonated hespe ⁇ din, phosphonated chalcone, phosphonated phloretin, phosphonated phlo ⁇ zdin, phosphonated quercetin, phosphonated isoquercetin, phosphonated fisetin, phosphonated
  • a flavonol is utilized in the methods desc ⁇ bed herein
  • the flavonol is selected from the group consisting of quercetin, fisetin, monn, rutin, my ⁇ cetin, galangin, and kaempferol, and combinations thereof
  • the flavonol is selected from the group consisting of quercetin, fisetin, galangin, and kaempferol, and combinations thereof
  • the flavonol is quercetin or a substituted analog thereof
  • the flavonol is fisetin or a substituted analog thereof
  • the flavonol is galangin or a substituted analog thereof
  • the flavonol is kaempferol or a substituted analog thereof
  • a compound of Formula I to XXXV above contains at least one phosphate group In other embodiments, a compound of Formula 1 to XXXV above contains at least one phosphonate group
  • a phosphorylated flavonol is utilized in the methods desc ⁇ bed herein
  • the phosphorylated flavonol is selected from the group consisting of phosphorylated quercetin, phosphorylated fisetin, phosphorylated monn, phosphorylated rutin, phosphorylated my ⁇ cetin, phosphorylated galangin, phosphorylated kaempferol, and combinations thereof
  • the phosphorylated flavonol is selected from the group consisting of phosphorylated quercetin, phosphorylated fisetin, phosphorylated galangin, and phosphorylated kaempferol, and combinations thereof
  • the phosphorylated flavonol is phosphorylated galangin or a phosphorylated galangin de ⁇ vative
  • the phosphorylated flavonol is phosphorylated kaempferol or a phosphorylated kaempferol de ⁇ vative
  • R 31 . R 32 . and R 33 are independently selected from the group of hydrogen, hydroxyl, -OPO 3 WY, or - OPO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, Z is a multivalent cation, and wherein at least one of the R24, R 25 , R2 6 . R271 R28. ⁇ 29, R 30 .
  • R 3 2. or R33 is - OPO 3 WY, or -OPO 3 Z
  • the phosphorylated pyrone analog can have the structure shown below as Formula XXXVI and its pharmaceutically acceptable salts, esters, prodrugs, analogs, isomers, stereoisomers or tautomers thereof
  • R 26 , R 28 , R 29 . ⁇ 32 , and R 33 can be independently selected from the group consisting of hydrogen, C
  • Useful phosphorylated pyrone analogs of the present invention are phosphorylated pyrone analogs of the structure of Formula XXXVII or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • the phosphorylated pyrone analog can comp ⁇ se a cyclic phosphate
  • the invention is a composition comprising a compound of Formula XXXVIIl or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • R 34 , R 35 , and R 36 are independently selected from the group of hydrogen, -PO 3 WY, and -PO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, and Z is a multivalent cation, and wherein R 39 is selected from the group of hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation
  • a useful phosphorylated pyrone analog comprises a compound of Formula XXXIX, XXXIXa, or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • Formula XXXIX Formula XXIXa wherein R 36 , R 37 and R 38 are independently selected from the group consisting of hydrogen, -PO 3 WY, and -PO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, and Z is a multivalent cation, and wherein at least one of the R 36 , R 37 or R 38 is -PO 3 WY or -PO 3 Z [00224]
  • Some Examples of phosphorylated pyrone analogs are quercetin-3'-O-phosphate and quercetin-4'-O- phosphate
  • Another useful phosphorylated flavonol is phosphorylated fisetin Fisetin may be used to illustrate compositions, formulations and methods descnbed herein However, it is understood that the discussion of fisetin applies equally to other phosphorylated pyrone analogs, flavonols, and pyrone analogs described herein,
  • Useful phosphorylated pyrone analogs of the present invention are phosphorylated pyrone analogs of the structur e O f Formula XXXX or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • the phosphorylated pyrone analog can comp ⁇ se a cyclic phosphate
  • the invention is a composition comp ⁇ sing a compound of Formula XXXXI or its pharmaceutically or vetenna ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • R 34 and R 36 are independently selected from the group of hydrogen, -PO 3 WY, and -PO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, and Z is a multivalent cation, and wherein R 39 is selected from the group of hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation
  • a useful phosphorylated pyrone analog comprises a compound of Formula XXXXII, or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • R 36 , R 37 and R 38 are independently selected from the group consisting of hydrogen, -PO 3 WY, and -POiZ, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, and Z is a multivalent cation, and wherein at least one of the R 36 , R 37 , or R 38 is -PO 3 WY, or -PO 3 Z [00228]
  • Some Examples of phosphorylated pyrone analogs are fisetin-3'-O-phosphate, fisetin-4'-O-phosphate, or fisetin-3-O-phosphate
  • the level of purity of the compound can affect its performance
  • the invention comp ⁇ ses quercetin-3'-O-phosphate at a purity of between about 90% and about 99 999%, in some embodiments at a pu ⁇ ty of between about 95% and about 99 99%, in some embodiments at a purity of between about 98% and about 99 99%, in some embodiments at a purity of between about 99% and about 99 9%, in some embodiments at a pu ⁇ ty of between about 99 5% and about 99 9%, and in some embodiments at a purity of between about 99 8% and about 99 9%
  • the invention comp ⁇ ses quercetin-3'-O-phosphate at a pu ⁇ ty greater than about 90%, 95%, 96%, 97%, 98% 98 5%, 99%, 99 5%, 99 8%, 99 9%, 99 99%, 99 999% or greater [00230]
  • the level of pu ⁇ ty of the compound can affect its performance
  • the level of pu ⁇ ty of the compound can affect its performance
  • the level of pu ⁇ ty of the compound can affect its performance
  • the invention comp ⁇ ses fisetin-3' -O-phosphate at a pu ⁇ ty of between about 90% and about 99 999%, in some embodiments at a pu ⁇ ty of between about 95% and about 99 99%, in some embodiments at a purity of between about 98% and about 99 99%, in some embodiments at a purity of between about 99% and about 99 9%, in some embodiments at a pu ⁇ ty of between about 99 5% and about 99 9%, and in some embodiments at a pu ⁇ ty of between about 99 8% and about 99 9%
  • the invention comp ⁇ ses fisetin-3'-O-phosphate at a pu ⁇ ty greater than about 90%, 95%, 96%, 97%, 98% 98 5%, 99%, 99 5%, 99 8%, 99 9%, 99 99%, 99 999% or greater [00233]
  • the level of pu ⁇ ty of the compound can affect its performance
  • the invention comp ⁇ ses fisetin
  • the invention utilizes a phosphonated flavonol
  • the phosphonated flavonol is selected from the group consisting of phosphonated quercetin, phosphonated fisetin, phosphonated mo ⁇ n, phosphonated rutin, phosphonated my ⁇ cetm, phosphonated galangin, phosphonated and phosphonated kaempherol, and a combination thereof
  • the phosphonated flavonol is selected from the group consisting of phosphonated quercetin, phosphonated fisetin, phosphonated 5,7-dideoxyquercetin, phosphonated galangin, and phosphonated kaempherol, and a combination thereof
  • the phosphonated flavonol is phosphonated quercetin
  • the phosphonated flavonol is phosphonated galangin
  • the phosphonated pyrone analog comprises a compound with the structure of
  • Formula XXXV its pharmaceutically or vetenna ⁇ ly acceptable salts, esters, or prodrugs wherein R 24 , R 25 . R 26 . R 27 .
  • R 31 . R 32 . and R 33 are independently selected from the group of hydrogen, halogen, hydroxyl, -
  • OLPO 3 WY, or -OLPO 3 Z wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, L is methyl, ethyl, alkyl or a carbohydate, Z is a multivalent cation, and wherein at least one of R 24 , R 25 , R 26 , R 27 , R 28 , R 29 , R 30 .
  • R 31 . R 32 . and R 33 is - OLPO 3 WY, or -OLPO 3 Z
  • the phosphonated pyrone analog can have the structure shown below as Formula
  • R 26 , R 28 - R 29 , R 32 . and R 33 can be independently selected from the group consisting of hydrogen, C
  • a useful phosphonated flavonol is phosphonated quercetin Quercetin may be used to illustrate formulations and methods useful in the invention, however, it is understood that the discussion of quercetin applies equally to other phosphorylated pyrone analogs, flavonols, and pyrone analogs useful in the invention, e g , kaempferol and galangin
  • the basic structure of quercetin is the structure of Formula XXXVII where R 34 -R 3S are hydrogen
  • This form of quercetin can also be referred to as quercetin aglycone
  • quercetin can also refer to glycosides of quercetin, wherein one or more of the R 34 -R 38 comp ⁇ se a carbohydrate
  • Useful phosphonated pyrone analogs of the present invention are phosphonated pyrone analogs of the structure of Formula XXXVU-i or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • R 14 , R 35 , R 36 , R 17 , and R 38 are independently selected from the group of hydrogen, -LPO 3 WY and ⁇ LPO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, L is methyl, ethyl, alkyl or a carbohydate, and Z is a multivalent cation, and wherein at least one of the R 34 - R 38 is -LPO 3 WY or -LPO 3 Z
  • the phosphonated pyrone analog can comprise a cyclic phosphonate
  • the invention is a composition comprising a compound of Formula XXXVIlla-i or Formula XXXVIlIb-i, its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • R 34 , R 35 , and R 36 are each independently selected from the group of hydrogen, -LPO 3 WY, and ⁇ LPO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, L is alkyl, L is methyl, ethyl, alkyl or a carbohydate, and Z is a multivalent cation, and wherein R 39 is selected from the group of hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation
  • a useful phosphonated pyrone analog comprises a compound of Formula XXXIX-i, XXXIXa-i, or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • LPO 3 WY 1 and -LPO 3 Z wherein W and Y are independently selected from hydrogen, methyl, ethyl, alky], carbohydrate, and a cation, L is methyl, ethyl, alkyl or a carbohydate, and Z is a multivalent cation, and wherein at least one of the R 36 , R 37 or R 38 is -LPO 3 WY or -LPO 3 Z
  • the compounds quercetin-3'- O-methylphosphonate, quercet ⁇ n-4'- O-methylphosphonate, or quercetin-3- O-methylphosphonate can be useful in the invention [00247]
  • Another useful phosphonated flavonol is phosphonated fisetin Fisetin may be used to illustrate compositions, formulations and methods desc ⁇ bed herein However, it is understood that the discussion of fisetin applies equally to other phosphorylated pyrone analogs, flavonols, and pyrone analogs desc ⁇ bed
  • Useful phosphonated pyrone analogs of the present invention are phosphonated pyrone analogs of the structure of Formula XXXX-i or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • R 34 , R 36 , R 37 , and R 3 g are independently selected from the group of hydrogen, -LPO 3 WY and - LPO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, L is methyl, ethyl, alkyl or a carbohydate, and Z is a multivalent cation, and wherein at least one of the R 34 , R 36 , R 37 , or R 38 is -LPO 3 WY or -LPO 3 Z
  • the phosphonated pyrone analog can comp ⁇ se a cyclic phosphonate
  • the invention is a composition comprising a compound of Formula XXXXIa-i or Formula XXXXlb-i, its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs
  • Formula XXXXIa-i Formula XXXXlb-i wherein R 34 and R 36 are independently selected from the group of hydrogen, -LPO 3 WY, and -LPO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, L is methyl, ethyl, alkyl or a carbohydate, and Z is a multivalent cation; and wherein R 39 is selected from the group of hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation
  • a useful phosphonated pyrone analog comprises a compound of Formula XXXXII-i, or its pharmaceutically or vete ⁇ na ⁇ ly acceptable salts, glycosides, esters, or prodrugs:
  • Formula XXXXII-i wherein R 36 , R 37 and R 38 are independently selected from the group consisting of hydrogen, -LPO 3 WY, and -LPO 3 Z, wherein W and Y are independently selected from hydrogen, methyl, ethyl, alkyl, carbohydrate, and a cation, L is methyl, ethyl, alkyl or a carbohydate, and Z is a multivalent cation; and wherein at least one of the R 36 , R 37 , or R 38 is -LPO 3 WY or -LPO 3 Z.
  • the phosphonated pyrone analog is a compound of the following Formula XXXXIII-i
  • each R 40 is independently -H, -OH, or -O-(C r C
  • R 4 ' is -H or -(Ci-Ci 0 alkyl)-P(O)(OR 42 ) 2 ; each R 42 is independently -H or -(C 1 -Ci 0 alkyl); and at least one R 40 is -0-(C 1 -C 10 alkyl)-P(O)(OR 42 ) 2 or R 41 is -(C 1 -C 10 alkyl)-P(O)(OR 42 ) 2 .
  • each R 40 is independently -H or -OH. In some embodiments of the compound of Formula XXXXIII-i, at least one R 40 is -OH. In some embodiments of the compound of Formula XXXXIII-i, R 41 is -(C 1 -C 10 alkyl)-P(O)(OR 42 ) 2 , and R 42 is H or -CH 2 CH 3 . [00253] Illustrative Examples of phosphonated pyrone analogs are depicted in the Table below:
  • phosphonated pyrone analogs are fiseiin-3'-0-phosphonate, fisetin-4'-0-phosphonate, or f ⁇ setin-3-O-phosphonate
  • the invention comprises quercetin-3'-0-methylphosphonate at a pu ⁇ ty of between about 90% and about 99 999%, in some embodiments at a purity of between about 95% and about 99 99%, in some embodiments at a pu ⁇ ty of between about 98% and about 99 99%, in some embodiments at a pu ⁇ ty of between about 99% and about 99 9%, in some embodiments at a purity of between about 995% and about 999%, and in some embodiments at a purity of between about 99 8% and about 99 9%
  • the invention comprises quercetin-3'-O- methylphosphonate at a pu ⁇ ty greater than about 90%, 95%, 96%, 97%, 98% 98 5%, 99%, 99 5%, 99 8%, 99 9%, 99 99%, 99 999% or greater
  • the level of purity of the compound can affect its performance
  • the invention compnses quercetin-4'-0-methylphosphonate at a purity of between about 90% and about 99 999%, in some embodiments at a purity of between about 95% and about 99 99%, in some embodiments at a pu ⁇ ty of between about 98% and about 99 99%, in some embodiments at a pu ⁇ ty of between about 99% and about 99 9%, in some embodiments at a purity of between about 99 5% and about 99 9%, and in some embodiments at a pu ⁇ ty of between about 99 8% and about 99 9%
  • the invention comprises quercetin-4'-O- methylphosphonate at a pu ⁇ ty greater than about 90%, 95%, 96%, 97%, 98% 98 5%, 99%, 99 5%, 99 8%, 99 9%, 99 99%, 99 999% or greater
  • the level of pu ⁇ ty of the compound can affect its performance
  • the invention comp ⁇ ses quercetin-3-O-methylphosphonate at a pu ⁇ ty of between about 90% and about 99 999%, in some embodiments at a pu ⁇ ty of between about 95% and about 9999%, in some embodiments at a pu ⁇ ty of between about 98% and about 99 99%, in some embodiments at a pu ⁇ ty of between about 99% and about 99 9%, in some embodiments at a purity of between about 99 5% and about 99 9%, and in some embodiments at a purity of between about 99 8% and about 99 9%
  • the invention comp ⁇ ses quercetin-3-O- methylphosphonate at a pu ⁇ ty greater than about 90%, 95%, 96%, 97%, 98% 98 5%, 99%, 99 5%, 99 8%, 99 9%, 99 99%, 99 999% or greater
  • quercetin-3'-O-methylphosphonate and quercetin-4'-0-methylphosphonate can be useful in the invention
  • the invention can comp ⁇ se mixtures wherein quercetin-3'-O-methylphosphonate is present at about 50% to about 100% and quercetin-4'-0-methylphosphonate is present between about 50% and about 0%
  • the invention can compnse mixtures wherein quercetin-4'-O-methylphosphonate is present at about 50% to about 100% and quercetin-3'-O-methylphosphonate is present between about 50% and about 0%
  • the quercetin-3'-0-methylphosphonate is present at about 80% to about 100% and the quercetin-4'-O- methylphosphonate is present at between about 20% and about 0%
  • the quercetin-3'-O- methylphosphonate is present at about 85% to about 100% and the quercetin-4'-O-methylphosphonate is present at between about 15% and about 0%
  • the level of pu ⁇ ty of the compound can affect its performance
  • the invention comp ⁇ ses fisetin-3' -O-methylphosphonate at a pu ⁇ ty of between about 90% and about 99 999%, in some embodiments at a pu ⁇ ty of between about 95% and about 99 99%, in some embodiments at a purity of between about 98% and about 99 99%, in some embodiments at a purity of between about 99% and about 99 9%, in some embodiments at a pu ⁇ ty of between about 99 5% and about 99 9%, and in some embodiments at a pu ⁇ ty of between about 99 8% and about 99 9%
  • the invention comp ⁇ ses fisetin-3'-O-methylphosphonate at a purity greater than about 90%, 95%, 96%, 97%, 98% 98 5%, 99%, 99 5%, 99 8%, 99 9%, 99 99%, 99 999% or greater [00260]
  • the level of purity of the compound can affect
  • the level of pu ⁇ ty of the compound can affect its performance
  • the invention comp ⁇ ses fisetin-3-O-methylphosphonate at a pu ⁇ ty of between about 90% and about 99 999%, in some embodiments at a purity of between about 95% and about 99 99%, in some embodiments at a purity of between about 98% and about 99 99%, in some embodiments at a purity of between about 99% and about 99 9%, in some embodiments at a purity of between about 99 5% and about 99 9%, and in some embodiments at a pu ⁇ ty of between about 99 8% and about 99 9%
  • the invention comp ⁇ ses fisetin-3-O-methylphosphonate at a purity greater than about 90%, 95%, 96%, 97%, 98% 98 5%, 99%, 99 5%, 99 8%, 99 9%, 99 99%, 99 999% or greater
  • fisetin-3'-0-methylphosphonate and fisetin-4'-O-methylphosphonate can be useful in the invention
  • the invention can comp ⁇ se mixtures wherein fisetin-3'-O-methylphosphonate is present at about 50% to about 100% and fisetin-4'-O-methylphosphonate is present between about 50% and about 0%
  • the invention can comp ⁇ se mixtures wherein fisetin-4'-O-methylphosphonate is present at about 50% to about 100% and fisetin-3'-O-methylphosphonate is present between about 50% and about 0%
  • the fisetin-3'-O- methylphosphonate is present at about 80% to about 100% and the fisetin-4'-O-methylphosphonate is present at between about 20% and about 0%
  • the fisetin-3'-O-methylphosphonate is present at about 85% to about 100% and the fisetin-4'-O-methylphosphonate is present at between about 15% and about 0%
  • the fisetin-3''-O-methylphosphonate is
  • pharmaceutically acceptable cation refers to a posi ⁇ vely charged inorganic or organic ion that is generally considered suitable for human consumption
  • pharmaceutically acceptable cations are hydrogen, alkali metal (lithium, sodium and potassium), magnesium, calcium, ferrous, feme, ammonium, alkylammomum, dialkylammonium, t ⁇ alkylammonium, tetraalkylammomum, and guanidimum ions and protonated forms of lysine, choline and procaine
  • the compounds presented herein may possess one or more chiral centers and each center may exist in the R or S configuration
  • the compounds presented herein include all diastereome ⁇ c, enantiome ⁇ c, and epime ⁇ c forms as well as the appropriate mixtures thereof
  • Stereoisomers may be obtained, if desired, by methods known in the art as, for example, the separation of stereoisomers by chiral chromatographic columns
  • the methods and formulations described herein include the use of N-oxides, crystalline forms (also known as polymorphs), or pharmaceutically acceptable salts of compounds having the structure of Formula I, as well as active metabolites of these compounds having the same type of activity
  • the compounds desc ⁇ bed herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like
  • the solvated forms of the compounds presented herein are also considered to be disclosed herein II.
  • compositions may also be prepared from compounds desc ⁇ bed herein and one or more pharmaceutically acceptable excipients suitable for rectal, buccal, sublingual, intranasal, transdermal, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, or topical administration
  • pharmaceutically acceptable excipients suitable for rectal, buccal, sublingual, intranasal, transdermal, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, or topical administration
  • Preparations for such pharmaceutical compositions are well-known in the art See, e g , See, e g , Anderson, Philip O , Knoben, James E , Troutman, William G, eds , Handbook of Clinical Drug Data, Tenth Edition, McGraw-Hill, 2002, Pratt and Taylor, eds , Principles of Drug Action, Third Edition, Churchill Livingston, New York, 1990, Katzung, ed , Basic and Clinical Pharmacology, Ninth
  • the flavonoid is fisetin, fisetin de ⁇ vative, quercetin or quercetin derivative
  • the flavonoid is phosphorylated or phosphonated fisetin, phosphorylated or phosphonated fisetin de ⁇ vative, phosphorylated or phosphonated quercetin or phosphorylated or phosphonated quercetin de ⁇ vative
  • fisetin or phosphorylated or phosphonated fisetin is in a carbohydrate-de ⁇ vatized form, e g , a phosphorylated or phosphonated fisetin-O-saccha ⁇ de
  • Phosphorylated or phosphonated f ⁇ setin-O- saccha ⁇ des include, but are not limited to, phosphorylated or phosphonated fisetin 3-O-glycoside, phosphorylated or phosphonated fisetin 3-O-glucorhamnoside, phosphorylated or phospho
  • quercetin or phosphorylated or phosphonated quercetin is in a carbohydrate- de ⁇ vatized form, e g , a phosphorylated or phosphonated quercetin-O-saccha ⁇ de
  • Phosphorylated or phosphonated quercetin-O-saccha ⁇ des include, but are not limited to, phosphorylated or phosphonated quercetin 3-O-glycoside, phosphorylated or phosphonated quercetin 3-O-glucorhamnoside, phosphorylated or phosphonated quercetin 3-O- galactoside, phosphorylated or phosphonated quercetin 3-O-xyloside, phosphorylated or phosphonated quercetin 3- O-rhamnoside, and phosphorylated or phosphonated quercetin 7-O-saccha ⁇ de
  • the compound is a phosphorylated or phosphonated fisetin aglycone or a phosphorylated or phosphonated quercetin aglycone
  • a combination of aglycone and carbohydrate-de ⁇ vatized phosphorylated or phosphonated fisetin can be used
  • a combination of aglycone and carbohydrate-de ⁇ vatized phosphorylated or phosphonated quercetin can be used It will be appreciated that the various forms of phosphorylated or phosphonated fisetin or various forms of phosphorylated or phosphonated quercetin may have different properties useful in the compositions and methods described herein, and that the route of administration can determine the choice of forms, or combinations of forms, used in the composition or method Choice of a single form, or of combinations, may be determined empirically [00276] In some embodiments, fisetin or a phosphorylated or phosphonated fisetin
  • the lipid transport protein modulator comprises a phosphorylated or phosphonated pyrone analog
  • a phosphorylated or phosphonated pyrone analog can be phosphorylated or phosphonated fisetin, phosphorylated or phosphonated isofisetin, phosphorylated or phosphonated flavon, phosphorylated or phosphonated chrysin, phosphorylated or phosphonated apigenin, phosphorylated or phosphonated rhoifohn, phosphorylated or phosphonated diosmin, phosphorylated or phosphonated galangin, phosphorylated or phosphonated mo ⁇ n, phosphorylated or phosphonated rutin, phosphorylated or phosphonated kaempferol, phosphorylated or phosphonaled my ⁇ cetin, phosphorylated or phosphonated taxifolin, phosphorylated or phosphonated na ⁇ ngenin, phosphorylated or phosphorylated or phosphonated
  • the symptom of hyperglycemia that is reduced includes, but is not limited to, glucosu ⁇ a, polyphagia, polyuria, polydipsia, loss of consciousness, blurred vision, headaches, coma, ketoacidosis, decrease in blood volume, decrease in renal blood flow, accelerated hpolysis, weight loss, stomach problems, intestinal problems, poor wound healing, dry mouth, nausea, vomiting, dry skin, itchy skin, impotence, hypeventilation, ketoanemia, fatigue, weakness on one side of the body, hallucinations, impairment in cognitive function, increase sadness, anxiety, recurrent genital infections, increase sugar in urine, retinopathy, nepropathy, arteriosclerotic disorders, cardiac arrhythmia, stupor, susceptibility to infection, neuropathy, nerve damages causing cold feet, nerve damage causing insensitive feet and loss of hair
  • the symptom of hyperglycemia is glucosuria [00282] In some embodiment
  • substantially eliminated encompasses no measurable or no statistically significant symptom (one or more symptoms) of hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia as disclosed herein
  • the phosphorylated or phosphonated pyrone analog is phosphorylated or phosphonated fisetin
  • the phosphorylated or phosphonated pyrone analog is phosphorylated or phosphonated fisetin de ⁇ vative
  • the phosphorylated or phosphonated pyrone analog is phosphorylated or phosphonated quercetin
  • the phosphorylated or phosphonated pyrone analog is phosphorylated or phosphonated quercetin de ⁇ vative
  • the amount of one or more phosphorylated or phosphonated pyrone analogs for use in such compositions may be equal to or less than 10 g, 9 5 g, 9 0 g, 8 5 g, 8 0 g, 7 5 g, 7 0 g, 6 5 g, 6 0 g, 5 5 g, 5 0 g, 4 5 g, 4 0 g, 3 5 g, 3 0 g, 2 5 g, 2 0 g, 1 5 g, 1 0 g, 095 g, 09 g, 0 85 g, 0 8 g, 0 75 g, 0 7 g, 065 g, 0 6 g, 0 55 g, 0 5 g, 0 45 g, 04 g, 0 35 g, 0 3 g, 0 25 g, 0 2 g, 0 15 g, 0 1 g, 0 09 g, 0 08 g,
  • the amount of one or more phosphorylated or phosphonated pyrone analogs for use in such compositions may be more than 0 0001 g, 00002 g, 00003 g, 00004 g, 0 0005 g, 0 0006 g, 0 0007 g, 0 0008 g, 00009 g, 0001 g, 00015 g, 0002 g, 00025 g, 0003 g, 00035 g, 0 004 g, 00045 g, 0005 g, 00055 g, 0006 g, 00065 g, 0 007 g, 00075 g, 0008 g, 0 0085 g, 0 009 g, 00095 g, 0 01 g, 0015 g, 0 02 g, 0 025 g, 003 g, 0 035 g,
  • the amount of one or more of the phosphorylated or phosphonated pyrone analogs for use in such compositions may be in the range of 0 0001 - 10 g, 00005-9 g, 0 001 -8 g, 0 005-7 g, 0 01-6 g, 005-5 g, 0 1 -4 g, 0 5-4 g, or 1 -3 g
  • the amount of one or more of the phosphorylated or phosphonated pyrone analogs for use in such compositions may be in the range of about 1 - 1000 mg, about 10- 1000 mg, about 50- 1000 mg, about 100- 1000 mg, about 1-500 mg, about 5-500 mg, about 50-500 mg, about 100-500 mg, about 200- 1000 mg, about 200-800 mg, or about 200-700 mg one or more phosphorylated or phosphonated pyrone analogs may present in an amount of about 10 mg, about 25 mg, about 50 mg, about 100 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, about 500 mg, about 600 mg, about 700 mg, about 800 mg, about 900 mg, or about 1000 mg
  • the compositions disclosed herein further include a pharmaceutical excipient
  • the composition may include phosphorylated or phosphonated fisetin, a phosphorylated or phosphonated fisetin derivative, phosphorylated or phosphonated quercetin, or a phosphoryl
  • More than one phosphorylated or phosphonated pyrone analog may be formulated in a composition for administration to a subject
  • the phosphorylated or phosphonated pyrone analog may be any compound within the phosphorylated or phosphonated pyrone family having the formula as described herein
  • the phosphorylated or phosphonated pyrone analogs in a combination (mixture) may be administered to a subject simultaneously (e g , same or different compositions) or sequentially in separate composition When administered sequentially, the phosphorylated or phosphonated pyrone analog may be administered prior to, or after, a second agent in the combination
  • the phosphorylated or phosphonated pyrone analogs may interact with each other in a synergistic or additive manner to exert a biological effect or effects, for example, reducing lipid and glucose levels in the subject
  • the synergy between phosphorylated or phosphonated pyrone analogs can potentially allow a reduction in the dose required for each phosphorylated or phosphon
  • a solid pharmaceutical composition for oral administration contains a phosphorylated or phosphonated pyrone analog at about 5- 1000 mg and a pharmaceutically acceptable excipient
  • a liquid pharmaceutical composition for oral administration In some embodiments, the liquid pharmaceutical composition for oral administration contains a phosphorylated or phosphonated pyrone analog at about 5- 1000 mg and a pharmaceutically acceptable excipient
  • compositions suitable for oral administration can be presented as discrete dosage forms, such as capsules, cachets, or tablets, or liquids or aerosol sprays each containing a predetermined amount of an active ingredient as a powder or in granules, a solution, or a suspension in an aqueous or non-aqueous liquid, an oil- in- water emulsion, or a water-in-oil liquid emulsion
  • dosage forms can be prepared by any of the methods of pharmacy, but all methods include the step of bringing the active ingredient into association with the carrier, which constitutes one or more necessary ingredients
  • the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid earners or finely divided solid earners or both, and then, if necessary, shaping the product into the desired presentation
  • a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients
  • Compressed tablets can be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as powder or granul
  • An active ingredient can be combined in an intimate admixture with a pharmaceutical earner according to conventional pharmaceutical compounding techniques
  • the earner can take a wide variety of forms depending on the form of preparation desired for administration
  • any of the usual pharmaceutical media can be employed as earners, such as, for example, water, glycols, oils, alcohols, flavo ⁇ ng agents, preservatives, colo ⁇ ng agents, and the like in the case of oral liquid preparations (such as suspensions, solutions, and elixirs) or aerosols, or carriers such as starches, sugars, micro-crystalline cellulose, diluents, granulating agents, lubricants, binders, and disintegrating agents can be used in the case of oral solid preparations, in some embodiments without employing the use of lactose
  • suitable earners include powders, capsules, and tablets, with the solid oral preparations If desired, tablets can be coated by standard aqueous or nonaqueous techniques
  • Binders suitable for use in pharmaceutical compositions and dosage forms include, but are not limited to, corn starch, potato starch, or other starches, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, powdered tragacanth, guar gum, cellulose and its de ⁇ vatives (e g , ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof [00295]
  • suitable fillers for use in the pharmaceutical compositions and dosage forms disclosed herein include, but are not limited to, talc, calcium carbonate (e g , granules or powder), microcrystalline cellulose, powdered cellulose, dextrates, kaolin, mannitol, silicic acid, sorb
  • Disintegrants may be used in the compositions to provide tablets that disintegrate when exposed to an aqueous environment Too much of a disintegrant may produce tablets which may disintegrate in the bottle Too little may be insufficient for disintegration to occur and may thus alter the rate and extent of release of the active ⁇ ngredient(s) from the dosage form Thus, a sufficient amount of disintegrant that is neither too little nor too much to detrimentally alter the release of the active ingredient(s) may be used to form the dosage forms of the compounds disclosed herein The amount of disintegrant used may vary based upon the type of formulation and mode of administration, and may be readily discernible to those of ordinary skill in the art About 0 5 to about 15 weight percent of disintegrant, or about 1 to about 5 weight percent of disintegrant, may be used in the pharmaceutical composition Disintegrants that can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, agar-agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium,
  • Lub ⁇ cants which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e g , peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures thereof
  • Additional lub ⁇ cants include, for example, a syloid silica gel, a coagulated aerosol of synthetic silica, or mixtures thereof
  • a lub ⁇ cant can optionally be added, in an amount of less than about 1 weight percent of the pharmaceutical composition
  • the essential active ingredient therein may be combined with va ⁇ ous sweetening or flavoring agents, coloring matter or dyes and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glyce ⁇ n and va ⁇ ous combinations thereof
  • the tablets can be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer pe ⁇ od
  • a time delay material such as glyceryl monostearate or glyceryl distearate can be employed
  • Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example, peanut oil, liquid paraffin or olive oil
  • the tablet can be prepared for immediate-release
  • the tablet can be an erodible tablet A solubihzer, such as Captisol® when compressed, that erodes rather than disintegrates can be mixed with the active ingredient to form the erodible tablet Formulation for oral use can also be present as a hard gelatin capsule using suboptimal lyophihzation process
  • Surfactant which can be used to form pharmaceutical compositions and dosage forms include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof That is, a mixture of hydrophilic surfactants may be employed, a mixture of lipophilic surfactants may be employed, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be employed
  • a suitable hydrophilic surfactant may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value of or less than about 10
  • An empincal parameter used to characte ⁇ ze the relative hydrophilicity and hydrophobicity of non-ionic amphiphilic compounds is the hydrophilic-hpophilic balance (" HLB" value)
  • HLB hydrophilic-hpophilic balance
  • surfactants with lower HLB values are more lipophilic or hydrophobic, and have greater solubility in oils, while surfactants with higher HLB values are more hydrophilic, and have greater solubility in aqueous solutions
  • Hydrophilic surfactants are generally considered to be those compounds having an HLB value greater than about 10, as well as anionic, cationic, or zwitte ⁇ onic compounds for which the HLB scale is not generally applicable
  • lipophilic (i e , hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10
  • Hydrophilic surfactants may be either ionic or non-ionic Suitable ionic surfactants include, but are not limited to, alkylammonium salts, fusidic acid salts, fatty acid de ⁇ vatives of amino acids, oligopeptides, and polypeptides, glyce ⁇ de de ⁇ vatives of amino acids, oligopeptides, and polypeptides, lecithins and hydrogenated lecithins, lysolecithins and hydrogenated lysolecithins, phospholipids and de ⁇ vatives thereof, lysophospholipids and de ⁇ vatives thereof, carnitine fatty acid ester salts, salts of alkylsulfates, fatty acid salts, sodium docusate, acyl lactylates, mono- and di-acetylated tartaric acid esters of mono- and di-glyce ⁇ des, succinylated mono- and di- glyce ⁇ des,
  • preferred ionic surfactants include, by way of example lecithins, lysolecithin, phospholipids, lysophospholipids and de ⁇ vatives thereof, carnitine fatty acid ester salts, salts of alkylsulfates, fatty acid salts, sodium docusate, acyl lactylates, mono- and di-acetylated tartaric acid esters of mono- and di-glyce ⁇ des, succinylated mono- and di-glyce ⁇ des, cit ⁇ c acid esters of mono- and di-glyce ⁇ des, and mixtures thereof
  • Ionic surfactants may be the ionized forms of lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatide acid, phosphatidylse ⁇ ne, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylsenne, PEG- phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactylic esters of fatty acids, stearoyl-2-lactylate, stearoyl lactylate, succinylated monoglyce ⁇ des, mono/diacetylated tartaric acid esters of mono/diglyce ⁇ des, cit ⁇ c acid esters of mono/diglyce ⁇ des, cholylsarcosine, caproate
  • Hydrophilic non-ionic surfactants may include, but not limited to, alkylglucosides, alkylmaltosides, alkylthioglucosides, lauryl macrogolglyce ⁇ des, polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers, polyoxyalkylene alkylphenols such as polyethylene glycol alkyl phenols, polyoxyalkylene alkyl phenol fatty acid esters such as polyethylene glycol fatty acids monoesters and polyethylene glycol fatty acids diesters, polyethylene glycol glycerol fatty acid esters, polyglycerol fatty acid esters, polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters, hydrophilic transeste ⁇ f ⁇ cation products of a polyol with at least one member of the group consisting of glyce ⁇ des, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols,
  • hydrophilic-non-ionic surfactants include, without limitation, PEG- 10 laurate, PEG- 12 laurate, PEG- 20 laurate, PEG-32 laurate, PEG-32 dilaurate, PEG- 12 oleate, PEG- 15 oleate, PEG-20 oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400 oleate, PEG- 15 stearate, PEG-32 distearate, PEG-40 stearate, PEG- 100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate, PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 gly
  • Suitable lipophilic surfactants include, by way of example only fatty alcohols, glycerol fatty acid esters, acetylated glycerol fatty acid esters, lower alcohol fatty acids esters, propylene glycol fatty acid esters, sorbitan fatty acid esters, polyethylene glycol sorbitan fatty acid esters, sterols and sterol derivatives, polyoxyethylated sterols and sterol de ⁇ vatives, polyethylene glycol alkyl ethers, sugar esters, sugar ethers, lactic acid derivatives of mono- and di-glyce ⁇ des, hydrophobic transeste ⁇ fication products of a polyol with at least one member of the group consisting of glyce ⁇ des, vegetable oils, hydrogenated vegetable oils, fatty acids and sterols, oil-soluble vitamins/vitamin de ⁇ vatives, and mixtures thereof Within this group, preferred lipophilic surfactants include glycerol fatty acid esters,
  • the composition may include a solubihzer to ensure good solubilization and/or dissolution of the phosphorylated or phosphonated pyrone analog and to minimize precipitation of the phosphorylated or phosphonated pyrone analog This can be especially important for compositions for non-oral use, e g , compositions for injection
  • a solubihzer may also be added to increase the solubility of the hydrophilic drug and/or other components, such as surfactants, or to maintain the composition as a stable or homogeneous solution or dispersion
  • Cyclodext ⁇ ns and their de ⁇ vatives can be used to enhance the aqueous solubility of hydrophobic compounds
  • Cyclodext ⁇ ns are cyclic carbohydrates de ⁇ ved from starch
  • the unmodified cyclodext ⁇ ns differ by the number of glucopyranose units joined together in the cylind ⁇ cal structure
  • the parent cyclodextrins typically contain 6, 7, or 8 glucopyranose units and are referred to as alpha-, beta-, and gamma-cyclodext ⁇ n respectively
  • Each cyclodext ⁇ n subunit has secondary hydroxyl groups at the 2 and 3-positions and a p ⁇ mary hydroxyl group at the 6- position
  • the cyclodext ⁇ ns may be pictured as hollow truncated cones with hydrophilic exte ⁇ or surfaces and hydrophobic inte ⁇ or cavities In aqueous solutions, these hydrophobic cavities can incorporate hydrophobic organic compounds, which can fit all, or part of their
  • Cyclodext ⁇ ns can be de ⁇ vatized to improve their properties
  • Cyclodext ⁇ n de ⁇ vatives that are useful for pharmaceutical applications include the hydroxypropyl de ⁇ vatives of alpha-, beta- and gamma-cyclodext ⁇ n, sulfoalkylether cyclodext ⁇ ns such as sulfobutylether beta-cyclodext ⁇ n, alkylated cyclodext ⁇ ns such as the randomly methylated beta -cyclodext ⁇ n, and va ⁇ ous branched cyclodext ⁇ ns such as glucosyl- and maltosyl-beta - cyclodextnn Chemical modification of the parent cyclodext ⁇ ns (usually at the hydroxyl moieties) has resulted in de ⁇ vatives with sometimes improved safety while retaining or improving the complexation ability of the cyclodext ⁇ n
  • solubilizers include, but are not limited to, the following alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaeryth ⁇ tol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol.
  • alcohols and polyols such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butanediols and isomers thereof, glycerol, pentaeryth ⁇ tol, sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene glycol.
  • polypropylene glycol polyvinylalcohol, hydroxypropyl methylcellulose and other cellulose derivatives, cyclodext ⁇ ns and cyclodext ⁇ n derivatives, ethers of polyethylene glycols having an average molecular weight of about 200 to about 6000, such as tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG , amides and other nitrogen-containing compounds such as 2-pyrrohdone, 2-pipe ⁇ done, epsilon -caprolactam, N- alkylpyrrohdone, N-hydroxyalkylpyrrolidone, N-alkylpipe ⁇ done, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone, esters such as ethyl propionate, t ⁇ butylcitrate, acetyl t ⁇ ethylcitrate, acetyl t ⁇ butyl cit
  • solubihzers may also be used Examples include, but not limited to, t ⁇ acetin, t ⁇ ethylcitrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cyclodext ⁇ ns, ethanol, polyethylene glycol 200- 100, glycofurol, transcutol, propylene glycol, and dimethyl isosorbide
  • Preferred solubihzers include sorbitol, glycerol, t ⁇ acetin, ethyl alcohol, PEG-400, glycofurol and propylene glycol
  • the amount of solubilizer that can be included is not particularly limited
  • the amount of a given solubihzer may be limited to a bioacceptable amount, which may be readily determined by one of skill in the art
  • the solubilizer can be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by weight, based on the combined weight of the drug, and other excipients
  • very small amounts of solubilizer may also be used, such as 5%, 2%, 1 % or even less
  • the solubilizer may be present in an amount of about 1 % to about 100%, more typically about 5% to about 25% by weight
  • the composition can further include one or more pharmaceutically acceptable additives and excipients
  • additives and excipients include, without limitation, detackifiers, anti-foaming agents, buffe ⁇ ng agents, polymers, antioxidants, preservatives, chelating agents, viscomodulators, tonicifiers, flavorants, colorants, odorants, opacifiers, suspending agents, binders, fillers, plasticizers, lub ⁇ cants, and mixtures thereof
  • an acid or a base may be incorporated into the composition to facilitate processing, to enhance stability, or for other reasons
  • pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, dnsopropylethylamine, ethanolamine, ethylenediamine, t ⁇ ethanolamine, t ⁇ ethylamine, t ⁇ isopropanolamine, t ⁇ methylamine, t ⁇ s(hydroxymeihyl)aminomethane (TRIS) and the like
  • bases that are salts of a pharmaceutically acceptable acid such as acetic acid, acrylic acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids, ascorbic acid, benzoic acid, bone acid, buty ⁇ c acid, carbonic acid
  • the phosphorylated or phosphonated pyrone analog may be administered to an animal alone or in combination with one or more other agents of one or more other forms to have a biological effect on lipid, triglyceride or glucose levels in the animal
  • Such combination may comp ⁇ se agents including but not limited to chemical compounds, nucleic acids (i e , DNA, RNA), proteins, peptides, peptidomimetics, peptoids, or any other forms of a molecule
  • the agents in a combination may be administered to an animal simultaneously or sequentially
  • These agents in a combination may be of any category of agents mentioned herein, and may interact with each other in a synergistic or additive manner to exert a biological effect or effects
  • the synergy between the phosphorylated or phosphonated pyrone analog and the agents can potentially allow a reduction in the dose required for each agent, leading to a reduction in the side effects and enhancement of the clinical utility of these agents
  • the symptom measured may be any symptom as desc ⁇ bed herein
  • the symptom that is reduced includes, but is not limited to, xanthoma, skin lesion, pancreatitis, enlargement of liver and spleen, chest pain, heart attack or a combination thereof
  • the measurable amount may be an average of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95% as desc ⁇ bed herein
  • a lipid-lowe ⁇ ng compound may be a compound that lowers the level of cholesterol in a subject (i e cholesterol-lowe ⁇ ng compound)
  • Cholesterol-lowe ⁇ ng compounds include, but are not limited to, clofibrate, gemfibrozil, and fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, chol
  • a hpid-lowe ⁇ ng compound may be a compound that lowers the level of triglyceride in a subject (i e t ⁇ clyce ⁇ de-lowe ⁇ ng compounds)
  • T ⁇ glyce ⁇ de-lowe ⁇ ng compounds include, but are not limited to, ascorbic acid, asparaginase, clofibrate, colestipol, fenofibrate mevastatin, pravastatin, simvastatin, fluvastatin, or omega-3 fatty acid
  • a hpid-lowenng compound may also be a compound that lowers the level of LDL-cholesterol in a subject
  • triglyceride is plasma t ⁇ glyce ⁇ de and/or liver triglyceride
  • triglyceride is plasma t ⁇ glyce ⁇ de
  • t ⁇ glyce ⁇ de is liver t ⁇ glyce ⁇ de
  • Compositions may comprise a phosphorylated or phosphonated pyrone analog and a hpid-lowenng compound wherein the phosphorylated or phosphonated pyrone analog is, for example, phosphorylated or phosphonated fisetin, phosphorylated or phosphonated isofisetin, phosphorylated or phosphonated flavon, phosphorylated or phosphonated chrysin, phosphorylated or phosphonated apigenin, phosphorylated or phosphonated rhoifolin, phosphorylated or phosphonated diosmin, phosphorylated or phosphonated galangm, phosphorylated or phosphonated mo ⁇ n, phosphorylated or phosphonated rutin, phosphorylated or phosphonated kaempferol, phosphorylated or phosphonated my ⁇ cetin, phosphorylated or phosphonated taxifolin, phosphorylated or phosphonated na ⁇ ngenin,
  • the hpid-lowenng compound may be present in an amount sufficient to exert a therapeutic effect and the phosphorylated or phosphonated pyrone analogs may be present in an amount sufficient to decrease hyperlipiderrua, hypercholesterolemia, hypert ⁇ glyce ⁇ demia and/or one or more symptoms of thereof by a measurable amount, compared to treatment without the phosphorylated or phosphonated pyrone analogs when administered to an animal
  • the measurable amount may be an average of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95% as desc ⁇ bed herein
  • compositions compnse a phosphorylated or phosphonated pyrone analog which is phosphorylated or phosphonated fisetin, a phosphorylated or phosphonated fisetin de ⁇ vative, phosphorylated or phosphonated quercetin or a phosphorylated or phosphonated quercetin de ⁇ vative in an amount sufficient to decrease the concentration of lipid including but not limited to cholesterol and t ⁇ glyce ⁇ de in a physiological compartment by
  • the concentration of one or more of the lipid-lowe ⁇ ng compounds and/or phosphorylated or phosphonated pyrone analog may be greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19 75%, 19 50%, 19 25% 19%, 18 75%, 18 50%, 18 25% 18%, 17 75%, 17 50%, 17 25% 17%, 16 75%, 16 50%, 16 25% 16%, 15 75%, 15 50%, 15 25% 15%, 14 75%, 14 50%, 14 25% 14%, 13 75%, 13 50%, 13 25% 13%, 12 75%, 12 50%, 12 25% 12%, 1 1 75%, 1 1 50%, 1 1 25% 1 1 1 %, 10 75%, 10 50%, 1025% 10%, 9 75%, 9 50%, 9 25% 9%, 8 75%, 8 50%, 8 25% 8%, 7 75%, 7 50%, 7 25% 7%, 6 75%, 6 50%, 6 25% 6%, 5 75%, 5 50%, 5 25% 5%, 4 75%, 4 50%, 4 25%,
  • compositions comp ⁇ se a phosphorylated or phosphonated pyrone analog with a compound that lowers glucose levels i e a glucose-lowe ⁇ ng compound
  • the phosphorylated or phosphonated pyrone analog can be any of those described herein
  • the glucose-lowe ⁇ ng compound may be present in an amount sufficient to exert a therapeutic effect and the phosphorylated or phosphonated pyrone analog may be present in an amount sufficient to decrease hyperglycemia and/or one or more symptoms thereof by a measurable amount, compared to treatment without the phosphorylated or phosphonated pyrone analog when the composition is administered to an animal
  • the measurable amount may be an average of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95%
  • the symptom of hyperglycemia may be any symptom as desc ⁇ bed herein including, but not limited to, glucosu ⁇ a, polyphagia, polyuria, polydipsia, loss of consciousness, blurred vision, headaches, coma, ketoacidosis, decrease in blood volume, decrease in renal blood flow, accelerated lipolysis, weight loss, stomach problems, intestinal problems, poor wound healing, dry mouth, nausea, vomiting, dry skin, itchy skin, impotence, hypeventilation, ketoanemia, fatigue, weakness on one side of the body, hallucinations, impairment in cognitive function, increase sadness, anxiety, recurrent genital infections, increase sugar in u ⁇ ne, retinopathy, nepropathy, arteriosclerotic disorders, cardiac arrhythmia, stupor, susceptibility to infection, neuropathy, nerve damages causing cold feet, nerve damage causing insensitive feet and loss of hair
  • the symptom of hyperglycemia is glucosu ⁇ a
  • Glucose-lowering compounds include, but are not limited to, glipizide, exenatide, incretins, sitagliptin, pioghtizone, glimepi ⁇ de, rosightazone, metformin, exantide, vildaghptin, sulfonylurea, glucosidase inhibitor, biguanide, repaglimde, acarbose, troglitazone, nateglinide, or a variant thereof
  • the glucose-lowering compound may be present in a composition in an amount sufficient to exert a therapeutic effect and the phosphorylated or phosphonated pyrone analog may be present in an amount sufficient to decrease hyperglycemia and/or one or more symptoms thereof by a measurable amount, compared to treatment without the phosphorylated or phosphonated pyrone analog when administered to an animal
  • the measurable amount may be an average of at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95%
  • the symptom of hyperglycemia may be any symptom as desc ⁇ bed herein
  • a composition comprises a glucose-lowering compound and a phosphorylated or phosphonated pyrone analog
  • the concentration of one or more of the glucose-lowering compounds and/or phosphorylated or phosphonated pyrone analog may be less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1 %, 0 5%, 04%, 0 3%, 0 2%, 0 1 %, 009%, 0 08%, 0 07%, 006%, 0 05%, 0 04%, 003%, 002%, 0 01 %, 0 009%, 0008%, 0 007%, 0 006%, 0005%, 0 004%, 0 003%, 0
  • the concentration of one or more of the glucose-lowering compounds and/or phosphorylated or phosphonated pyrone analog may be greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19 75%, 19 50%, 19 25% 19%, 18 75%, 18 50%, 18 25% 18%, 17 75%, 17 50%, 17 25% 17%, 16 75%, 16 50%, 16 25% 16%, 15 75%, 15 50%, 15 25% 15%, 14 75%, 14 50%, 14 25% 14%, 13 75%, 13 50%, 13 25% 13%, 12 75%, 12 50%, 12 25% 12%, 1 1 75%, 1 1 50%, 1 1 25% 1 1 1 %, 10 75%, 10 50%, 10 25% 10%, 9 75%, 9 50%, 9 25% 9%, 8 75%, 8 50%, 8 25% 8%, 7 75%, 7 50%, 7 25% 7%, 6 75%, 6 50%, 6 25% 6%, 5 75%, 5 50%, 5 25% 5%, 4 75%, 4 50%, 4 25%, 4%, 3 7
  • both components may be mixed into a preparation or both components may be formulated into separate preparations to use them in combination separately or at the same time
  • compositions contain, as the active ingredient, a phosphorylated or phosphonated pyrone analog or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, earners, including inert solid diluents and fillers, diluents including ste ⁇ le aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants
  • a phosphorylated or phosphonated pyrone analog and/or the lipid or glucose lowe ⁇ ng compound may be prepared into pharmaceutical compositions in dosages as desc ⁇ bed herein Such compositions are prepared in a manner well known in the pharmaceutical art
  • a pharmaceutical composition for injection comp ⁇ ses a phosphorylated or phosphonated pyrone analog that reduces or eliminates hyperhpidemia, hypercholesterolemia, hypert ⁇ glyce ⁇ demia, or hyperglycemia and/or one or more symptoms thereof, and a pharmaceutical excipient suitable for injection
  • a pharmaceutical composition comp ⁇ ses a combination of a phosphorylated or phosphonated pyrone analog, a lipid lowe ⁇ ng compound and a pharmaceutical excipient suitable for injection
  • a pharmaceutical composition comp ⁇ ses a combination of a phosphorylated or phosphonated pyrone analog, a glucose lowe ⁇ ng compound and a pharmaceutical excipient suitable for injection
  • the pharmaceutical composition comp ⁇ ses cyclodextnn-phosphorylated or phosphonated pyrone analog, and a suitable pharmaceutical excipient Components and amounts of phosphorylated or phosphonated pyrone analogs in the compositions are as desc
  • the pharmaceutical composition for injection is made using an aqueous composition comp ⁇ sing a phosphorylated or phosphonated pyrone analog, and a pharmaceutically or vete ⁇ na ⁇ ly acceptable aqueous earner wherein the phosphorylated or phosphonated pyrone analog is present in a concentration of greater than 05 mM, 1 mM, 5 mM, 10 mM, 15 mM, 20 mM, 30 mM, 33 mM, 40 mM, 50 mM, 60 mM, or 80 mM
  • the forms in which the compositions may be incorporated for administration by injection include aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, manmtol, dextrose, or a stenle aqueous solution, and similar pharmaceutical vehicles
  • Aqueous solutions in saline are also conventionally used for injection Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextnn de ⁇ vatives, and vegetable oils may also be employed
  • Ethanol, glycerol, propylene glycol, liquid polyethylene glycol, and the like (and suitable mixtures thereof), cyclodextnn de ⁇ vatives, and vegetable oils may also be employed
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants
  • va ⁇ ous antibacte ⁇ al and antifungal agents for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like
  • Ste ⁇ le injectable solutions are prepared by incorporating the transport protein modulator in the required amount in the appropnate solvent with va ⁇ ous other ingredients as enumerated above, as required, followed by filtered sterilization
  • dispersions are prepared by incorporating the various ste ⁇ hzed active ingredients into a sle ⁇ le 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 ste ⁇ le-filtered solution thereof
  • Pharmaceutical composition for injection can be made into a solid formulation that is produced by drying the aqueous composition, for example by freeze drying or lyophihzation Having a d ⁇ ed, solid formulation can be advantageous for increasing the shelf-life The solid formulation can then be re-dissolved into solution for injection The d ⁇ ed powder
  • compositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders
  • the liquid or solid compositions may comprise suitable pharmaceutically acceptable excipients as desc ⁇ bed supra
  • the compositions may be administered by an oral or nasal respiratory route for local or systemic effect
  • Compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent, or intermittent positive pressure breathing machine Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an approp ⁇ ate manner
  • a pharmaceutical composition for oral administration compnsing a phosphorylated or phosphonated pyrone analog that reduces or eliminates hyperlipiderrua, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia and/or one or more symptoms thereof, and a pharmaceutical excipient suitable for oral administration
  • a pharmaceutical composition for oral administration compnsing a combination of a phosphorylated or phosphonated pyrone analog and a lipid lowe ⁇ ng compound that reduces or eliminates hyperhpidemia, hypercholesterolemia, hypert ⁇ glyce ⁇ demia and/or one or more symptoms thereof and a pharmaceutical excipient suitable for oral administration
  • composition for oral administration comprising
  • compositions may further comprise (in) an effective amount of a lipid lowe ⁇ ng compound
  • compositions may further comp ⁇ se (in) an effective amount of a glucose lowering compound
  • the above pharmaceutical compositions may be liquid pharmaceutical compositions suitable for oral consumption In some embodiments, the above pharmaceutical compositions may be solid pharmaceutical compositions suitable for oral consumption
  • composition for oral administration comprising
  • a phosphorylated pyrone analog that is phosphorylated fisetin, phosphorylated lsofisetin, phosphorylated flavon, phosphorylated chrysin, phosphorylated apigenin, phosphorylated rhoifohn, phosphorylated diosmin, phosphorylated galangin, phosphorylated mo ⁇ n, phosphorylated rutin, phosphorylated kaempferol, phosphorylated my ⁇ cetin, phosphorylated taxifolin, phosphorylated na ⁇ ngenin, phosphorylated na ⁇ ngin, phosphorylated hesperetin, phosphorylated hespe ⁇ din, phosphorylated chalcone, phosphorylated phloretin, phosphorylated phlo ⁇ zdin, phosphorylated genistein, phosphorylated biochanin A, phosphorylated catechin, or phosphorylated epicatechin, and (ii)
  • composition for oral administration comprising
  • a phosphonated pyrone analog that is phosphonated fisetin, phosphonated isofisetin, phosphonated flavon, phosphonated chrysin, phosphonated apigenin, phosphonated rhoifolin, phosphonated diosmin, phosphonated galangin, phosphonated mo ⁇ n, phosphonated rutin, phosphonated kaempferol, phosphonated my ⁇ cetin, phosphonated taxifolin, phosphonated na ⁇ ngenin, phosphonated na ⁇ ngin, phosphonated hesperetin, phosphonated hespe ⁇ din, phosphonated chalcone, phosphonated phloretin, phosphonated phlo ⁇ zdin, phosphonated genistein, phosphonated biochanin A, phosphonated catechin, or phosphonated epicatechjn, and ( ⁇ )
  • compositions may further comp ⁇ se (in) an effective amount of a lipid lowe ⁇ ng compound
  • compositions may further comp ⁇ se (in) an effective amount of a glucose lowe ⁇ ng compound
  • composition for oral administration comprising
  • compositions may further contain (in) an effective amount of a lipid lowering compound
  • compositions may further contain (in) an effective amount of a glucose lowering compound
  • compositions that include a phosphonated phosphorylated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin, that reduces or eliminates side effect of one or more substances
  • the substance is a therapeutic agent with which the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetm is co-administered "Co-adrrunistration," "administered in combination with,” and their grammatical equivalents, as used herein, encompasses administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at
  • the invention provides compositions containing a combination of a therapeutic agent and an agent that reduces or eliminates a side effect of the therapeutic agent
  • the invention provides pharmaceutical compositions that further include a pharmaceutically acceptable excipient
  • the pharmaceutical compositions are suitable for oral administration
  • the pharmaceutical compositions are suitable for transdermal administration
  • the pharmaceutical compositions are suitable for injection Other forms of administration are also compatible with embodiments of the pharmaceutical compositions of the invention, as described herein
  • the reduction or elimination of side effects is due to the modulation of a BTB transport protein by a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin and/or its metabolite
  • the BTB transport protein is an ABC transport protein
  • the BTB transport protein modulator is a BTB transport protein activator
  • the BTB transport protein modulator is a modulator of P-gP
  • the side effect modulator comprises a phosphonated polyphenol and/or its metabolite that acts as a BTB transport protein modulator
  • the side effect modulator comp ⁇ ses a phosphonated polyphenol and/or its metabolite which acts to lower a side effect of a therapeutic agent through a non- BTB transport protein-mediated mechanism, or that acts to lower a side effect of a therapeutic agent through a BTB transport protein-mediated mechanism and a non-BTB transport protein-mediated mechanism, is used
  • the phosphonated polyphenol is a phosphonated pyrone analog such as a phosphonated flavonoid
  • the phosphonated polyphenol is selected from the group consisting of phosphonated quercetin, phosphonated lsoquerce ⁇ n, phosphonated flavon, phosphonated chrysin, phosphon
  • the side effect is a side effect of the therapeutic agent that is reduced is selected from the group consisting of drowsiness, impaired concentration, sexual dysfunction, sleep disturbances, habituation, dependence, alteration of mood, respiratory depression, nausea, vomiting, lowered appetite, lassitude, lowered energy, dizziness, memory impairment, neuronal dysfunction, neuronal death, visual disturbance, impaired mentation, tolerance, addiction, hallucinations, lethargy, myoclonic jerking, endoc ⁇ nopathies, and combinations thereof
  • the side effect of the therapeutic agent that is reduced is selected from the group consisting of impaired concentration and sleep disturbances
  • the side effect of the therapeutic agent that is reduced is impaired concentration
  • the side effect of the therapeutic agent that is reduced is sleep disturbances
  • the side effect is a renal and/or urogenital side effect selected from the group consisting of nephrotoxicity, renal function impairment, creatinine increase, u ⁇ nary tract infection,
  • the therapeutic agent is an immunosuppressant
  • the immunosuppressant can be, for example, a calcineu ⁇ n inhibitor, e g , tacrolimus or a tacrolimus analog
  • the immunosuppressant can be, for example, sirolimus, tacrolimus, mycophenolate, methadone, cyclospo ⁇ n, prednisone, or voclospo ⁇ n
  • the therapeutic agent is an agent selected from the group of antivirals, antibiotics, antineoplastics, amphetamines, antihypertensives, vasodilators, barbiturates, membrane stabilizers, cardiac stabilizers, glucocorticoids, antilipedemics, antiglycemics, cannabinoids, antidepressants, antineuroleptics, and antnnfectives
  • the therapeutic agent is an antihypertensive
  • the therapeutic agent is an antunfective
  • the invention provides a composition containing a therapeutic agent and an phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, phosphonated 5,7-dideoxyquercetin, where the therapeutic agent is present in an amount sufficient to exert a therapeutic effect and the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, phosphonated 5,7-dideoxyquercetin and/or its metabolite is present in an amount sufficient to decrease a side effect of the therapeutic agent by a measurable amount, compared to the side effect without the phosphonated polyphenol, when the composition is administered to an animal
  • a side effect of the therapeutic agent is decreased by an average of at least about 1 , 5,
  • the invention provides compositions that contain a phosphonated polyphenol, e g , a phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin, and an immunosuppressive agent, e g , tacrolimus or sirohmus, where the immunosuppressive agent is present in an amount sufficient to exert an immunosuppressive effect and the phosphonated polyphenol, e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin is present in an amount sufficient to decrease side effect of the immunosuppressive agent by a measurable amount, compared to the side effect without the phosphonated polyphenol, when the composition is administered to an immunosuppressive agent, e g
  • the invention provides compositions that contain a phosphonated flavonol that is phosphonated quercetin, phosphonated isoquercetin, phosphonated flavon, phosphonated chrysin, phosphonated apigenin, phosphonated rhoifohn, phosphonated diosmin, phosphonated galangin, phosphonated fisetin, phosphonated mo ⁇ n, phosphonated rutin, phosphonated kaempferol, phosphonated my ⁇ cetin, phosphonated taxifolin, phosphonated naringenin, phosphonated na ⁇ ngin, phosphonated hesperetin, phosphonated hespe ⁇ din, phosphonated chalcone, phosphonated phloretin, phosphonated phlorizdin, phosphonated genistein, phosphonated 5, 7-dideoxyquercetin
  • the invention provides compositions that contains phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin and an immunosuppressant, e g , tacrolimus (FK-506) where the immunosuppressant, e g , tacrolimus, is present in an amount sufficient to exert an immunosuppressive effect and the phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin is present in an amount sufficient to decrease a side effect, or hyperglycemia, of the immunosuppressant by a measurable amount, compared to the side effect without the phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin when the composition is administered to an animal
  • the measurable amount may be an average of at least about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65
  • the phosphonated polyphenol, e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin and or its metabolite is a side effect modulator, e g BTB transport protein modulator, which is present in an amount sufficient to decrease a side effect of the therapeutic agent by a measurable amount and to increase a therapeutic effect of the therapeutic agent by a measurable amount, compared to the side effect and therapeutic effect without the side effect modulator, e g BTB transport protein modulator, when the composition is administered to an animal
  • a therapeutic effect of the therapeutic agent is increased by an average of at least about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or more than 95%, compared to the therapeutic effect without the side effect modul
  • an "average" as used herein is preferably calculated in a set of normal human subjects, this set being at least about 3 human subjects, preferably at least about 5 human subjects, preferably at least about 10 human subjects, even more preferably at least about 25 human subjects, and most preferably at least about 50 human subjects
  • the invention provides a composition that contains a therapeutic agent and a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin
  • the concentration of the therapeutic agents is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 1 1 %, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1
  • a concentration of the therapeutic agent is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19 75%, 19 50%, 19 25% 19%, 18 75%, 18 50%, 18 25% 18%, 17 75%, 17 50%, 17 25% 17%, 16 75%, 16 50%, 16 25% 16%, 15 75%, 15 50%, 15 25% 15%, 14 75%, 14 50%, 14 25% 14%, 13 75%, 13 50%, 13 25% 13%, 12 75%, 12 50%, 12 25% 12%, 1 1 75%, 1 1 50%, 1 1 25% 1 1 1 %, 10 75%, 10 50%, 10 25% 10%,
  • a concentration of the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19 75%, 19 50%, 19 25% 19%, 18 75%, 18 50%, 18 25% 18%, 17 75%, 17 50%, 17
  • the invention provides methods of treating tissue rejection, using therapeutic agents and the phosphonated compositions of the invention Any suitable type of tissue rejection, whether acute or chronic, may be treated by the methods of the invention
  • the invention provides a method of treating an animal for graft protection by administering to an animal at ⁇
  • a concentration of the therapeutic agent is in the range from approximately 0 0001 % to approximately 50%, approximately 0001 % to approximately 40 %, approximately 001 % to approximately 30%, approximately 002% to approximately 29%, approximately 003% to approximately 28%, approximately 004% to approximately 27%, approximately 0 05% to approximately 26%, approximately 0 06% to approximately 25%, approximately 007% to approximately 24%, approximately 008% to approximately 23%, approximately 009% to approximately 22%, approximately 0 1 % to approximately 21 %, approximately 0 2% to approximately 20%, approximately 0 3% to approximately 19%, approximately 0 4% to approximately 18%, approximately 0 5% to approximately 17%, approximately 0 6% to approximately 16%, approximately 0 7% to approximately 15%, approximately 0 8% to approximately 14%, approximately 0 9% to approximately 12%, approximately 1 % to approximately 10% w/w, w/v or v/v v/v in the composition In some embodiments, a concentration of the therapeutic agent is in the range from approximately
  • a concentration of the therapeutic agent is in the range from approximately 0 001 % to approximately 10%, approximately 0 01 % to approximately 5%, approximately 002% to approximately 4 5%, approximately 0 03% to approximately 4%, approximately 0 04% to approximately 3 5%, approximately 005% to approximately 3%, approximately 0 06% to approximately 2 5%, approximately 0 07% to approximately 2%, approximately 008% to approximately 1 5%, approximately 009% to approximately 1%, approximately 0 1 % to approximately 09% w/w, w/v or v/v in the composition
  • a concentration of the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin is in the range from approximately 0001 % to approximately 10%, approximately 0 01 % to approximately 5%, approximately 00
  • an amount of the therapeutic agent is equal to or less than 10 g, 9 5 g, 9 0 g, 8 5 g, 8 0 g, 7 5 g, 7 0 g, 6 5 g, 6 0 g, 5 5 g, 5 0 g, 4 5 g, 4 0 g, 3 5 g, 3 0 g, 2 5 g, 2 0 g, 1 5 g, 1 0 g, 0 95 g, 0 9 g, 0 85 g, 0 8 g, 0 75 g, 0 7 g, 0 65 g, 06 g, 0 55 g, 0 5 g, 0 45 g, 0 4 g, 0 35 g, 0 3 g, 0 25 g, 0 2 g, 0 15 g, 0 1 g, 009 g, 008 g, 007 g, 006 g,
  • an amount of the therapeutic agent is more than 0 0001 g, 00002 g, 0 0003 g, 00004 g, 00005 g, 00006 g, 00007 g, 0 0008 g, 00009 g, 0001 g, 00015 g, 0002 g, 00025 g, 0003 g, 00035 g, 0004 g, 00045 g, 0005 g, 0 0055 g, 0006 g, 00065 g, 0007 g, 0 0075 g, 0008 g, 0 0085 g, 0009 g, 0 0095 g, 001 g, 0 015 g, 0 02 g, 0025 g, 003 g, 0035 g, 004 g, 0045 g, 0 05 g, 0055 g, 006 g, 0 065 g, 007 g, 0075
  • an amount the therapeutic agent is in the range of 00001-10 g, 00005-9 g, 0001-8 g, 0005-7 g, 001-6 g, 005-5 g, 01-4 g, 05-4 g, or 1-3 g in the composition
  • an amount of the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin is in the range of 00001-10 g, 00005-9 g, 0001-8 g, 0005-7 g, 001-6 g, 005-5 g, 01-4 g, 05-4 g, or 1-3 g in the composition
  • a molar ratio of the therapeutic agent to the phosphonated polyphenol e g phosphonated pyrone analog such as a
  • the phosphonated polyphenols of the invention are usually administered in the form of pharmaceutical compositions
  • the drugs described above are also administered in the form of pharmaceutical compositions.
  • both components may be mixed into a preparation or the two components may be formulated into separate preparations to use them in combination separately or at the same time
  • compositions that contain, as the active ingredient, a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, earners, including inert solid diluents and fillers, diluents, including ste ⁇ le aqueous solution and various organic solvents, permeation enhancers, solubihzers and adjuvants
  • compositions that contain, as the active ingredient, a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin which acts as a side effect modulator, e g BTB transport protein modulator or a pharmaceutically acceptable salt and/or coordination complex thereof, a therapeutic agent or a pharmaceutically acceptable salt and/or coordination complex thereof, and one or more pharmaceutically acceptable excipients, earners, including inert solid diluents and fillers, diluents, including sterile aqueous solution and va ⁇ ous organic solvents, permeation enhancers, solubihzers and adjuvants [00384] Such compositions are prepared in a manner well known in the pharmaceutical art [00385] In some embodiments, the invention provides a pharmaceutical composition for oral administration containing a phosphonated quercetin
  • composition further comprising (iv) an effective amount of a second therapeutic agent
  • the pharmaceutical composition may be a solid pharmaceutical composition suitable for oral consumption
  • the therapeutic agent is an immunosuppressive agent In some embodiments, the therapeutic agent is a calcineu ⁇ n inhibitor In some embodiments, the therapeutic agent is tacrolimus or sirohmus In some embodiments, the phosphonated polyphenol, capable of reducing or eliminating one or more side effects of the therapeutic agent, is a BTB transport protein modulator In some embodiments, the BTB transport protein modulator is a BTB transport protein activator [00390] In some embodiments, the invention provides a pharmaceutical composition comp ⁇ sing
  • a therapeutic agent that is tacrolimus, sirolimus, mycophenolate, methadone, cyclosporin, prednisone, voclospo ⁇ n, oxycodone, gabapentin, pregabalin , hydrocodone, fentanyl, hydromorphone, levorphenol, morphine, methadone, mycophenolate, tramadol, hydromorphine, topiramate, diacetyl morphine, codeine, olanzapine, hydrocortisone, prednisone, sufentanyl, alfentanyl, carbamazapine, lamotrigine, doxepin, or halope ⁇ dol,
  • composition further contains (iv) an effective amount of a second therapeutic agent
  • second therapeutic agents include aspirin, acetaminophen, and ibuprofen
  • the pharmaceutical composition may be a solid pharmaceutical composition suitable for oral consumption
  • the invention provides a pharmaceutical composition comprising
  • the composition further contains (iv) an effective amount of a second therapeutic agent
  • second therapeutic agents include aspirin, acetaminophen, and ibuprofen
  • the pharmaceutical composition may be a solid pharmaceutical composition suitable for oral consumption In some embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral consumption
  • the invention provides a solid pharmaceutical composition for oral administration containing an effective amount of sirolimus, an amount of phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin that is effective in reducing or eliminating a side effect of sirolimus, and a pharmaceutically acceptable excipient
  • the composition further includes an effective amount of acetaminophen
  • the invention provides a liquid pharmaceutical composition for oral administration containing an effective amount of sirolimus, an amount of phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin that is effective in reducing or eliminating a side effect of sirolimus, and a pharmaceutically acceptable excipient
  • the composition further includes an effective amount of acetaminophen
  • the invention provides a solid pharmaceutical composition for oral administration containing sirolimus at about 1 - 160 mg, phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin at about 10-1000 mg and a pharmaceutically acceptable excipient
  • the invention provides a liquid pharmaceutical composition for oral administration containing sirolimus at about 1-200 mg/ml, phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin at about 10- 1000 mg/ml and a pharmaceutically acceptable excipient
  • the composition further includes acetaminophen at about 10-750 mg/ml
  • the invention provides a solid pharmaceutical composition for oral administration containing an effective amount of tacrolimus, an amount of phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-d ⁇ deoxyquercet ⁇ n that is effective in reducing or eliminating a side effect of tacrolimus, and a pharmaceutically acceptable excipient
  • the invention provides a liquid pharmaceutical composition for oral administration containing an effective amount of tacrolimus, an amount of phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin that is effective in reducing or eliminating a side effect of tacrolimus, and a pharmaceutically acceptable excipient
  • the invention provides a solid pharmaceutical composition for oral administration containing tacrolimus at about 1 - 160 mg, phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin at about 10-1000 mg and a pharmaceutically acceptable excipient
  • the composition further includes acetaminophen at about 200-750 mg
  • the invention provides a liquid pharmaceutical composition for oral administration containing tacrolimus at about 1-200 mg/ml, phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin at about 10- 1000 mg/ml and a pharmaceutically acceptable excipient
  • the invention provides a solid pharmaceutical composition for oral administration containing an effective amount of cyclospo ⁇ n, an amount of phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin that is effective in reducing or eliminating a side effect of cyclospo ⁇ n, and a pharmaceutically acceptable excipient
  • the invention provides a liquid pharmaceutical composition for oral administration containing an effective amount of cyclospo ⁇ n, an amount of phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin that is effective in reducing or eliminating a side effect of cyclospo ⁇ n, and a pharmaceutically acceptable excipient
  • the invention provides a solid pharmaceutical composition for oral administration containing cyclospo ⁇ n at about 100-800 mg, phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin at about 10-1000 mg and a pharmaceutically acceptable excipient
  • the invention provides a liquid pharmaceutical composition for oral administration containing cyclospo ⁇ n at about 5- 500 mg/ml, phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin at about 10- 1000 mg/ml and a pharmaceutically acceptable excipient HI.
  • Desc ⁇ bed herein are compounds, pharmaceutical compositions and methods for regulating, preventing, and treating one or more of cholesterol, chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL), high density lipoprotein (HDL), hyperhpidemia, hypercholesterolemia, triglycerides, hypert ⁇ glyce ⁇ demia, lipid transport, glucose intolerance, hyperglycemia, diabetes mellitus, atherosclerosis, hypertension, liver diseases (e g , NAFLD (Non-alcoholic fatty liver disease) or NASH (nonalcoholic steatohepatitis)), pancreatitis, obesity, kidney diseases, Niemann-Pick disease, cardiovascular disease, hypoinsulinemia, insulin resistance, vascular sentosis, inflammation, or development of atherosclerotic plaques by administe ⁇ ng an effective amount of a pyrone analog (or a de ⁇ vative thereof) or a phosphorylated
  • a method of maintaining cellular physiological conditions for cell survival comprising administe ⁇ ng to a subject in an effective amount of a pyrone analog that modulates activity of a cellular transporter
  • Cellular transporters include, but are not limited to, ABCA l, ABCA2, ABCA7, ALDP, ALDR, ABCG l , ABCG4, ABCG5, ABCG6 or ABCG8
  • a method of treating a disease comprising administe ⁇ ng to a subject an effective amount of a pyrone analog, wherein the pyrone analog modulates activity of a cell surface transporter
  • a method of treating a metabolic disease and promoting pancreatic function e g , increase islet cell function, increase islet cell survival, protection against hyperglycemia, protection against insulin insufficiency du ⁇ ng nut ⁇ ent stimulated insulin release and synthesis, protection against t ⁇ glyce ⁇ de elevation, protection against cholesterol elevation, protection against weight gain, protection against stress of glucose
  • a method of maintaining cellular physiological conditions for pancreatic islet cell survival comprising administering to a subject an effective amount of a pyrone analog
  • pancreatic cell stress or injury comprising administering to a subject an effective amount of at least one pyrone analog, wherein at least one effect of stress or injury is improved in one or more cell types of the subject
  • a pyrone analog modulates insulin levels in the subject In another embodiment, a pyrone analog modulates glucose levels in the subject In another embodiment, a pyrone analog modulates tnglyce ⁇ de levels in the subject In another embodiment, a pyrone analog modulates body weight in the subject In another embodiment, a pyrone analog modulates fat weight in the subject In another embodiment, a pyrone analog modulates adiponectin levels in the subject In another embodiment, a pyrone analog modulates cholesterol in the subject In another embodiment, a pyrone analog modulates high density lipoprotein levels in the subject In another embodiment, a pyrone analog modulates medium density lipoprotein levels in the subject In another embodiment, a pyrone analog modulates low density lipoprotein levels in the subject In another embodiment, a pyrone analog modulates very low density lipoprotein levels in the subject In another embodiment, a pyrone analog modulates prostaglandin levels in the subject In another embodiment, a pyrone analog modulates development of cancer in
  • HbA 1C Glycated hemoglobin
  • Adiponectin (also referred to as Acrp30, apM l) is a protein hormone that modulates a number of metabolic processes, including glucose regulation and fatty acid catabolism Adiponectin is secreted from adipose tissue into the bloodstream and is abundant in plasma relative to many hormones Levels of the hormone are inversely correlated with body fat percentage in adults, while the association in infants and young children is more unclear The hormone plays a role in the suppression of the metabolic derangements that may result in type 2 diabetes, obesity, atherosclerosis and non-alcoholic fatty liver disease (NAFLD) [00409] Somatostatin (also known as growth hormone inhibiting hormone (GHlH) or somatotropin release- inhibiting factor (SRIF)) is a peptide hormone that regulates the endoc ⁇ ne system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors and inhibition of the release of numerous secondary hormones Somatostatin has two active
  • Glucagon helps maintain the level of glucose in the blood by binding to glucagon receptors on hepatocytes, causing the liver to release glucose - stored in the form of glycogen - through a process known as glycogenosis As these stores become depleted, glucagon then encourages the liver to synthesize additional glucose by gluconeogenesis This glucose is released into the bloodstream Both of these mechanisms lead to glucose release by the liver, preventing the development of hypoglycemia Glucagon also regulates the rate of glucose production through lipolysis
  • Ghrelin is a hormone that signals appetite and stimulates food intake
  • Ghrehn is known to exist in at least two forms 1 ) n-octanoyl ghrelin in which the third se ⁇ ne residue is n-octanoylated and 2) des-n-octanoyl ghrelin in which the n-octanoyl group is removed
  • Ghrelin is the first identified peripheral hormone signaling appetite People who were given ghrelin increased their appetite resulting in up to one third more food intake than control subjects In addition to stimulating food intake, ghrelin levels drop once an individual starts eating Consequently, ghrelin may act as a trigger to start food intake, ghrelin levels do not fall after eating in obese individuals which suggests that this t ⁇ gger is not reset in such individuals
  • Vasoactive intestinal peptide is a 28 amino acid peptide This peptide belongs to a family of structurally related, small polypeptides that includes helodermin, secretin, the somatostatins, and glucagon
  • the biological effects of VIP are mediated by the activation of membrane-bound receptor proteins that are coupled to the intracellular cAMP signaling system
  • Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide belonging to the secretin/glucagon/vasoactive intestinal polypeptide (VIP) family
  • PACAP is a neuropeptide belonging to the secretin/glucagon/vasoactive intestinal polypeptide (VIP) family
  • the physiological function of the peptide is responsible for diverse roles such as the regulating actions on hormonal synthesis and secretion in pituitary and adrenal medulla, and the differentiation and growth-promoting actions of nerve cells and germ cells
  • PACAP immuno-positive nerve projects into islets, the expressions of a
  • Prostaglandins are a family of substances showing a wide diversity of biological effects Prostaglandins of the 1 -, 2-, and 3-se ⁇ es, respectively, incorporate one, two, or three double bonds in their basic 20-carbon carboxylic fatty acid structure which incorporates a 5-member cyclopentene ⁇ ng
  • the 1-se ⁇ es of prostaglandins are strong vasodilators, and inhibit cholesterol and collagen biosynthesis, as well as platelet aggregation
  • the 2-se ⁇ es prostaglandins are known to enhance platelet aggregation, cholesterol, and collagen biosynthesis, and also to enhance endothelial cell proliferation
  • the main effect of the 3-se ⁇ es prostaglandins, particularly PGE3 is the suppression of the 2-se ⁇ es prostaglandins
  • the precursor of the 2-se ⁇ es prostaglandins is arachidonic acid (AIl-Z- 5,8, 1 1 , 14-eicosatetraenoic acid) DH
  • a method of assessing cellular protective effects in pancreatic islet cells comprising i) selecting a patient for treatment based on one or more biomolecule levels in a sample compared to a control sample, ii) administering an effective amount of a pyrone analog to a subject, and in) monitoring said one or more biomolecule levels in a subject
  • Biomolecules include, but are not limited to, insulin, somatostatin, glucagon, grehlin, VIP, glucose, and adiponectin In one embodiment, insulin levels are stable and do not decrease
  • Certain biomarkers biomolecules
  • biomolecules can be expressed at increased or decreased levels in response to administration of a pyrone analog to a patient
  • the term "expression,” when used in connection with detecting the expression of a gene, can refer to detecting transcription of the gene and/or to detecting translation of the gene
  • To detect expression of a gene refers to the act of actively determining whether a gene is expressed or not This can include determining whether the gene expression is upregulated as compared to a control, downregulated as compared to a control, or unchanged as compared to a control Therefore, the step of detecting expression does not require that expression of the gene actually is upregulated or downregulated, but rather, can also include detecting that the expression of the gene has not changed (i e , detecting no expression of the gene or no change in expression of the gene)
  • Biomarkers (biomolecules) to be assessed in connection with the present invention include, but are not limited to, insulin, somatostatin, glucagon, grehlin, VlP, glucose, amylin, GP-I and adiponectin [00419] For assessment of biomark
  • immunological methods can be used to detect such proteins on whole cells, or well known computer-based sequence analysis methods can be used to predict the presence of at least one extracellular domain (i e , including both secreted proteins and proteins having at least one cell-surface domain)
  • Expression of a marker protein having at least one portion which is displayed on the surface of a cell which expresses it can be detected without necessarily lysing the cell (e g , using a labeled antibody which binds specifically with a cell-surface domain of the protein)
  • Expression of biomarkers can be assessed by any of a wide va ⁇ ety of well known methods for detecting expression of a transcribed nucleic acid or protein
  • Non-limiting examples of such methods include, for example, immunological methods for detection of secreted, cell-surface, cytoplasmic, or nuclear proteins, protein pu ⁇ fication methods, protein function or activity assays, nucleic acid hybridization methods, nucleic acid reverse transcription methods, and nucleic acid amplification methods or any other method known in the art
  • a mixture of transcribed polynucleotides obtained from the sample can be contacted with a substrate having fixed thereto a polynucleotide complementary to or homologous with at least a portion (e g , at least 7, 10, 15, 20, 25, 30, 40, 50, 100, 500, or more nucleotide residues) of a biomarker nucleic acid If polynucleotides complementary to, or homologous with, are differentially detectable on the substrate (e g , detectable using different chromophores or fluorophores, or fixed to different selected positions), then the levels of expression of a plurality of biomarkers can be assessed simultaneously using a single substrate (e g , a "gene chip" microarray of polynucleotides fixed at selected positions) When a method of assessing biomarker expression is used which involves hybridization of one nucleic acid with another, hybridization can be performed under st ⁇ ngent hybridization conditions [00423] An exemplary method for detecting
  • a general principle of such diagnostic and prognostic assays involves preparing a sample or reaction mixture that may contain a biomarker, and a probe, under appropriate conditions and for a time sufficient to allow the biomarker and probe to interact and bind, thus forming a complex that can be removed and/or detected in the reaction mixture
  • biomarker/probe complex formation without further manipulation or labeling of either component (biomarker or probe), for example by utilizing the technique of fluorescence energy transfer (i e , FET, see for example, Lakowicz et al , U S Pat No 5,631 , 169, and Stav ⁇ anopoulos, et al , U S Pat No 4,868, 103)
  • determination of the ability of a probe to recognize a biomarker can be accomplished without labeling either assay component (probe or biomarker) by utilizing a technology such as realtime Biomolecular Interaction Analysis (BIA, see, e g , Sjolander, S and Urbaniczky, C , 1991 , Anal Chem 63 2338-2345 and Szabo et al , 1995, Curr Opin Struct Biol 5 699-705)
  • BIOA or "surface plasmon resonance” refer to a technology for studying biospecific interactions in real time, without labeling any of the interactants (e g , BIAcore) Changes in the mass at the binding surface (indicative of a binding event) result in alterations of the refractive index of light near the surface (the optical phenomenon of surface plasmon resonance (SPR)), resulting in a detectable signal which can be used as an indication of real-time reactions between biological molecules
  • determinations can be based on the normalized expression level of the biomarker
  • Expression levels are normalized by correcting the absolute expression level of a biomarker by compa ⁇ ng its expression to the expression of a gene that is not a biomarker, e g , a housekeeping gene that is constitutively expressed
  • Suitable genes for normalization include housekeeping genes such as the actin gene, or epithelial cell-specific genes This normalization allows the compa ⁇ son of the expression level in one sample, e g , a patient sample, to another sample, e g , a non-tumor sample, or between samples from different sources
  • the expression level can be provided as a relative expression level
  • the level of expression of the biomarker is determined for 10 or more, 20 or more, 30 or more, 40 or more, or 50 or more samples of normal versus cell isolates p ⁇ or to the determination of the expression level for the sample in question
  • the mean expression level assayed in the larger number of samples is determined and this is used as a baseline expression level for the biomarker
  • the expression level of the biomarker determined for the test sample absolute level of expression
  • a biomarker protein is detected
  • One type of agent for detecting biomarker protein is an antibody capable of binding to such a protein or a fragment thereof such as, for example, a detectably labeled antibody
  • Antibodies can be polyclonal or monoclonal An intact antibody, or an antigen binding fragment thereof (e g , Fab, F(ab')2, Fv, scFv, single binding chain polypeptide) can be used.
  • the term "labeled,” with regard to the probe or antibody is intended to encompass direct labeling of the probe or antibody by coupling (i e , physically linking) a detectable substance to the probe or antibody, as well as indirect labeling of the probe or antibody by reactivity with another reagent that is directly labeled
  • Examples of indirect labeling include detection of a p ⁇ mary antibody using a fluorescently labeled secondary antibody and end-labeling of a DNA probe with biotin such that it can be detected with fluorescently labeled streptavidin
  • pancreatic pancreas consists primarily of islet cells that synthesize and secrete the peptide hormone glucagon, insulin, somatostatin and pancreatic polypeptide Insulin gene expression is restricted to pancreatic islet beta-cells of the mammalian pancreas through control mechanisms mediated, in part, by transcription factors [00431]
  • pancreatic gene expression profile is meant to include one or more genes that are normally transcriptionally silent in non-endoc ⁇ ne tissues, e g , a pancreatic transcription factor an endoc ⁇ ne gene, or an exocrine gene, for example, expression of PCl/3, insulin, glucagon, somatostatin or endogenous PDX- I
  • the method includes administering to a subject a pyrone analog and assessing gene expression in a sample obtained from said subject [00432] Induction of a pancre
  • Cholesterol is a lipid found in the cell membranes and transported in the blood plasma of all animals It is an essential component of mammalian cell membranes where it is required to establish proper membrane permeability and fluidity Cholesterol is the principal sterol synthesized by animals while smaller quantities are synthesized in other eukaryotes such as plants and fungi In contrast cholesterol is almost completely absent among prokaryotes Most cholesterol is synthesized by the body but significant quantities can also be absorbed from the diet While minimum level of cholesterol is essential for life, excess can contribute to diseases such as atherosclerosis
  • cholesterol Since cholesterol is insoluble in blood, it is transported in the circulatory system within lipoproteins, complex spherical particles which have an exte ⁇ or composed mainly of water-soluble proteins, fats and cholesterol are earned internally There is a large range of lipoproteins within blood, generally called, from larger to smaller size chylomicrons, very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL), low density lipoprotein (LDL) and high density lipoprotein (HDL)
  • VLDL very low density lipoprotein
  • IDL intermediate density lipoprotein
  • LDL low density lipoprotein
  • HDL high density lipoprotein
  • Cholesterol is minimally soluble in water, it cannot dissolve and travel in the water-based bloodstream Instead, it is transported in the bloodstream by lipoproteins that are water-soluble and carry cholesterol and t ⁇ glyce ⁇ des internally
  • the apolipoproteins forming the surface of the given lipoprotein particle determine from what cells cholesterol will be removed and to where it will be supplied
  • Chylomicrons are the largest ( 1000 nm) and least dense ( ⁇ 0 95) of the lipoproteins They contain only 1 -2% protein, 85-88% triglycerides, ⁇ 8% phospholipids, -3% cholesteryl esters and - 1 % cholesterol Chylomicrons contain several types of apolipoproteins including apo-AI, II & IV, apo-B48, apo-CI, II & III, apo-E and apo-H Chylomicrons are produced for the purpose of transporting dietary triglycerides and cholesterol absorbed by intestinal epithelia Chylomicron assembly originates in the intestinal mucosa Excretion into the plasma is facilitated through the lymphatic system In the plasma, chylomicrons acquire apo-ClI and apo-E from HDL Once transported to tissues, triglycerides contained in chylomicrons are hydrolyzed by apo-CII-dependent activation of lipoprotein lipase contained on the end
  • VLDL Very Low Density Lipoproteins
  • Very low density lipoproteins are the next step down from chylomicrons in terms of size and lipid content They are approximately 25-90 nm in size (MW 6-27 million), with a density of -0 98 They contain 5- 12% protein, 50-55% t ⁇ glyce ⁇ des, 18-20% phospholipids, 12- 15% cholesteryl esters and 8- 10% cholesterol VLDL also contains several types of apohpoproteins including apo-B 100, apo-CI, II & III and apo-E VLDL also obtains apo-CII and apo-E from plasma HDL VLDL assembly in the liver involves the early association of lipids with apo-B 100 mediated by microsomal triglyceride transfer protein while apo-B 100 is translocated to the lumen of the ER Lipoprotein lipase also removes triglycerides from VLDL in the same way as from chylomicrons
  • Intermediate density lipoproteins are smaller than VLDL (40 nm) and more dense (- 1 0) They contain the same apolipoproteins as VLDL They are composed of 10-12% protein, 24-30% triglycerides, 25-27% phospholipids, 32-35% cholesteryl esters and 8- 10% cholesterol IDLs are derived from t ⁇ glyce ⁇ de depletion of VLDL IDLs can be taken up by the liver for reprocessing, or upon further triglyceride depletion, become LDL
  • LDL Low Density Lipoproteins
  • a Lipoprotein
  • Low density lipoproteins are smaller than IDL (26 nm) (MW approximately 3 5 million) and more dense (- 1 04) They contain the apolipoprotein apo-B 100 LDL contains 20-22% protein, 10- 15% t ⁇ glyce ⁇ des, 20-28% phospholipids, 37-48% cholesteryl esters and 8- 10% cholesterol LDL and HDL transport both dietary and endogenous cholesterol in the plasma LDL is the main transporter of cholesterol and cholesteryl esters and makes up more than half of the total lipoprotein in plasma LDL is absorbed by the liver and other tissues via receptor mediated endocytosis The cytoplasmic domain of the LDL receptor facilitates the formation of coated pits, receptor- ⁇ ch regions of the membrane The ligand binding domain of the receptor recognizes apo-B 100 on LDL, resulting in the formation of a clathrin-coated vesicle ATP-dependent proton pumps lower the pH inside the vesicle resulting dissociation of LDL from its
  • High density lipoproteins are the smallest of the lipoproteins (6- 12 5 nm) (MW 175-500KD) and most dense (- 1 12) HDL contains several types of apohpoproteins including apo-AI, Il & IV 1 apo-CI, Il & III, apo-D and apo-E HDL contains approximately 55% protein, 3- 15% t ⁇ glyce ⁇ des, 26-46% phospholipids, 15-30% cholesteryl esters and 2- 10% cholesterol HDL is produced as a protein ⁇ ch particle in the liver and intestine, and serves as a circulating source of Apo-CI & II and Apo-E proteins
  • the HDL protein particle accumulates cholesteryl esters by the este ⁇ fication of cholesterol by lecithin-cholesterol acyl-transferase (LCAT) LCAT is activated by apo-AI on HDL HDL can acquire cholesterol from cell membranes and can transfer cholesteryl esters to VLDL and LDL via transfera
  • Hyperlipidemia is an elevation of lipids in the bloodstream These lipids include cholesterol, cholesterol esters, estersphosphohpids and triglycerides Lipid and lipoprotein abnormalities are considered as a highly modifiable risk factor for cardiovascular disease due to the influence of cholesterol, one of the most clinically relevant lipid substances, on atherosclerosis In addition, some forms may predispose to acute pancreatitis
  • Hyperchlesterolemia refers to an abnormally high cholesterol level
  • Higher concentrations of LDL and lower concentrations of functional HDL are strongly associated with cardiovascular disease because these promote atheroma development in arteries (atherosclerosis)
  • This disease process leads to myocardial infarction (heart attack), stroke and peripheral vascular disease
  • LDL particles are often termed "bad cholesterol” because they have been linked to atheroma formation
  • high concentrations of functional HDL which can remove cholesterol from cells and atheroma, offer protection and are sometimes referred to colloquially as "good cholesterol"
  • Elevated levels of the lipoprotein fractions, LDL, IDL and VLDL are regarded as atherogenic (prone to cause atherosclerosis) Levels of these fractions, rather than the total cholesterol level, correlate with the extent and progress of atherosclerosis Conversely, the total cholesterol can be within normal limits, yet be made up p ⁇ ma ⁇ ly of small LDL and small HDL particles, under which conditions atheroma growth rates would still be high In contrast, however, if LDL particle number is low (mostly large particles) and a large percentage of the HDL particles are large, then atheroma growth rates are usually low, even negative, for any given total cholesterol concentration [00446] Multiple human t ⁇ als utilizing HMG-CoA reductase inhibitors, known as statins, have repeatedly confirmed that changing lipoprotein transport patterns from unhealthy to healthier patterns significantly lowers cardiovascular disease event rates, even for people with cholesterol values currently considered low for adults As a result, people with a history of cardiovascular disease may derive benefit from statins irrespective of statins
  • the desirable LDL level is considered to be less than 100 mg/dL (2 6 mmol/L), although a newer target of ⁇ 70 mg/dL can be considered in higher ⁇ sk individuals based on some of the above-mentioned trials
  • a ratio of total cholesterol to HDL, another useful measure, of far less than 5 1 is thought to be healthier
  • Triglyceride also known as t ⁇ acylglycerol, TAG or tnacylglyce ⁇ de is glyce ⁇ de in which the glycerol is este ⁇ fied with three fatty acids Triglycerides, as major components of VLDL and chylomicrons, play an important role in metabolism as energy sources and transporters of dietary fat In the intestine, triglycerides are split into glycerol and fatty acids via lipolysis, which are then moved into the cells lining the intestines (absorptive enterocytes) The t ⁇ glyce ⁇ des are rebuilt in the enterocytes from their fragments and packaged together with cholesterol and proteins to form chylomicrons These are excreted from the cells and collected by the lymph system and transported to the large vessels near the heart before being mixed into the blood Various tissues can capture the chylomicrons, releasing the t ⁇ glyce ⁇ des to be used as a source of energy Fat and liver cells can synthesize and store
  • T ⁇ glyce ⁇ de levels as tested after fasting 8 to 12 hours [00451]
  • a method of treating acute hypertriglyceridemia during acute lymphoblastic leukemia by administering to a patient an effective amount of a pyrone analog, such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin, which reduces or eliminates hypertriglyceridemia and/or one or more symptoms of hypertriglyceridemia
  • ATP-binding cassette transporters are members of a superfamily, i e , ATP-mediated transporter family that is one of the largest and most ancient families with representatives in all extant phyla from prokaryotes to humans These are transmembrane proteins that function in the transport of a wide variety of substrates across extra- and intracellular membranes, including metabolic products, lipids and sterols, and drugs Proteins are classified as ABC transporters based on the sequence and organization of their ATP-binding domain(s), also known as nucleotide-binding folds (NBFs) ABC transporters are involved in tumor resistance, cystic fibrosis, bacte ⁇ al multidrug resistance, and a range of other inherited human diseases
  • ABC-transporters utilize the energy of ATP hydrolysis to transport various substrates across cellular membranes within eukaryotes, ABC-transporters mainly transport molecules to the outside of the plasma membrane or into membrane-bound organelles such as the endoplasmic reticulum, mitochondria, etc
  • the transported compounds include but are not limited to lipids and sterols, ions and small molecules, drugs and large polypeptides
  • the lipid transport protein is an ABC transport protein
  • the lipid transport protein modulator is a lipid transport protein activator
  • the lipid transport protein modulator is a modulator of ABCA I , ABCA2, ABCA7, ALDP, ALDR, ABCG 1 , ABCG4, ABCG5, ABCG6 or ABCG8
  • the lipid transport protein modulator is a modulator of ABCA 1
  • the lipid transport protein modulator is a modulator of ABCG l
  • the lipid transport protein modulator is a modulator of ABC
  • the pyrone analog modulates a cholesterol transporter
  • the cholesterol transporter is ATP-binding cassette, sub-family A member 1 (ABCAl )
  • the ABCA l gene belongs to a group of genes called the ATP-binding cassette family, which provides instructions for making proteins that transport molecules across cell membranes This transporter is a major regulator of cellular cholesterol and phospholipid homeostasis With cholesterol and phospholipids as its substrate, this protein functions as a cholesterol and phospholipids efflux pump in the cellular lipid removal pathway Mutations in this gene have been associated with Tangier's disease
  • PPAR ⁇ has been implicated in the regulation of CD36 expression and macrophage uptake of oxidized LDL (oxLDL)
  • oxLDL oxidized LDL
  • PPAR ⁇ regulates a pathway of cholesterol efflux PPAR ⁇ induces ABCA l expression and cholesterol removal from macrophages through a transcriptional cascade mediated by the nuclear receptor LXR alpha
  • Ligand activation of PPAR ⁇ leads to primary induction of LXR alpha and to coupled induction of ABCA l
  • Transplantation of PPAR ⁇ null bone marrow into LDLR -/- mice results in a significant increase in atherosclerosis, consistent with the hypothesis that regulation of LXR alpha and ABCA l expression is protective in vivo
  • PPAR ⁇ coordinates a complex physiologic response to oxLDL that involves particle uptake, processing, and cholesterol removal through ABCAl
  • ATP-binding cassette, sub-family G member 1 is another cholesterol transporter
  • ABCG l sub-family G member 1
  • Hyperglycemia or high blood sugar is a condition in which an excessive amount of glucose circulates in the blood plasma This is generally a blood glucose level of 100+ mmol/L, but symptoms and effects may not start to become noticeable until later numbers such as 150-200+ mmol/L
  • Hypoinsulinemia is a condition wherein lower than normal amounts of insulin circulate throughout the body and wherein obesity is generally not involved This condition includes Type I diabetes
  • Diabetes mellitus is encompassed within insulin resistance and hypoinsulinemia and refers to a state of chronic hyperglycemia, i e , excess sugar in the blood, consequent upon a relative or absolute lack of insulin action
  • diabetes mellitus is encompassed within insulin resistance and hypoinsulinemia and refers to a state of chronic hyperglycemia, i e , excess sugar in the blood, consequent upon a relative or absolute lack of insulin action
  • Type 1 or insulin-dependent diabetes mellitus IDDM
  • Type 2 or non-insulin-dependent diabetes mellitus NIDDM
  • Type A insulin resistance results from either mutations in the insulin receptor gene or defects in post-receptor sites of action c ⁇ tical for glucose metabolism
  • Diabetic subjects can be easily recognized by the physician, and are characterized by fasting hyperglycemia, impaired glucose tolerance, glycosylated hemoglobin, and, in some instances, ketoacidosis associated with trauma or illness
  • Non-insulin dependent diabetes mellitus or “NIDDM” refers to Type 2 diabetes NIDDM patients have an abnormally high blood glucose concentration when fasting and delayed cellular uptake of glucose following meals or after a diagnostic test known as the glucose tolerance test Diabetes mellitus is a syndrome of disordered metabolism, usually due to a combination of hereditary and environmental causes, resulting in hyper
  • ABCA l and ABCG l are highly expressed in pancreatic islet cells
  • Mice with specific inactivation of ABCA 1 in pancreatic ⁇ -cells had markedly impaired glucose tolerance and defective insulin secretion but normal insulin sensitivity
  • Islets isolated from these mice showed altered cholesterol homeostasis and impaired insulin secretion in vitro Modulating the activities of pancreatic ABCA l and ABCG l is expected to improve pancreatic islet function and normalize glucose stimulated insulin secretion
  • ABCA I and ABCG l are expressed in skeletal muscles Excess fatty acid stored in skeletal muscle cells interferes with insulin signaling and desensitize insulin induced glucose uptake Modulating the activities of skeletal muscle ABCA l and ABCG l is expected to improve muscle glucose uptake and reduce insulin resistance
  • a method of treating diabetes melhtus by administering to a patient, e g a diabetic patient an effective amount of a pyrone analog, such as phosphorylated or phosphonated f ⁇ setin or phosphorylated or phosphonated quercetin, which reduces or eliminates hyperglycemia and/or one or more symptoms of hyperglycemia Modulation of insulin regulation, glucose tolerance, and glucose transport can be evaluated with a variety of imaging and assessment techniques known in the art
  • Assessment cnte ⁇ a known in the art include, but are not limited to assessment of insulin levels, assessment of blood glucose levels and glucose uptake studies by oral glucose challenge, assessment of cytokin
  • a method of treating hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia by administering one or more pyrone analogs, which modulate and activate ABCAl and ABCG l , thereby increasing cholesterol and phospholipid efflux from cells containing excess lipids to ApoA l and HDL particles in circulating blood
  • the reduced cellular levels of cholesterol and fatty acids restore or normalize glucose- stimulated insulin-induced glucose uptake and ⁇ -cell energy metabolism, and also restore glucose sensing through increased insulin synthesis and release as well as ⁇ -cell expansion
  • a method of treating hyperhpidemia the method comp ⁇ sing administering a therapeutically effective amount of a pyrone analog to a subject in need thereof, wherein the pyrone analog reduces hyperhpidemia and/or one or more symptoms associated with hyperhpidemia in the subject
  • a method of treating hypercholesterolemia the method comp ⁇ sing administering a therapeutically effective amount of a pyrone analog to a subject in need thereof, wherein the pyrone analog reduces hypercholesterolemia and/or one or more symptoms associated with hypercholesterolemia in the subject
  • a method of treating hypertriglyceridemia the method comp ⁇ sing administe ⁇ ng a therapeutically effective amount of a pyrone analog to a subject in need thereof, wherein the pyrone analog reduces hypert ⁇ glyce ⁇ demia and/or one or more symptoms associated with hypert ⁇ glyce ⁇ demia in the
  • Inflammatory mediator responses (e g , PGE2, IL- I beta, and TNF-alpha) represent a ⁇ sk marker for periodontal diseases in insulin-dependent diabetes mellitus patients
  • Tumor necrosis factor (TNF 1 ) is a cytokine produced primarily by monocytes and macrophages TNF is found in higher amounts within the plasma of patients with diabetes
  • TNF 1 Tumor necrosis factor
  • a method of lowering levels of TNF in a diabetic patient Also provided herein are methods for facilitating metabolic control in a subject In one aspect, the method for facilitating metabolic control in a subject decreases the level of IL- I beta in the subject
  • the methods described herein generally involve the administration of one or more drugs for the treatment of one or more diseases
  • Combinations of agents can be used to treat one disease or multiple diseases or to modulate the side-effects of one or more agents in the combination
  • a pyrone analog and a lipid or glucose-lowering compound as described herein are used in combination for treatment of a condition such as diabetes mellitus
  • any suitable ratio of the two agents e g , molar ratio, wt/wt ratio, wt/volume ratio, or volume/volume ratio, as described herein, may be used
  • provided herein are methods for treating hyperhpidemia associated diseases by administering to a subject in need a pyrone analog or a derivative thereof that modulates a lipid transporter.
  • methods for treating hyperglycemia associated diseases by administering to a subject in need a pyrone analog or a de ⁇ vative thereof that modulates a lipid transporter
  • Cardiovascular disease refers to the class of diseases that involve the heart or blood vessels (arteries and veins) While the term technically refers to any disease that affects the cardiovascular system, it is usually used to refer to those related to atherosclerosis (arterial disease) These conditions have similar causes, mechanisms, and treatments
  • Atherosclerosis the most prevalent of cardiovascular diseases, is the p ⁇ ncipal cause of heart attack, stroke, and gangrene of the extremities, and thereby a principle cause of death Atherosclerosis is a complex disease involving many cell types and molecular factors
  • SMCs smooth muscle cells
  • SMCs smooth muscle cells
  • the advanced lesions of atherosclerosis may occlude the artery concerned, and result from an excessive lnflammatory-fibroprohferative response to numerous different forms of insult
  • shear stresses are thought to be responsible for the frequent occurrence of atherosclerotic plaques in regions of the circulatory system where turbulent blood flow occurs, such as branch points and irregular structures
  • Foam cells are cells in an atheroma derived from both macrophages and smooth muscle cells which have accumulated low density lipoproteins, LDLs, by endocytosis
  • LDLs low density lipoproteins
  • Foam cells can also be known as fatty like streaks and typically line the intima media of the vasculature
  • Foam cells can become a health problem when they accumulate at a particular foci, thus creating a necrotic center of the atherosclerosis If the fibrous cap that prevents the necrotic center from spilling into the lumen of a vessel ruptures, a thrombus can form which can lead to emboli occluding smaller vessels The occlusion of small vessels results in ischemia, and contributes to stroke and myocardial infarction, two of the leading causes of cardiovascular-related death
  • Vascular stenosis is a pathological condition which often results from vascular trauma or damage to blood vessel walls Vascular trauma or damage is relatively common when a patient undergoes vascular surgery or other therapeutic techniques such as angioplasty
  • vascular stenosis is used in a broad sense and refers to a pathological process in which the cavity of a blood vessel is narrowed and which usually results in a pathological condition characterized by impaired flow through the vessel Following administration of a compound described herein to a patient, the patient's physiological condition can be monitored in various ways well known to the skilled practitioner
  • Atherosclerosis is a disease affecting arterial blood vessels It is a chronic inflammatory response in the walls of arteries, in large part due to the accumulation of foam cells de ⁇ ved from macrophage white blood cells promoted by oxidized low density lipoproteins (oxLDL) and without adequate removal of fats and cholesterol from the macrophages by high density lipoproteins (HDL) Increased activity of ABCA l and ABCGl are expected to increase removal of cholesterol and lipids from macrophages and prevent the development of foam cells
  • oxLDL oxidized low density lipoproteins
  • HDL high density lipoproteins
  • a method of treating atherosclerosis by administering a pyrone analog or a de ⁇ vative thereof to a subject Pyrone analogs or derivatives thereof may also be administered in combination with other agents to treat atherosclerosis
  • a pyrone analog or a derivative thereof may be co-administered with a statin, niacin, low dose aspi ⁇ n, intestinal cholesterol absorption-inhibiting supplements (ezetimibe and others, and to a much lesser extent fibrates), or a combination thereof
  • a pyrone analog or a de ⁇ vative thereof to a subjec Hypertension also referred to as high blood pressure
  • a subjec Hypertension also referred to as high blood pressure
  • hypertension is related to hyperglycemia and hyperhpidemia
  • insulin may stimulate sympathetic activity without elevating mean arterial pressure
  • the increased sympathetic neural activity may over- ⁇ de the vasodilatory effects of insulin Insulin resistance and/or hype ⁇ nsulinemia have been suggested as being responsible for the increased arterial pressure in some patients with hypertension
  • antihypertensives which, by varying means, act by lowering blood pressure
  • ACE inhibitors angiotensin II receptor antagonists
  • alpha blockers beta blockers
  • calcium channel blockers direct renin inhibitors
  • diuretics drugs for treating hypertension
  • Hypercholesterolemia is a common feature of primary biliary cirrhosis (PBC) and other forms of cholestatic liver disease
  • Primary biliary cirrhosis is an autoimmune disease of the liver marked by the slow progressive destruction of the small bile ducts (bile canaliculi) within the liver When these ducts are damaged, bile builds up in the liver (cholestasis) and over time damages the tissue This can lead to scarring, fibrosis, cirrhosis, and ultimately liver failure
  • Hyperlipemia with a marked increase of low-density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol levels is a common feature in patients with chronic cholestatic liver disease (Matteo Longo Current Treatment Options in Gastroenterology, 2007)
  • pancreatitis is the inflammation of the pancreas
  • hypertriglyceridemia but not hypercholesterolemia
  • triglyceride values exceed 1500 mg/dl ( 16 mmol/L)
  • development of pancreatitis in pregnant women could be a reflection of the hypertriglyceridemia because estrogen may raise blood triglyceride levels
  • a method of treating acute hyperlipidemic pancreatitis in pregnancy by administering to a patient an effective amount of a pyrone analog, such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin, which reduces or eliminates hyperhpidemia and/or one or more symptoms of hyperlipidemia
  • Metabolic syndrome is a combination of medical disorders which often includes diabetes mellitus type 2, high blood pressure, high blood cholesterol, and triglyceride levels (Grundy SM (2004), J Clin Endocrinol Metab 89(6) 2595-600)
  • Orlistat which reduces intestinal fat absorption by inhibiting pancreatic lipase
  • sibutrarrune which is a specific inhibitor of the neurotransmitters norepinephrine, serotonin, and dopamine in the brain Orlistat and ⁇ monabant lead to a reduced incidence of diabetes, and all drugs have some effect on cholesterol Kidney diseases
  • kidney diseases Diabetes is the most common cause of chronic kidney disease and kidney failure, accounting for nearly 44 percent of new cases Even when diabetes is controlled, the disease can lead to chronic kidney disease and kidney failure Most people with diabetes do not develop chronic kidney disease that is severe enough to progress to kidney failure Nearly 24 million people in the United States have diabetes, and nearly 180,000 people are living with kidney failure as a result of diabetes High blood pressure, or hypertension, is a major factor in the development of kidney problems in people with diabetes
  • Niemann-Pick disease is one of a group of lysosome storage diseases that affect metabolism and that are caused by genetic mutations
  • the three most commonly recognized forms are Niemann-Pick Types A, B and C Niemann-Pick Type C (NPC) patients are not able to metabolize cholesterol and other lipids properly within the cell
  • NPC Niemann-Pick Type C
  • cholesterol and glycolipids are the mate ⁇ als being stored rather than sphingomyelin
  • These fats have va ⁇ ed roles in the cell
  • Cholesterol is normally used to either build the cell, or forms an ester
  • NPC Niemann-Pick Type C
  • ⁇ are methods that can be used to prevent or treat other disorders including but not limited to eating disorders that result in hyperlipemia and/or hyperglycemia
  • eating disorders that result in hyperlipemia and/or hyperglycemia
  • hyperglycemia occurs naturally during times of infection and inflammation
  • endogenous catecholamines are released that serve to raise the blood glucose levels
  • compounds of the present invention may be administered in combination with hpid- lowe ⁇ ng compounds
  • Atorvastatin (marketed under the name Lipitor, Lipidra, Aztor, Torvatin, Sortis, Torvast, Torvacard, Totalip, Tulip, Xarator, Atorpic, Lip ⁇ mar, Atorhp and other names), is a member of the drug class known as statins, used for lowe ⁇ ng blood cholesterol Atorvastatin inhibits the rate-determining enzyme located in hepatic tissue that produces mevalonate, a small molecule used in the synthesis of cholesterol and other mevalonate derivatives This lowers the amount of cholesterol produced which in turn lowers the total amount of LDL cholesterol
  • atorvastatin is a competitive inhibitor of HMG-CoA reductase It is a completely synthetic compound HMG- CoA reductase catalyzes the reduction of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) to mevalonate, which is the rate-limiting step in hepatic cholesterol biosynthesis Inhibi
  • Atorvastatin calcium tablets are currently marketed by Pfizer under the trade name Lipitor®, in tablets ( 10, 20, 40 or 80 mg) for oral administration Tablets are white, elliptical, and filrn coated Pfizer also packages the drug in combination with other drugs, such as is the case with its Caduet Lipitor
  • the recommended Lipitor dosage for patients who arejust starting the medication is Lipitor 10 mg to 20 mg once a day, however, some people may start on Lipitor 40 mg once a day if their cholesterol is extremely high
  • the recommended Lipitor dosage for children ages 10 to 17 is begins at Lipitor 10 mg once a day, the maximum recommended dose for children is Lipitor 20 mg
  • Drugs that decrease triglyceride level include but are not limited to ascorbic acid, asparaginase, clofibrate, colestipol, fenofibrate mevastatin, pravastatin, simvastatin, fluvastatin, or omega-3 fatty acid
  • Drugs that decrease LDL cholesterol level include but are not limited to clofibrate, gemfibrozil, and fenofibrate, nicotinic acid, mevinolin, mevastatin, pravastatin, simvastatin, fluvastatin, lovastatin, cholesty ⁇ ne, colestipol or probucol
  • compounds of the present invention may be administered in combination with glucose- lowe ⁇ ng compounds
  • thiazohdinedione also called ghtazones
  • TZDs Thiazolidinediones
  • PPARs peroxisome proliferator-activated receptors
  • PPAR ⁇ gamma
  • the normal ligands for these receptors are free fatty acids (FFAs) and eicosanoids
  • FFAs free fatty acids
  • eicosanoids When activated, the receptor migrates to the DNA, activating transcription of a number of specific genes
  • the members of thus class are derivatives of the parent compound thiazohdinedione, and include but are not limited to Rosiglitazone (Avandia) and Pioglitazone (Actos)
  • the oral dosage for monotherapy is 15-30 mg once daily, if response is inadequate, the dosage may be increased in increments up to 45 mg once daily
  • the maximum recommended dose is 45 mg once
  • Drugs that decrease glucose level include but are not limited to glipizide, exenatide, incretins, sitagliptin, pioghtizone, glimepi ⁇ de, rosiglitazone, metformin, exantide, vildagliptin, sulfonylurea, glucosidase inhibitor, biguanide, repaghnide, acarbose, troglitazone, and nateglinide
  • lipid transport protein activator sufficient to reduce or eliminate hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia and/or one or more symptoms of hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia
  • provided herein is a method of treating a condition by administering to an animal suffe ⁇ ng from the condition an effective amount a lipid transport protein activator in combination with a lipid- lowe ⁇ ng compound sufficient to reduce or eliminate hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia and/or one or more symptoms of hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia.
  • a method of treating a condition by administering to an animal suffe ⁇ ng from the condition an effective amount a lipid transport protein activator in combination with a glucose-lowering compound sufficient to reduce or eliminate hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia and/or one or more symptoms of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia
  • a method of treating a condition by administering to an animal suffe ⁇ ng from the condition an effective amount a lipid transport protein activator, e g a pyrone analog, sufficient to reduce lipid level, cholesterol level, t ⁇ glyce ⁇ de level or glucose level in a physiological compartment
  • the physiological compartment is a lipid accumulating cell
  • the physiological compartment is a macrophage
  • the physiological compartment is a muscle cell
  • the physiological compartment is an adipocyte
  • the physiological compartment is a pancreatic islet cell
  • the physiological compartment is a pancreatic beta-cell
  • the physiological compartment is a hepatocyte
  • the subject is an animal
  • the animal is a mammal
  • mammals are primates (e g lemurs, Aye-aye, lo ⁇ ds, galagos, tarsiers, monkeys, chimpanzees, gorillas, orangutans, and humans), cetaceans (e g whales, dolphins and porpoises), chiropterans (e g bats), per ⁇ sodactyls (e g horses and rhinoceroses), rodents (e g mice, rats, squirrels, chipmunks, gophers, porcupines, beavers, hamsters, gerbils, guinea pigs, degus, chinchillas, prai ⁇ e dogs, and groundhogs), and certain kinds of insectivores such as shrews, moles and hedgehogs
  • the mammal is a human
  • the subject is
  • the pyrone analog and the hpid-lowe ⁇ ng compound are co-administered 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
  • the pyrone analog is present in the composition in an amount sufficient to reduce hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia and/or one or more symptoms of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia
  • the pyrone analog is present in the composition in an amount sufficient to substantially eliminate or reduce hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia and/or one or more symptoms of hyperlipidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia by an average of at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, compared to the effect without
  • Administration of the compounds desc ⁇ bed herein may be by any suitable means
  • the pyrone analog is administered by oral administration, transdermal administration, or by injection (e g , intravenous)
  • a pyrone analog and a second compound may be by any suitable means If the pyrone analog and a second compound (e g , a lipid- lowe ⁇ ng compound or a glucose-lowe ⁇ ng compound) are administered as separate compositions, they may be administered by the same route or by different routes If the pyrone analog and the second compound are administered in a single composition, they may be administered by any suitable route such as, for example, oral administration, transdermal administration, or by injection [00508] In some embodiments, dosages for pyrone analogs may be determined based on patient weight, for example, a dosage may be about 0 5- 100 mg/kg of body weight, between 0 1 -50 mg/kg of body weight, between 0 1 - 10 mg/kg of body weight, between 0 1 -50 mg/kg of body weight, or between 0 1 -3 mg/kg of body weight [00509
  • cardiovascular disease in a patient by administering to the patient an effective amount of a pyrone analog, such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin, which reduces or eliminates hyperhpidemia and/or hyperglycemia and/or one or more symptoms of hyperhpidemia or hyperglycemia
  • a pyrone analog such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin
  • cardiovascular diseases include but are not limited to atherosclerosis, Ischemic heart disease, acute myocardial infarction, congestive heart failure and stroke
  • Hyperhpidemia Hypercholesterolemia, Hypertriglyceridemia, and Hyperglycemia
  • a method of treating non-diabetic hyperglycemia by adrruniste ⁇ ng to a patient in need of treatment an effective amount of a pyrone analog, such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin, which reduces or eliminates hyperglycemia and/or one or more symptoms of hyperglycemia
  • a pyrone analog such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin
  • Certain eating disorders can produce acute non-diabetic hyperglycemia, as in the binge phase of bulimia nervosa, when the subject consumes a large amount of calories at once, frequently from foods that are high in simple and complex carbohydrates
  • Certain medications increase the ⁇ sk of hyperglycemia, including beta blockers, thiazide diuretics, corticosteroids, niacin, pentamidine, protease inhibitors, L
  • a method of treating stress-induced hyperglycemia by administering to a patient in need of treatment an effective amount of a pyrone analog, such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin, which reduces or eliminates hyperglycemia and/or one or more symptoms of hyperglycemia
  • a pyrone analog such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin
  • a method of treating inflammation-induced hyperglycemia by administering to a patient in need of treatment an effective amount of a pyrone analog, such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin, which reduces or eliminates hyperglycemia and/or one or more symptoms of hyperglycemia
  • a pyrone analog such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin
  • a method of preventing, decreasing and/or reversing hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia and/or one or more symptoms of hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia by administering a lipid transport protein activator to a patient with a known or suspected symptom of hyperhpidemia, hypercholesterolemia, hypertriglyceridemia, or hyperglycemia
  • the patient has tested positive for hyperglycemia (e g after a fasting glucose test) p ⁇ or to administering the lipid transport protein activator, i e pyrone analog
  • the patient, e g human has tested positive for hyperhpidemia (e g after a fasting cholesterol test) prior to administering the lipid transport protein activator, i e pyrone analog
  • the patient has displayed one or more symptoms of
  • a method for reversing hyperglycemia or hyperhpidemia and/or one or more symptoms of hyperglycemia or hyperhpidemia in a human by administe ⁇ ng to the human an amount of a pyrone analog e g phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin, sufficient to partially or completely reverse hyperglycemia or hyperhpidemia and/or one or more symptoms of hyperglycemia or hyperhpidemia in that human
  • the lipid transport protein modulator is a pyrone analog
  • the pyrone analog can be administered by any suitable route such as orally or by injection, e g , intravenously or intraperitoneally, in a dose sufficient to partially or completely reverse hyperglycemia, hyperhpidemia, and/or one or more symptoms of hyperglycemia or hyperhpidemia
  • a dose in a human can be, e g ,
  • the lipid transporter activator i e pyrone analog
  • pharmaceutical compositions such as tablets, pills, capsules, solutions, suspensions, creams, ointments, gels, salves, lotions and the like, using such pharmaceutically acceptable excipients and vehicles which per se are well known in the art
  • preparation of topical formulations are well described in Remington's Pharmaceutical Science, Edition 17, Mack Publishing Company, Easton, Pa, for topical application, the pyrone analog could also be administered as a powder or spray, particularly in aerosol form If the pyrone analog is to be administered systemically, it may be prepared as a powder, pill, tablet or the like or as a syrup or elixir suitable for oral administration
  • intravenous lipid transporter activator
  • a pharmaceutical composition comprising the pyrone analog is administered orally Such composition may be in the form of a liquid, syrup, suspension, tablet, capsule, or gelatin-coated formulation
  • a pharmaceutical composition comprising a pyrone analog is topically administered Such composition may be in the form of a patch, cream, lotion, emulsion, or gel
  • a pharmaceutical composition comprising the pyrone analog may be inhaled
  • Such composition may be formulated as an inhalant, suppository or nasal spray
  • a pyrone analog such as phosphorylated or phosphonated fisetin or phosphorylated or phosphonated quercetin, is administered alone or with a pharmaceutically acceptable earner
  • a pyrone analog is administered in combination with a lipid-lowe ⁇ ng compound that reduces hyperhpidemia and/or one or more symptoms of hyperhpidemia
  • a pyrone analog is administered in combination with a glucose-lowering compound that reduces hyperglycemia and/or one or more symptoms of hyperglycemia
  • more than one pyrone analogs and/or lipid or glucose-lowering compounds or other agents are also administered.
  • they may be co-administered in any suitable manner, e g , as separate compositions, in the same composition, by the same or by different routes of administration
  • a pyrone analog is administered in a single dose In some embodiments, a pyrone analog or a combination (mixture) of compounds is administered in multiple doses
  • Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day In some embodiments, dosing may be about once a month, once every two weeks, once a week, once every other day or any other suitable interval In some embodiments, the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year In some cases, continuous dosing is achieved and maintained as long as necessary, e g , in a diabetic patient, which may require dosing for the rest of his or her life [00525] Administration of the one or more agents may continue as long as necessary In some embodiments, a pyrone analog is administered for more than about 1 , 2, 3, 4, 5, 6, 7, 14, or 28 days In some embodiments, a pyrone analog is administered for less than about 28, 14, 7, 6, 5, 4, 3, 2, or 1 day In some embodiments, a pyrone analog is administered chronically on an ongoing basis, e g , for the treatment of chronic effects
  • An effective amount of a lipid transport protein modulator may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arte ⁇ al injection, intravenously, intrape ⁇ toneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer
  • the lipid transport protein modulator i e pyrone analog may be administered in dosages as described herein Dosing ranges for lipid-lowe ⁇ ng or glucose-lowering compounds are known in the art and are contemplated herein lndividualization of dosing regimen may be utilized for optimal therapy due to inter-subject variability and pharmacokinetics Dosing for the lipid transport modulator may be determined empirically
  • typical daily dose ranges include, for example, about 1 -5000 mg, about 1-3000 mg, about 1-2000 mg, about 1 -1000 mg, about 1 -500 mg, about 1 -100 mg, about 10-5000 mg, about 10-3000 mg, about 10-2000 mg, about 10-1000 mg, about 10-500 mg, about 10-200 mg, about 10- 100 mg, about 20-2000 mg, about 20-1500 mg, about 20- 1000 mg, about 20-500 mg, about 20- 100 mg, about 50-5000 mg, about 50-4000 mg, about 50-3000 mg, about 50-2000 mg, about 50-1000 mg, about 50-500 mg, about 50- 100 mg, about 100-5000 mg, about 100-4000 mg, about 100-3000 mg, about 100-2000 mg, about 100- 1000 mg, or about 100-500 mg
  • Daily doses may be administered in single or multiple doses
  • the lipid transport modulator is administered 3 times per day of an oral dose of 500 mg
  • the lipid transport modulator is administered 3 times per day of an i v dose of 150 mg
  • Daily doses of fisetin, a fisetin derivative, a phosphorylated or phosphonated fisetin, or a phosphorylated or phosphonated fisetin de ⁇ vative may be administered in the same or separate composition as other pyrone analogs, lipid-lowe ⁇ ng compound or glucose- lowe ⁇ ng compound Daily dose range may depend on the form of flavonoid, e g , the carbohydrate moieties attached to the flavonoid, and/or factors with which the flavonoid is administered, as desc ⁇ bed herein [00530] When a lipid transport protein, which is the target of the pyrone analog, is present on the cells, unit dose forms of the pyrone analog may be adjusted such that hyperglycemia
  • the invention provides methods, including methods of treatment, methods of decreasing the concentration of a substance in a physiological compartment (e g , methods of delaying the onset or preventing chronic neurodegenerative diseases), methods of enhancing a therapeutic effect of a substance, methods of delaying, preventing, reducing or eliminating tolerance or dependence in an animal that is administered a substance, methods of drug wash-out, and methods for identifying modulators of bloodtissue barrier transport proteins [00532]
  • methods will be desc ⁇ bed in terms of reduction of a side effect of a substance It is understood that the methods apply equally to exclusion of a substance from the fetal compartment, or reduction of fetal effects of a substance
  • animal or "animal subject” as used herein includes humans as well as other mammals
  • the methods generally involve the administration of one or more drugs for the treatment of one or more diseases
  • Combinations of agents can be used to treat one disease or multiple diseases or to modulate the side-effects of one or more agents in the combination
  • treating and its grammatical equivalents as used herein include achieving a therapeutic benefit and/or a prophylactic benefit
  • therapeutic benefit is meant eradication or amelioration of the underlying disorder being treated
  • 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
  • the compositions may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made
  • the invention provides a method of treating a condition by administering to an animal in need of treatment an effective amount of a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin sufficient to reduce or eliminate a side effect of the therapeutic agent
  • a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin
  • the activator reduces or eliminates a plurality of side effects of the therapeutic agent
  • the animal is a mammal, e g , a human
  • the therapeutic agent and the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin are co-administered "Co-administration," “administered in combination with,” and their grammatical equivalents, as used herein, encompasses administration of two or more agents to an animal so that both agents and/or their metabolites are present in the animal at the same time Co-administration includes simultaneous administration in separate compositions, administration at different times in separate compositions, or administration in a composition in which both agents are present
  • the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin are administered
  • phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin
  • the methods of the invention are used to reduce the side effect and/or increase the effectiventss of an immunosuppressant
  • the immunosuppressant can be a cyclosporin (Neoral, Sandimmune,
  • dachzumab (Zenapax), muromonab CD3 (Orthoclone OKT3), tacrolimus (Prograf®), ascomycin, pimecrolimus (Elidel), azathiop ⁇ ne (Imuran), cyclospo ⁇ n (Sandimmune, Neoral), glatiramer acetate (Copaxone), mycopehnolate (CellCept), sirolimus (Rapamune), or voclospo ⁇ n
  • methods of the invention are used to reduce the side effect and/or increase the effectiventss of a calcineurin inhibitor such as tacrolimus (Prograf®),
  • the methods of the invention can be used to reduce the side effect and/or increase the effectiventss of a selective estrogen receptor modulator (SERM), such as tamoxifen
  • SERM selective estrogen receptor modulator
  • the methods of the invention can be used to reduce the side effect and/or increase the effectiventss of an antilipedimic agent such as an HMG-CoA inhibitor such as lovastatin, simvastatin, pravastatin, fluvastatin, or atorva statin
  • the methods of the invention can be used to reduce the side effect and/or increase the effectiventss of an antihyperglycemic agent (antiglycemics, hypoglycemic agents) such as glybu ⁇ de, glipizide, ghclazide, or ghmepnde, a meghtinide such as repaglinide or netaglimde, a biguanide such as metformin, a thiazolidinedione, an ⁇ -glucosidase inhibitor such as acarbose or mightol, glucagon, somatostatin, or diazoxide
  • an antihyperglycemic agent antiglycemics, hypoglycemic agents
  • an antihyperglycemic agents such as glybu ⁇ de, glipizide, ghclazide, or ghmepnde
  • meghtinide such as repaglinide or netaglimde
  • the methods of the invention can be used to reduce the side effect and/or increase the effectiventss of a cannabinoid
  • the methods of the invention can be used to reduce the side effect and/or increase the effectiventss of an antidepressant
  • antidepressants cause the side effects of high blood sugar and diabetes
  • the methods of the invention can be used, for example to reduce these side effects
  • the therapeutic agent is an antidepressant selected from the group of a ⁇ piprazone (Abilify), nefazodone (Serzone), escitalopram oxalate (Lexapro), sertraline (Zoloft), escitalopram (Lexapro), fluoxetine (Prozac), bupropion
  • the methods of the invention can be used to reduce the side effect and/or increase the effecliventss of an antineuropatruc agent such as gabapentin [00545]
  • the methods of the invention can be used to reduce the side effect and/or increase the effectiventss of an anticonvulsant In some cases, it can be an anticonvulsant that also has efficacy in the treatment of pain
  • the therapeutic agent can be, for example, acetazolamide (Diamox), carbamazepine (Tegretol), clobazam (F ⁇ sium), clonazepam (Klonopin/Rivot ⁇ l), clorazepate (Tranxene-SD), diazepam (Valium), divalproex sodium (Depakote), ethosuximide (Zarontin), ethotoin (Peganone), felbamate (Felbatol), fosphenytoin (Cerebyx), gabapent
  • the phosphonated polyphenol will have higher water solubility than the non- phosphonated polyphenol
  • the phosphonated polyphenol will have multiple phosphonates and will have higher water solubility than the polyphenol with fewer phosphonate groups
  • quercetin aglycone has relatively low solubility in water, and relatively low solubility in the blood
  • the addition of a phosphonate to quercetin will tend to improve the solubility of the quercetin in water and in the blood and thus increase its bioavailability
  • the addition of the phosphonate group can increase water solubility by adding pola ⁇ ty, by adding an ionic substituent, and in some cases due to geometrical (molecular shape) factors
  • the phosphonated polyphenol is at least about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 90%, or 100% or at least about 2, 3, 4 5, 10, 20, 50, 100, 1 ,000, or 10,000 times
  • One embodiment of the invention is a method for the treatment of an animal by oral administration of a therapeutic agent and a phosphonated polyphenol, e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin that is greater than about 10%, 20%, 25%, 30%, 40%, 50%, 60%, 75%, 90%, or 100% or about 2, 3, 4 5, 10, 20, 50, 100, 1 ,000, or 10,000 times more soluble in water than the corresponding non-phosphonated polyphenol
  • One embodiment of the invention is a method for the treatment of an animal by oral administration of a therapeutic agent and a phosphonated polyphenol, e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin
  • the increased water solubility will result in increased solubility of the polyphenol in a bodily fluid
  • the increased solubility in a bodily fluid will result in greater bioavailability of the phosphonated polyphenol than for the corresponding non-phosphonated polyphenol
  • the phosphonated polyphenol will provide a longer half-life of drug effect than for a non-phosphonated polyphenol
  • the amount of active form can depend on the rate of de-phosphonation If the rate of de- phosphonation is relatively slow, the de-phosphonation process can act to delay the delivery of the active form Under these conditions, the phosphonated form acts as a kind of reservoir for the active form of the drug, thus extending the half life of drug effect
  • the de- phosphonation of the phosphonated form can be used as a
  • the therapeutic agent and the phosphonated polyphenol are administered, at least in part, as an ionic complex between an opiate or an immunomodulator and a phosphonated polyphenol
  • the administration of the ionic complex results in higher solubility and greater bioavailability than where the compounds are administered without comprising an ionic complex
  • Administration of the therapeutic agent and the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin may be any suitable means If the agents are administered as separate compositions, they may be administered by the same route or by different routes If the agents are administered in a single composition, they may be administered by any suitable route In some embodiments, the agents are administered as a single composition by oral administration In some embodiments, the agents are administered as a single composition by transdermal administration In some embodiments, the agents are administered as a single composition by injection [00553] In some embodiments, the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin
  • the therapeutic agent may be any therapeutic agent desc ⁇ bed herein
  • the therapeutic agent is an immunosuppressant, antineoplastic, amphetamine, antihypertensive, vasodilator, barbiturate, membrane stabilizer, cardiac stabilizer, glucocorticoid, chemotherapeutic agent, or an ⁇ infective, lmmunomodulator, tolerogen, immunostimulants, drug acting on the blood and the blood-forming organs, hematopoietic agent, growth factor, mineral, and vitamin, anticoagulant, thrombolytic, antiplatelet drug, hormone, hormone antagonist, pituitary hormone, thyroid and antithyroid drug, estrogen and progestin, androgen, adrenocorticotropic hormone, adrenocortical steroid and synthetic analogs, insulin, oral hypoglycemic agents, calcium, phosphonate, parathyroid hormone, vitamin D, calcitonin, and other compounds
  • the methods of the invention may be used for treatment of any suitable condition, e g , diseases of the heart, circulation, lipoprotein metabolism, hemostasis and thrombosis, respiratory system, kidney, gastrointestinal tract, endocrine system, reproductive system, or hemopoeitic system, where one or more therapeutic agents are used that have side effect
  • the methods of the invention include the treatment of hypertension in an animal by administering to an animal in need of treatment an effective amount of an antihypertensive and an effective amount of a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin that reduces or eliminates a side effect of the hypertensive
  • Another exemplary embodiment is the treatment or prevention of infection in an animal by administering to an animal in need of treatment or prevention of infection an effective amount of an ant
  • Another exemplary embodiment is the prevention of organ rejection in an animal by administering to an animal that has received or will receive an organ transplant an effective amount of a calcineurin inhibitor such as tacrolimus or a tacrolimus analog and an effective amount of a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin that reduces or eliminates a side effect, e g , a hyperglycemic effect or a side effect of the calcineurin inhibitor
  • a calcineurin inhibitor such as tacrolimus or a tacrolimus analog
  • a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-
  • a therapeutic agent and a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin that reduces or eliminates a side effect of the therapeutic agent
  • a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin that reduces or eliminates a side effect of the therapeutic agent
  • any suitable ratio of the two agents e g , molar ratio , wt/wt ration, wt/volume ratio, or volume/volume ratio, as desc ⁇ bed herein, may be used
  • the invention provides a method of treating a condition by administering to an animal suffe ⁇ ng from the condition an effective amount of tacrolimus and an amount of a BTB transport protein modulator sufficient to change the concentration of tacrolimus in a physiological compartment
  • the physiological compartment is selected from the group consisting of blood, lymph nodes, spleen, peyer's patches, lungs, heart kidney, pancreas liver, and gull bladder
  • the BTB transport modulator decrease the clearance of tacrolimus from a compartment where the drug is exerting therapeutic effect
  • compositions of the invention may be administered chronically to an individual in order to prevent, delay the appearance, or slow or halt the progression of a chronic neurodegenerative condition
  • compositions of the invention may be administered chronically to an individual in order to remove from the CNS one or more substances associated with a chronic neurodegenerative condition
  • the neurodegenerative condition is prion disease, Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), ALS, multiple sclerosis, transverse myelitis, motor neuron disease, Pick's disease, tuberous sclerosis, lysosomal storage disorders, Canavan's disease, Rett's syndrome, spinocer
  • the invention provides a method of increasing the concentration of a therapeutic agent in a non-CNS compartment by the administration of a phosphonated polyphenols, e g phosphonated pyrone analog such as a phosphonated flavonoid such as phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin
  • a BTB transport protein activator can result in the exclusion of a compound or removal of compound from the CNS compartment
  • the concentration of therapeutic agent in a non-CNS compartment is at least about 1 , 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
  • the invention provides methods of treating pain such as acute or chronic pain, using therapeutic agents and the phosphonated compositions of the invention Any suitable type of pain, whether acute or chronic, may be treated by the methods of the invention
  • the invention provides a method of treating an animal for pain by administering to an animal in pain an effective amount of an opioid analgesic agent, e g an opioid receptor agonist such as oxycodone or morphine and an amount of a polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin sufficient to reduce a side effect of the opioid agent
  • an opioid analgesic agent e g an opioid receptor agonist such as oxycodone or morphine
  • a polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin
  • the invention further provides methods of reversing one or more side effects of a substance by administering a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin to an animal that has received an amount of the substance sufficient to produce one or more side effects
  • a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin described herein may be used
  • the invention provides a method for reversing a side effect of an agent in a human by administering to the human an amount of a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin sufficient to partially or completely reverse a central nervous system effect of the agent, where the human has received an amount of said agent sufficient to produce a central nervous system effect
  • the agent is a general anesthetic Examples of general anesthetics include, but not limited to, .
  • the human has received an overdose of the agent producing the side effect
  • the individual continues to experience peripheral effects of the agent
  • the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin is a side effect modulator, e g BTB transport protein modulator
  • the phosphonated pyrone analog such as a phosphonated flavonoid is phospho
  • the methods of the invention involve the administration of a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin
  • a therapeutic agent that produces a side effect is administered in combination with a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated f ⁇ setin, or phosphonated 5,7- dideoxyquercetin that reduces a side effect of the therapeutic agent
  • other agents are also administered, e g , other therapeutic agents When two or more agents are co-administered, they may be coadministered in any suitable manner, e g , as separate compositions, in the same composition, by the same or by different
  • the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin is administered in a single dose
  • a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin may also be used when it is administered with the substance (
  • the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin is administered in multiple doses
  • Dosing may be about once, twice, three times, four times, five times, six times, or more than six times per day Dosing may be about once a month, once every two weeks, once a week, or once every other day
  • the drug is an immunosuppressive
  • the immunosuppressive compound and the transport protein activator are administered together about once per day to about 6 times per day
  • the administration of the immunosuppressive compound and the transport protein activator continues for less than about 7 days
  • the administration continues for more than about 6, 10, 14, 28 days, two months, six months, or one year
  • continuous dosing is achieved and maintained as long as necessary, e g , intravenous administration
  • an agent of the invention is administered for more than 1 , 2, 3, 4, 5, 6, 7, 14, or 28 days In some embodiments, an agent of the invention is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day In some embodiments, an agent of the invention is administered chronically on an ongoing basis, e g , for the treatment of chronic pain
  • An effective amount of a phosphonated polyphenol and an effective amount of a drug may be administered in either single or multiple doses by any of the accepted modes of administration of agents having similar utilities, including rectal, buccal, intranasal and transdermal routes, by intra-arte ⁇ al injection, intravenously, intrapentoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or via an impregnated or coated device such as a stent, for example, or an artery-inserted cylindrical polymer
  • the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin and the therapeutic agent may be administered in dosages as desc ⁇ bed herein (see, e g , Compositions) Dosing ranges for therapeutic agents are known in the art Dosing for the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin may be found by routine experimentation For a phosphonated pyrone analog such as a phosphonated flavonoid, e g , phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquer
  • the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin is administered two to three times a day with an oral dose of about 500 mg or an intravenous dose of about 150 mg
  • the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7- dideoxyquercetin is administered about one hour or about 30 minutes prior to administration of the therapeutic agent
  • the phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid, such as a phosphonated quercetin, phosphonated fisetin, or phosphonated
  • the serum half-life for, e g , quercetin aglycone is known to be about 19-25 hours Where a phosphonated polyphenol of the invention has a serum half life in the same range, single dose accuracy is not crucial
  • a phosphonated polyphenol e g phosphonated pyrone analog such as a phosphonated flavonoid such as phosphonated quercetin, phosphonated fisetin, or phosphonated 5,7-dideoxyquercetin
  • unit dose forms of the therapeutic agent and the BTB transport modulator may be adjusted accordingly
  • a typical unit dose form is, for example, if phosphonated polyphenol with a serum half life similar to that of quercetin is given in a composition also containing, e g , tramadol, a typical unit dose form is,
  • kits for use with the compounds described above Pyrone analogs or derivatives thereof can be provided in a kit
  • the kits will comprise, in suitable container means, a composition of one or more pyrone analogs or de ⁇ vatives thereof (e g , phosphorylated or phosphonated pyrone analogs)
  • the kit may comprise one or more compounds in suitable container means
  • the packages or kits provided herein can further include any of the other moieties provided herein such as, for example, one or more therapeutic agents that have a side effect, lipid- lowe ⁇ ng agents and/or glucose-lowe ⁇ ng agents
  • the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe and/or other container means, into which the at least one compound can be placed, and/or preferably, suitably ahquoted
  • the kits can include a means for containing at least one compound, and/or any other reagent containers in close confinement for commercial sale
  • Such containers may include injection and/or blow-molded plastic containers in which the desired vials are stored Kits can also include printed material for use of the materials in the kit [00580]
  • Packages and kits can additionally include, for example, pharmaceutically acceptable earners, excipients, diluents, buffering agents, preservatives, stabilizing agents, etc , in a pharmaceutical formulation
  • Each component of the kit can be enclosed within an individual container and all of the various containers can be within a single package
  • Invention kits can be designed for cold storage or room temperature storage
  • the preparations can contain stabilizers (such as bovine serum albumin (BSA)) to increase the shelf-life of the kits
  • the kit can contain further preparations of solutions to reconstitute the lyophilized preparations
  • Acceptable reconstitution solutions are well known in the art and include, for example, pharmaceutically acceptable phosphate buffered saline (PBS)
  • Packages and kits can further include one or more components for an assay Samples to be tested in this application include, for example, blood, plasma, and tissue sections and secretions, urine, lymph, and products thereof
  • Packages and kits can further include one or more components for collection of a sample (e g , a syringe, a cup, a swab, etc )
  • Packages and kits can further include a label specifying, for example, a product desc ⁇ ption, mode of administration, discussion of clinical studies, listing of side effects, and/or indication of treatment
  • Packages provided herein can include any of the compositions as described herein
  • the package can further include a label for treating a condition described herein
  • the term "packaging material” refers to a physical structure housing the components of the kit
  • the packaging material can maintain the components sterilely, and can be made of material commonly used for such purposes (e g , paper, corrugated fiber, glass, plastic, foil, ampules, etc )
  • the label or packaging insert can include appropriate written instructions Kits, therefore, can additionally include labels or instructions for using the kit components in any method described herein
  • a kit can include a compound in a pack, or dispenser together with instructions for administering the compound in a method described herein Where more than one compound is included in a kit, the package can include more than one pack, or dispenser together with instructions for administering the compounds in a method described herein
  • Instructions can include instructions for practicing any of the methods described herein including treatment methods Instructions can additionally include indications of a satisfactory clinical endpoint or any adverse symptoms that may occur, or additional information required by regulatory agencies such as the Food and Drug Administration for use on a human subject
  • the instructions may be on "printed matter," e g , on paper or cardboard within or affixed to the kit, or on a label affixed to the kit or packaging mate ⁇ al, or attached to a vial or tube containing a component of the kit Instructions may additionally be included on a computer readable medium, such as a disk (floppy diskette or hard disk), optical CD such as CD- or DVD-ROM/RAM, magnetic tape, electrical storage media such as RAM and ROM, IC tip and hybrids of these such as magnetic/optical storage media
  • kits comprising a pyrone analog effective for generating a cellular protective effect and p ⁇ nted instructions for using the pyrone analog
  • the kit further comprises one or more additional agents including, but not limited to, a hpid-lowe ⁇ ng agent, a glucose-lowering agent, or both
  • additional agents may be packaged in individual containers or combined in a single container
  • Kits may further comprise a label for treating a condition including, but not limited to, amyloidosis, diabetes, disorders of myelin formation, hyperglycemia, impaired wound healing, neuropathy, insulin resistance, hype ⁇ nsuhnemia, hypoinsuhnemia, hypertension, hyperhpidemia, hypertriglyceridemia, hyperchlesterolemia, malignancy, microvascular retinopathy, surfactant abnormalities, vascular stenosis, inflammation, and hydronephrosis
  • Fisetin-3'-O-phosphate Dibenzyl 5-(3,7-dihydroxy-4-oxo-4H-chromen-2-yl)-2-hydroxyphenyl phosphate (a) (5 8 g, 10 6 mmol) and palladium hydroxide (20 % wt, 2 1 g) were stirred in cyclohexene (200 mL) and ethanol (200 mL) The reaction was heated at reflux for 16 hr The reaction mixture was cooled to room temperature, filtered through Celite and concentrated in vacuo The residual solid was triturated with water to provide the product as orange solid (3 17 g, 8 66 mmol, 81 % yield)
  • Fisetin-3'-O-phosphate monosodium salt hydrate Fisetm-3'-O-phosphate (b) (2 52 g, 6 89 mmol, 1 equiv) was added to a mixture of methanol ( 130 mL) and ethanol (200 mL) The solid completely dissolved upon heating at -50 °C for 2 min Sodium acetate (0 56 g, 6 89 mmol, 1 equiv) was then added to the solution The mixture was stirred at room temperature for 3 hr , with formation of an off-white precipitate The solid was filtered, washed with ethanol and d ⁇ ed in a vacuum oven at room temperature to give the product as light yellow solid (1 94 g, 5 0 mmol, 72 % yield) 1 H NMR (300 MHz/D 2 O) ⁇ 7 65 (d, I H), 7 22-7 19 (m, 2H), 7 04 (s, I H), 7 01 (d, I H), 6 51 (d, I H)
  • Quercetin-3'-O-phosphate is dissolved in water at about pH 8 After 24 hours in water at pH 8, no degradation is seen by NMR and HPLC after 24 hours at ambient temperature
  • Fisetin-3'-O-phosphate is dissolved in water at about pH 8 After 24 hours in water at pH 8, no degradation is seen by NMR and HPLC after 24 hours at ambient temperature
  • Rat hippocampal slices are prepared by a standard method Twenty rat hippocampal slices are placed in a perfusion chamber, incubated at 37 0 C and perfused by a batch method while exchanging the incubation buffer every 10 minutes
  • the incubation buffer has the composition NaCl, 124 mM, KCl, 5 mM, KH 2 PO 4 , 1 24 mM, MgSO 4 , 1 3 mM, CaCl 2 , 2 4 mM, NaHCO 3 , 26 mM, D-glucose, and 10 mM
  • a mixed gas of oxygen (95%) and carbon dioxide (5%) is used to saturate the buffer
  • Somatostatin release (%) by the pyrone analog at each concentration is calculated as in the following The somatostatin amount of each fraction is expressed by the percentage (%) relative to the somatostatin residual amount at the time the fraction is obtained The value of fraction 8 immediately before high K + (50 mM) stimulation is taken as the base and the values exceeding the base value are added with regard to fraction 9 and the subsequent peak fractions exceeding the base value to give somatostatin release (%) The number of the test samples measured is 10 or 1 1 Each value (%) is expressed by mean+S E M The property of the pyrone analog is subjected to Dunnett's multiple comparison test relative to control group
  • Glugacon may be assessed using standard techniques such as, for example, a random blood glucose test, a fasting blood glucose test, a blood glucose test two hours after 75 g of glucose, or an even more formal oral glucose tolerance test (OGTT)
  • OGTT formal oral glucose tolerance test
  • the patient is then given a glucose solution to d ⁇ nk within 5 minutes
  • the standard dose is I 75 grams of glucose per kilogram of body weight, to a maximum dose of 75 g
  • Blood is drawn at intervals for measurement of glucose (blood sugar), and sometimes insulin levels
  • the intervals and number of samples vary according to the purpose of the test For simple diabetes screening, the most important sample is the 2 hour sample and the 0 and 2 hour samples may be the only ones collected In research settings, samples may be taken on many different time schedules
  • urine samples may also be collected for testing along with the fasting and 2 hour blood tests
  • Fasting plasma glucose should be below 6 1 mmol/1 ( 1 10 mg/dl) Fasting levels between 6 1 and 7 0 mmol/1
  • the 2 hour glucose level should be below 7 8 mmol/1 ( 140 mg/dl) Levels between this and 1 1 1 mmol/1
  • Pyrone analogs or de ⁇ vatives thereof can be tested with regard to their ability to stimulate ghrelin release using conventional means in the art
  • Examples of a pyrone analog include phosphorylated quercetin and phosphorylated f ⁇ setin
  • pyrone analogs are made as IOOX stock solutions by dissolving them in pure ethanol, as a vehicle
  • the pyrone analogs are then diluted 1/100 in the Leibovitz L- 15 medium containing 0 5% fetal bovine serum (FBS)
  • FBS fetal bovine serum
  • RF-48 cells are grown du ⁇ ng incubation at 37 0 C in Leibovitz's Ll 5 medium with 2 mM L- glutamine and containing 10% (vol/vol) FBS in the absence of CO 2
  • Each sample is cent ⁇ fuged at 3000 rpm to remove the cells from the sample and the supernatant (containing the ghrelin formed as well as the medium and the pyrone analog) is transferred to a separate tube Ghrelin release is measured using a commercial enzyme immunoassay kit (from Phoenix Pharmaceuticals, Belmont, Calif , USA)
  • human blood is drawn and peripheral monocytes are isolated by methods routinely practiced in the art These human monocytes can then be used immediately or cultured in vitro, using methods routinely practiced in the art, for 5 to 9 days where they develop more macrophage-hke characteristics such as the upregulation of scavenger receptors These cells are then treated for various lengths of time with pyrone analogs Control monocytes that are untreated or treated with native LDL are grown in parallel At a certain time after addition of the pyrone analogs or controls, the cells are harvested and analyzed for differential expression as described in U S Patent No 6, 124,433 which is incorporated herein by reference in its entirety [00616] Cells treated with pyrone analogs can be examined for phenotypes associated with cardiovascular disease In the case of monocytes, such phenotypes include but are not limited to increases in rates of LDL uptake, adhesion to endothelial cells, transmigration, foam cell formation.T '
  • Total RNA is isolated from frozen tissues using standard techniques and kits such as, for example, Tn- Reagent (Molecular Research Center, Ohio)
  • RT-PCR is performed, for example, on a LightCycler (Roche Applied Science, Mannheim, Germany), using SYBR-Green l dye
  • Amplification conditions include initial denaturation at 95 °C for 10 minutes, followed by 55 cycles for both specific genes, or 30 cycles for beta-actin The fluorescent signal is monitored A melting curve program is earned out according to standard techniques to analyze the specificity of the generated products Gene expression levels are normalized to the respective beta-actin mRNA levels, in the same samples
  • Fluorogenic probes such as from Assay-On-Demand (Applied Biosystems) and amplification conditions may be applied according to standard techniques The mRNA levels are corrected for human beta-actin mRNA
  • Example 11 Pancreatic Hormones Immunohistochemistry.
  • Sections are then incubated for 1 h at 37 0 C with monoclonal antibodies against human insulin and against human glucagon (Sigma), both at a dilution of 1 200 Slides are exposed to the secondary biotinylated IgG for 30 minutes at room temperature and then incubated in strepavidin- peroxidase followed by a chromogen peroxide solution A control using only secondary without p ⁇ mary antibodies followed by strepavidin-peroxidase and a chromogen peroxide solution is performed to rule out possible background of the system
  • Pancreas and livers are isolated, immediately frozen in liquid nitrogen, and stored at -70 °C Frozen tissues are homogenized in 0 18N HCl/35% ethanol The homogenates are extracted overnight at 4 0 C with continuous stirnng, and the supernatants are lyophihzed Samples are dissolved in 0 8 ml RIA Assay Buffer, supplemented by a cocktail of protease inhibitors (Sigma) Hepatic insulin and glucagon levels are determined using rat radioimmunoassay (RIA, catalog no SRI- 13K and GL-32K, Linco, Mo , USA, and Coat-A-Count, DPC, Calif , USA) Somatostatin concentrations are determined by RIA (Euro-diagnostica, Sweden) Hepatic content of pancreatic hormones is normalized to the weight of the extracted tissue
  • Serum biochemistry profile consisting of albumin, AST (Aspartate aminotransferase), ALT (Alanine aminotransferase) and total bilirubin may be determined using standard techniques and kits provided by, for example, Olympus AU 2700 Apparatus (Olympus, Germany) in serum samples
  • Insulin and C-peptide secretion and content from primary adult liver cells are measured by static incubation of 48 hours after 3 days of treatment Insulin secretion into the media is measured by RIA using the Ultra Sensitive
  • Insulin content is measured after homogenizing the cell pellet in 0 18 N HCl, 35% ethanol The homogenates are extracted overnight at 4 0 C with continuous stir ⁇ ng, and the supernatants are lyoprulized Samples are dissolved in 0 5 ml PBS containing 0 2% BSA and Protease Inhibitory cocktail (Sigma) One hundred ( 100) ⁇ l sample are used for the RIA Insulin content is normalized to total cellular protein, measured by the Bio-Rad Protein
  • the cells are preincubated for 2 hours in Krebs-Ringer buffer (KRB) containing
  • Liver cells are fixed in 2 5% gluteraldehyde, osmificated, dehydrated with a graded se ⁇ es of ethanol and propylene oxide, and embedded in Araladite solution (Polyscience Inc ) Ultra-thin sections are cut in an ultramicrotome, stained with 2% uranyl acetate and Reynolds' lead citrate solution For post-embedding immunogold reactions, 50-90 nm liver sections are put on nickel g ⁇ ds The grids are incubated with antibody against insulin (guinea-pig polyclonal, 7 8 ⁇ g/ml, Dako) at room temperature overnight and then incubated with lmmunogold- conjugated antibody against guinea-pig IgG ( 15-nm gold, diluted 1 40, Dako) for 1 5 hours at room temperature The sections are observed under an electron microscope (Jeol 1200EX2)
  • Blood glucose is measured twice weekly using, for example, an Accutrend® GC Glucose Analyzer
  • Example 18 In vitro toxicity screening of fisetin-3'-0-phosphate or quercetin-3'-0-phosphate
  • a secondary pharmacological screening of molecules of interest at a fixed concentration is often practiced in the pharmaceutical industry in order to evaluate the effect of the compound on secondary targets that could result in untoward toxicity in vivo
  • These secondary screens are well known in the art and can be earned out by labs which specialize in these tests such as MDS-Panlabs and CEREP
  • a secondary toxicity screen is performed with quercetin-
  • the compound is additionally tested in Adenosine ⁇ , Adrenergic, ⁇ , DopamineD 25 , Histamine H 1 -, and ⁇ -
  • PAF-5 could be acting as an inverse agonist in this assay
  • quercetin-3'-O-phosphate or fisetin-3'-O-phosphate has low toxicity properties, especially in light of the fact that the concentration tested, 10 ⁇ M, is high as compared to a therapeutic dose (e g greater than - 100 times)
  • Example 19 Py rone analog decreases cholesterol and triglyceride levels in human
  • a 32-year-old, obese, Caucasian male has a cholesterol level of 299 mg/dL, a triglyceride level of
  • the composition is a tablet containing 20 mg of phosphorylated quercetin or phosphorylated fisetin Additionally, he must strictly adhere to a low fat diet, and regularly exercise 30 minutes daily or 45 minutes every other day
  • the patient follows up with his doctor in 3 months with a repeat lipid profile
  • the blood test result shows an improvement of decreased cholesterol and triglycerides to 250 mg/dL and 280 mg/dL, respectively
  • the follow up plan also includes maintaining the same dosage of composition at 20 mg for two months, since the patient tolerates the medication well
  • a 45-year-old Hispanic male with a history of gout and gastritis has a triglyceride level of 950 mg/dL, and a cholesterol level of 300 mg/dL
  • the patient begins using a composition described herein, for example a tablet containing 50 mg of phosphorylated quercetin or phosphorylated fisetin, twice daily with no side effects
  • the patient is very compliant with respect to taking the medication everyday, along with consuming a low fat diet and regularly exercising
  • the patient's t ⁇ glyce ⁇ de level decreases to 450 mg/dL His gout and gast ⁇ tis conditions also improve as a direct result of lowering his triglycerides levels and his low fat diet He is to maintain the dosage of a composition described herein at 50 mg twice daily for the best results
  • Example 21 Pyrone analog decreases LDL level and increases HDL level in human [00638]
  • a 55-year-old Asian female has menopause, hypertension, and hyperhpidemia She is currently taking PramproTM hormone replacement therapy for menopause, and AtenololTM for hypertension, which is controlled at this time
  • Example 22 Pyrone analog in combination with other drugs prevent myocardial infarction in diabetic patient [00639]
  • a 34-year-old Hispanic female with diabetes melhtus type 2 has high cholesterol levels and high LDL levels During an office visit, she expe ⁇ ences a silent heart attack without congestive heart failure She is then admitted to the hospital for further cardiac evaluation and subsequently discharged after three days She is currently taking GlucotrolTM XL 5 mg daily, GlucophageTM 500 mg twice a day (diabetes medications), TenorminTM 25 mg/day, Zest ⁇ lTM 10 mg/day (to prevent chest pain, and high blood pressure), and aspi ⁇ n 81 mg/day She is also taking a composition desc ⁇ bed herein at the dosage of 10 mg-20 mg phosphorylated quercetin or phosphorylated fisetin daily to prevent a second myocardial infarction in the future
  • a 42-year-old Asian male has strong a familial hypercholesterolemia
  • Hypercholesterolemia is a condition in which cholesterol is overly produced by the liver for unknown reasons
  • hypercholesterolemia is a strong ⁇ sk factor for myocardial infarction (Ml), diabetes, obesity, and other illnesses
  • Ml myocardial infarction
  • the patient is not overweight, but is very thin He has a very high level of cholesterol, over 300 mg/dL, and a triglyceride level of over 600 mg/dL
  • His diet consists of very low fat, high protein foods, and no alcohol He has a very active lifestyle, but one which is not stressful However, he still has to take medication to lower his cholesterol and triglyceride levels
  • the medications he takes include a composition desc ⁇ bed herein He is advised to continue taking a composition described herein, for example a tablet containing 40 mg of phosphorylated quercetin or phosphorylated fisetin, daily for the remainder of his life in order
  • Example 24 Pyrone analog decreases triglyceride level in human
  • a 22-year-old male patient presents with t ⁇ glyce ⁇ de level of 250 mg/dL
  • the patient is given oral tablets containing about 20 mg to about 100 mg of a pyrone analog, for example phosphorylated quercetin or phosphorylated fisetin
  • the patient's level of t ⁇ glycende is measured 24 hours after ingesting the tablets The measurement shows a decrease of about 20% to 50% of triglycerides as compared to the initial level
  • Example 25 Pyrone analog decreases blood glucose level in human
  • a 46-year-old African American female with diabetes melhtus type 2 has hyperglycemia with a blood glucose level of 20 mmol/L, i e approximately 360 mg/dL She is taking tablets desc ⁇ bed herein at the dosage of
  • the patient's level of blood glucose is measured 24 hours after ingesting the tablets The measurement shows that the patient's blood glucose level returns to 6 mmol/L (i e 108 mg/dL) after fasting, which is within the normal range of about 80 to 120 mg/dL or 4 to 7 mmol/L
  • Example 26 Effect of pyrone anolog on serum triglyerides in cynomologus monkeys
  • Serum triglycerides (mg/dl) of male cynomolgus monkeys treated with phosphorylated quercetin by gastric intubation
  • Example 27 Effect of pyrone anologs on serum triglyerides and hepatic triglyceride outputin male SJL mice
  • Male SJL mice are dosed orally with vehicle, phosphorylated quercetin, or phosphorylated fisetin, for 4 consecutive days
  • the test compounds are dissolved in corn oil and given at a dosage/volume of 20 mg/5 mL/kg
  • serum t ⁇ glyce ⁇ des STG
  • animals are fasted after dosing, starting at 8 am
  • blood samples are collected p ⁇ or to intravenous injection of WR- 1339 at 100 mg/5m l/kg
  • Additional serum samples are collected at 1 and 2 hours after WR- 1339 injection WR- 1339, also known as T ⁇ ton WR 1339 or 4-(2,4,4-t ⁇ methylpentan-2-yl)phenol, is a detergent which inactivates lipoprotein lipase and thus prevent
  • Phosphorylated quercetin appears to lower non-fasting STG (Day 3, 8 a m ) but not fasting STG (Day 4, 2 p m ) A reduction of HTG output after WR- 1339 injection is observed with phosphorylated quercetin These effects are not observed with phosphorylated fisetin given orally
  • pyrone analogs are capable of lowe ⁇ ng serum t ⁇ glyce ⁇ des in mice when they are made bioavailable by proper route of administration Furthermore, this lowering of triglycerides of pyrone analogs may be due, at least partially, to a reduced HTG output
  • mice treated with phosphorylated fisetin by oral gavages day 1 to 3
  • subcutaneous injections day 3 to 4
  • Example 28 LIM-0705 and LIM-0741 protect against onset of Type 2 diabetes and attendant complications in diabetic rat model
  • Type 2 diabetes based on impaired glucose tolerance caused by the inherited obesity gene mutation that leads to insulin resistance
  • a male ZDF rat has high blood insulin levels when fed with
  • Pu ⁇ na 5008 chow that subsequently drop as pancreatic beta cells cease to respond to glucose
  • a male ZDF rat on a diet consisting of Purina 5008 chow is fully diabetic
  • Blood is collected from the rats at day 1 , 4, 7, 1 1 , 14, 21 , 28, 35, 42 and assayed for levels of cholesterol, serum glucose, insulin, and triglycerides Body weight is also measured on the same days Animals are sac ⁇ ficed at the end of the 6-week study to obtain liver and kidney weights, aspartate transaminase (AST) and alanine aminotransferase (ALT) levels for toxicity analysis, mesenteric and epididmyal fat weight, and glucagon, glycated hemoglobin (%HbAIc) and adiponectin levels Results:
  • Figure 7 illustrates cholesterol levels at days 1 , 7 and 14 of treatment in animals treated with controls, Rosightazone, LIM-0705 or LIM-0741
  • Figure 25 shows the effect of pyrone analogs LIM-0705 and LIM-0741 on cholesterol levels in ZDF rats over 2 weeks of daily treatment
  • AST and ALT levels AST levels also show no differences (see Figure 12), while ALT levels are down over vehicle control when [LIM-0705] and [LIM-0741 ] are used for treatment (see Figure 13) These results indicate that [LIM-07051 and [LIM-0741 ] have little effect on liver and kidney injury and toxicity [00662] Liver and kidney weight Treatment of either the pyrone analogs, [LIM-0705] and [LIM-0741 ], rosightazone or vehicles show similar liver and kidney weight at the end of week 6 (see Figures 14 and 15, respectively)
  • Example 29 LIM-0742 protect against onset of Type 2 diabetes and attendant complications in diabetic rat model
  • ZDF Diabetic Fatty
  • Blood is collected from the rats at day 1 , 4, 7, 1 1 , 14, 21 , 28, 35, 42 and assayed for levels of cholesterol, serum glucose, insulin, and triglycerides Body weight is also measured on the same days Animals are sacrificed at the end of the 6-week study to obtain liver and kidney weights, aspartate transaminase (AST) and alanine aminotransferase (ALT) levels for toxicity analysis, mesenteric and epididmyal fat weight, and glucagon, glycated hemoglobin (% HbAIc) and adiponectin levels
  • LIM-0742 has little impact on weight gain in ZDF rats Rosiglitazone treated animals gain excessive weight compared to control, LIM-0742 and Atorvastatin treated animals This increase in body weight by rosiglitazone can be att ⁇ ubbed directly to the increase in mesenteric and epididymal fat
  • Serum glucose levels Figure 17 shows the effect of pyrone analog LIM 0742 on glucose levels in ZDF rats during 6 weeks of daily treatment Rosiglitazone treated animals show optimal glucose control LIM-0742 treated animals show glucose control that is superior to vehicle control
  • Figure 21 shows that pyrone analog LIM 0742 protects against hyperglycemia after a glucose load (2 mg/kg) in fasted and aging ZDF rats Glucose level stays in physiologic range in LIM-0742 arm treated animals compared to the elevated level observed in Rosiglitazone treated animals
  • FIG. 18 shows that pyrone analog LIM 0742 produces elevated insulin levels in ZDF rats during 6 weeks of daily treatment Rosiglitazone treated animals are insulin sensitized LIM-0742 treated animals maintain insulin output throughout the study
  • FIG. 22 shows that pyrone analog LIM 0742 produces an insulin response after a glucose load (2gr/kg) in fasted and aging ZDF rats Rosiglitazone treated animals cannot maintain sufficient insulin output to handle glucose load LIM-0742 arm treated animals maintain an effective insulin response
  • Quercetin-S'-O-methylphosphonic acid (Compound 2) (2-(Benzyloxy)-5-(3,7-bis(benzyloxy)-5-hydroxy-4-oxo-4H- chromen-2-yl)phenoxy)methylphosphonic acid (e) (20 0 g, 300 mmol, 1 equiv) and palladium hydroxide (20 % wt) (1 2 g) are suspended in ethanol (1 2 L) The reaction is hydrogenated for 7 hr @ 50 psi The mixture is filtered through cehte, concentrated under reduced pressure and d ⁇ ed in vacuum oven for 16 hr to give yellow solid, at which time 1 H NMR indicated significant amount of ethanol The yellow solid is then stirred in D 1 U F water (deionized ultra-filtered water, 300 mL) at 35 0 C for 0 5 hr and lyophihzed for 2 days Compound 2 is obtained as yellow solid ( 12 g, 100 % yield, >98 % pu ⁇ ty by
  • Rat hippocampal slices are prepared by a standard method Twenty rat hippocampal slices are placed in a perfusion chamber, incubated at 37 0 C and perfused by a batch method while exchanging the incubation buffer every 10 minutes
  • the incubation buffer has the composition NaCl, 124 mM, KCl, 5 mM, KH 2 PO 4 , 1 24 mM, MgSO 4 , 1 3 mM, CaCl 2 , 2 4 mM, NaHCO 3 , 26 mM, D-glucose, and 10 mM
  • a mixed gas of oxygen (95%) and carbon dioxide (5%) is used to saturate the buffer
  • a phosphonated pyrone analog is added to fractions 7- 15 to the concentration of 10 9 M, 10 8 M, 10 7 M, and 10 M, respectively
  • a phosphonated pyrone analog include quercetin-3-O-methylphosphonate (compound 1), quercetin-3'-O-methylphosphonate (compound 2), fisetin-3-O-methylphosphonate (compound 3), fisetin-3'-O- methylphosphonate (compound 4), querceun-4'-O-methylphosphonate (compound 5), and f ⁇ setin-4'-O- methylphosphonate (comopund 6).
  • a secondary pharmacological screening of molecules of interest at a fixed concentration is often practiced in the pharmaceutical industry in order to evaluate the effect of the compound on secondary targets that could result in untoward toxicity in vivo
  • These secondary screens are well known in the art and can be earned out by labs which specialize in these tests such as MDS-Panlabs and CEREP
  • a secondary toxicity screen is performed with fisetin-3'- O-phosphonate at a concentration of l OuM against 122 targets in enzyme, radioligand binding, and cellular assays by MDS Pharma Services by methods well known in the art Inhibition may be found in some targets (percent inhibition at lO ⁇ M in parentheses) ATPase, Na+/K+, Heart, Pig (65%), Nit ⁇ c Oxide Synthase, Endothelial (eNOS) (72%), Protein Tyrosine Kinase, FGFR2 (94%), Protein Tyrosine Kinase, FGFR 1(96%), Protein Tyrosine Kinase
  • the compound may be additionally tested in Adenosine A ⁇ , Adrenergic, ⁇ , DopamineD 25 , Histamine H r , and ⁇ -Opiate GTP ⁇ S functional assays using a concentration of 10 ⁇ M
  • the compound may demonstrate 48% antagonist activity in the Adenosine ⁇ assay, and marked negative inhibition in the Adrenergic A2A assay, potentially indicating PAF-5 could be acting as an inverse agonist in this assay
  • fisetin-3'-O-phosphonate has low toxicity properties, especially in light of the fact that the concentration at 10 ⁇ M, is high as compared to a therapeutic dose (e g greater than - 100 times)
  • Example 36 Phosphonated pyrone analog decreases cholesterol and triglyceride levels in human [00693]
  • a 32-year-old, obese, Caucasian male has a cholesterol level of 299 mg/dL, a triglyceride level of 440 mg/dL, an LDL level of 199 mg/dL, and an HDL level of 25 mg/dL He does not have diabetes, kidney, or liver disease He has a family history of coronary artery disease-his father suffers a heart attack at age 50 Because this patient is a male, obese, and has a positive family history of heart disease, he is advised to immediately start using the composition described herein on a daily basis
  • the composition is a tablet containing 20 mg of a phosphonated pyrone analog Additionally, he must strictly adhere to a low fat diet, and regularly exercise 30 minutes daily or 45 minutes every other day
  • Examples of a phosphonated pyrone analog include quercetin-3-O- methylphosphonate (compound 1), quer
  • the patient follows up with his doctor in 3 months with a repeat lipid profile
  • the blood test result shows an improvement of decreased cholesterol and triglycerides to 250 mg/dL and 280 mg/dL, respectively
  • the follow up plan also includes maintaining the same dosage of composition at 20 mg for two months, since the patient tolerates the medication well
  • Example 37 Phosphonated pyrone analog decreases triglyceride level in human
  • a 45-year-old Hispanic male with a history of gout and gastritis has a triglyceride level of 950 mg/dL, and a cholesterol level of 300 mg/dL
  • the patient begins using a composition described herein, for example a tablet containing 50 mg of a phosphonated pyrone analog, twice daily with no side effects
  • a phosphonated pyrone analog include quercetin-3-O-methylphosphonate (compound 1), quercetin-3'-0-methylphosphonate (compound 2), fisetin-3-O-methylphosphonate (compound 3), fisetin-3'-O-methylphosphonate (compound 4), quercetin-4'-O-methylphosphonate (compound 5), and fisetin-4'-0-methylphosphonate (comopund 6).
  • the patient is very compliant with respect to taking the medication everyday, along with consuming a low fat diet and regularly exercising As a result, the patient's t ⁇ glyce ⁇ de level decreases to 450 mg/dL His gout and gastritis conditions also improve as a direct result of lowering his triglycerides levels and his low fat diet He is to maintain the dosage of a composition described herein at 50 mg twice daily for the best results
  • Example 38 Phosphonated pyrone analog decreases LDL level and increases HDL level in human [00696]
  • a 55-year-old Asian female has menopause, hypertension, and hyperlipidemia She is currently taking PramproTM hormone replacement therapy for menopause, and AtenololTM for hypertension, which is controlled at this time
  • Example 39 Phosphonated pyrone analog in combination with other drugs prevent myocardial infarction in diabetic patient
  • a 34-year-old Hispanic female with diabetes melhtus type 2 has high cholesterol levels and high LDL levels Du ⁇ ng an office visit, she expe ⁇ ences a silent heart attack without congestive heart failure She is then admitted to the hospital for further cardiac evaluation and subsequently discharged after three days She is currently taking GlucotrolTM XL 5 mg daily, GlucophageTM 500 mg twice a day (diabetes medications), TenorminTM
  • a phosphonated pyrone analog examples include quercetin- 3-O-methylphosphonate (compound 1), quercetin-3'-0-methylphosphonate (compound 2), fisetin-3-O- methylphosphonate (compound 3), fisetin-3'-0-methylphosphonate (compound 4), quercetin-4'-O- methylphosphonale (compound 5), and fisetin-4'-O-methylphosphonate (comopund 6).
  • Example 40 Phosphonated pyrone analog treats hypercholesterolemia in human
  • a 42-year-old Asian male has strong a familial hypercholesterolemia
  • Hypercholesterolemia is a condition in which cholesterol is overly produced by the liver for unknown reasons
  • hypercholesterolemia is a strong ⁇ sk factor for myocardial infarction (Ml), diabetes, obesity, and other illnesses
  • Ml myocardial infarction
  • the patient is not overweight, but is very thin He has a very high level of cholesterol, over 300 mg/dL, and a t ⁇ glyce ⁇ de level of over 600 mg/dL
  • His diet consists of very low fat, high protein foods, and no alcohol He has a very active lifestyle, but one which is not stressful However, he still has to take medication to lower his cholesterol and t ⁇ glyce ⁇ de levels
  • the medications he takes include a composition desc ⁇ bed herein He is advised to continue taking a composition desc ⁇ bed herein, for example a tablet containing 40 mg of a phosphonated pyrone analog, daily for the remainder of his life in
  • Example 41 Phosphonated pyrone analog decreases triglyceride level in human
  • a 22-year-old male patient presents with t ⁇ glyce ⁇ de level of 250 mg/dL
  • the patient is given oral tablets containing about 20 mg to about 100 mg of a phosphonated pyrone analog
  • a phosphonated pyrone analog include quercetin-3-O-methylphosphonate (compound 1), quercetin-3'-O-methylphosphonate (compound 2), fisetin-3-O-methylphosphonate (compound 3), fisetin-3'-0-methylphosphonate (compound 4), quercetin-4'-O- methylphosphonate (compound 5), and fisetin-4'-O-methylphosphonate (comopund 6).
  • the patient's level of t ⁇ glyce ⁇ de is measured 24 hours after ingesting the tablets The measurement shows a decrease of about 20% to 50% of t ⁇ glyce ⁇ des as compared to the initial level
  • Example 42 Phosphonated pyrone analog decreases blood glucose level in human
  • a 46-year-old Af ⁇ can Ame ⁇ can female with diabetes melhtus type 2 has hyperglycemia with a blood glucose level of 20 mmol/L, i e approximately 360 mg/dL She is taking tablets desc ⁇ bed herein at the dosage of 10 mg-20 mg of a phosphonated pyrone analog once daily
  • a phosphonated pyrone analog include quercetin-3-O-methylphosphonate (compound 1), quercetin-3'-O-methylphosphonate (compound 2), fisetin-3-O- methylphosphonate (compound 3), fisetin-3'-O-methy]phosphonate (compound 4), quercetin-4'-O- methylphosphonate (compound 5), and fisetin-4'-O-methylphosphonate (comopund 6).
  • the patient's level of blood glucose is measured 24 hours after ingesting the tablets The measurement shows that the patient's blood glucose level returns to 6 mmol/L (i e 108 mg/dL) after fasting, which is within the normal range of about 80 to 120 mg/dL or 4 to 7 mmol/L
  • Example 43 Phosphonated pyrone analogs protect against onset of Type 2 diabetes and attendant complications in diabetic rat model
  • ZDF Diabetic Fatty
  • Blood is collected from the rats at day 0, 7, 14, 21 and 28, and assayed for levels of plasma glucose, insulin, and triglycerides Body weight is also measured on the same days Animals are sac ⁇ ficed at the end of the 4 week study after the OGTT study to obtain pancreas, liver, and heart puncture blood
  • Plasma glucose levels show that both compound 2 and compound 3 treatment maintains steady glucose levels similar to rosightazone treatment while vehicle treatments cause increase in blood glucose levels These stable glucose levels indicate that both compound 2 and compound 3 protect against hyperglycemia See Figure 27
  • Insulin levels show that compound 2 or compound 3 treated animals require lower insulin levels to maintain nomal glucose levels compared to vehicle treated animals See Figure 28 As expected, by week- 1 1 the vehicle treated animals are fully diabetic with very high plasma glucose (Figure 27) and very low plasma insulin (Figure 28)
  • HbAIc levels Similar to rosightazone, both compound 2 and compound 3 treated animals show lower glycated hemoglobin levels (% HbA Ic) at termination compared to vehicle treated animals See Figure 29.
  • Triglyceride levels , Rosightazone, compound 2 and compound 3 cause marked decreases in triglycerides
  • Example 45 The histopathological effects of phosphonated pyrone analogs on insulitis and beta cell mass in diabetic rat model
  • pancreas samples from Example 26 are stored in 10% NBF and used in this study All tissue samples were processed through graded alcohols, cleared in xylene and infiltrated and embedded into paraffin For the pancreas four 4 micron sections were cut, one was stained with Hematoxylin and Eosin for histopathology, two were immunohistochemically stained with an antibody to insulin to determine beta cell mass and one was stained for apoptosis with the tunel technique
  • mice Twenty-three (23) week old C57B1/6 mice are placed on 60% high fat diet (HFD) After 9 weeks of HFD, mice are injected daily with either vehicle (PBS/NaCO 3 ) or fisetin-3-O-methylphosphonate (compound 3) at a dosage of 10 mg/kg delivered via 1 P injection HFD is continued throughout the injection period After 2 weeks
  • HFD high fat diet
  • mice are tested for basal blood (non-fasted) glucose levels by tail blood withdrawal
  • IP glucose tolerance test (IP-GTT) is performed at a dose of l gm dextrose per kilogram body weight
  • cannulation surgery is performed on anesthetized mice
  • mice are allowed to recover 6 days After 6 days, hype ⁇ nsulinemic euglycemic clamp studies are performed on the mice After 7 weeks (week 16) of injections, a second IP-GTT is performed on the mice Three days after the second IP-GTT, mice are sacrificed and blood and tissue samples are collected for further analysis
  • Figure 36 demonstrates that phosphonated pyrone analog compound 3 improves response to glucose challenge in diet-induced obese mice
  • Figure 37 demonstrates that less insulin output is required in response to glucose challenge in compound 3 treated diet-induced obese mice, indicating reduced insulin resistance compared to vehicle treated obese mice
  • Figure 38 demonstrates that phosphonated pyrone analog compound 3 enhances tissue glucose uptake during hype ⁇ nsulinemic euglycemic clamp study in diet-induced obese mice
  • Figure 39 demonstrates that phosphonated pyrone analog compound 3 impacts hepatic glucose output in diet-induced obese mice
  • Figure 40 demonstrates that phosphonated pyrone analog compound 3 reduces basal glucose in diet- induced obese mice
  • Querce ⁇ n-3'-0-methylphosphonate ( Compound 2) is dissolved in water at about pH 8 After 24 hours in water at pH 8, no degradation is seen by NMR after 24 hours at ambient temperature
  • Example 48 Blood glucose levels in rats co-administered with Quercetin-3'-0-methylphosphonate and tacrolimus
  • One set of 5 rats is treated from day 1 to day 25 with inert vehicle 2 intrape ⁇ toneally and treated from day 1 1 to day 25 with inert vehicle 1 intrape ⁇ toneally
  • a second set of 5 rats is treated from day 1 to day 25 with tacrolimus (Prograf®) at 05 mg/kg, and treated from day 1 1 to day 25 with inert vehicle 2
  • a third set 5 of rats is treated from day 1 to day 25 with tacrolimus (Prograf®) intrape ⁇ toneally at 0 5 mg/kg, and treated from day 1 1 to day 25 intraperitoneal ⁇ with quercetin-3'-O-methylphosphonate (Compound 2) at 1 14 mg/kg
  • the blood glucose level in the rats is measured on days 1 , 10, 15, 20, and 25
  • the results show that phosphonated pyrone analogs such as Compound 2 can attenuate tacrolimus induced hyperglycemia
  • Example 49 Renal Pathology in rats co-administered with Quercetin-3'-O-methylphosphonate and tacrolimus
  • Tissue is removed from the kidney of rats treated with tacrolimus (Prograf®) at 0 5 mg/kg and inert vehicle, and from rats treated with tacrolimus (Prograf®) at 0 5 mg/kg and quercetin-3'-O-methylphosphonate (Compound 2) at 1 1 mg/kg, 28 mg/kg, and at 1 14 mg/kg for 25 days
  • the tissue from rats treated with tacrolimus and vehicle show significant vacuolation
  • the tissue from rats treated with Compound 2 and tacrolimus show no vacuoles
  • the results indicate that Compound 2 exerts a significant protective effect with respect to the kidneys when coadministered with tacrolimus
  • a secondary pharmacological screening of molecules of interest at a fixed concentration is often practiced in the pharmaceutical industry in order to evaluate the effect of the compound on secondary targets that could result in untoward toxicity in-vivo
  • These secondary screens are well known in the art and can be earned out by labs which specialize in these tests such as MDS-Panlabs and CEREP
  • a secondary toxicity screen can be performed with Quercetin-3'-O-methylphosphonate (Compound 2) at a concentration of lO ⁇ M against 122 targets in enzyme, radioligand binding, and cellular assays by MDS Pharma Services by methods well known in the art
  • Inhibition can be found in the following targets (percent inhibition at lO ⁇ M in parentheses) ATPase, Na+/K+, Heart, Pig (65%), Nit ⁇ c Oxide Synthase, Endothelial (eNOS) (72%), Protein Tyrosine Kinase, FGFR2 (94%), Protein Tyrosine Kinase, FGFR 1 (9
  • the compound can be additionally tested in Adenosine A
  • the findings of this toxicology screen can be an indication that Quercetin-3'-O-methylphosphonate has low toxicity properties, especially in light of the fact that the concentration tested, lO ⁇ M, is high as compared to a therapeutic dose (e g greater than ⁇ 100 times)
  • Example 51 Phosphonated pyrone analog compound 1 protects against onset of Type 2 diabetes and attendant complications in diabetic rat model
  • Predose tail-vein-blood samples are collected from each rat at day 0, 7, 14, 21 and 28, and plasma glucose concentrations are determined Body weights are also measured on the same days Insulin and glycated hemoglobin (HbA Ic) concentrations are also determined on day-28 blood Oral glucose (2 g/kg, S ml/kg) tolerance test (.OGTT) including fasting insulin are performed on all animals on day-29 after 12-hr fast. Animals are sacrificed after OGTT to obtain pancreas for insulin and liver for triglyceride determination
  • Plasma glucose levels show that compound 1 treatment maintains a lower plasma glucose level than vehicle treatment Compound 1 treatment, however, did not stabilize plasma glucose levels as rosightazone treatment did ( Figure 41 ) Compound 1 appeas to slow down the development of diabetes and have a different mode of action from that of rosightazone
  • Insulin levels Plasma insulin measurements (Figure 42) showed that compound 1 treated animals maintain significantly higher plasma insulin levels under both fed and fasting conditions Untreated male ZDF rats under experimental conditions desc ⁇ bed above develop diabetes between the age of 8 and 10 weeks old (day- 14 to day-28 of this example) As shown in Figure 102, vehicle treated animals have low insulin levels corresponding to the full diabetic state The significantly higher insulin levels of compound 1 treated animals provides further evidence that compound 1 treatment slows down the development of diabetes in male ZDF rats
  • OGTT Plasma glucose concentrations at 15, 30, 60, and 90 minutes post oral glucose challenge
  • HbAIc levels Similar to rosightazone, 30 mg/kg compound 1 treated animals show significantly lower glycated hemoglobin levels (% HbA Ic) at termination compared to vehicle treated animals ( Figure 44)
  • pancreatic Insulin Similar to rosightazone treated animals, the pancreatic insulin levels of 30 mg/kg compound 1 treated animals are significantly higher than that of the vehicle treated animals ( Figure 45) This is consistent with compound 1 treatment slows down the development of diabetes
  • liver Triglyceride In contrast of rosightazone treatment, compound 1 treated animals did not increase liver triglyceride (Figure 46)
  • Example 52 Compound 1 protects against cyclosporine induced islet injury in rat
  • Experimental Design This study is a 2-week study conducted with male Wistar rats (25 animals, 5 treatment groups, 5 rats/group) 10 5-week old at the start of compound treatment The animals are maintained (starting at 9-week old) on a 12-hr light and 12-hr dark cycle, and provided with commercial rodent chow Pu ⁇ na 5008 and water ad libitum The animals are treated daily intrapentoneally (IP) with Treatment- 1 (at 6 hr, 45 minutes after the start of light cycle) followed by oral dose (PO) of Treatment-2 (at 7 hr after the start of the light cycle) as shown in the following table Neoral ® oral solution (containing 100 mg/ml of cyclospo ⁇ ne is used to prepare the cyclospo ⁇ ne dose
  • Predose tail-vein-blood samples are collected from each rat at day 0, 7, and 14, and plasma glucose concentrations are determined Body weights are also measured on the same days Oral glucose (2 g/kg, 5 ml/kg) tolerance test (OGTT) are performed on all animals on day-15 after 12-hr fast. Animals are sac ⁇ f ⁇ ced after OGTT to obtain pancreas for histopathological evaluation
  • OGTT Plasma glucose concentrations at 0, 15, 30, 60, 90, and 120 minutes post oral glucose challenge
  • Example 53 Compound 1 protects against cyclosporine induced islet apoptosis
  • Islet Cell Histopathology As shown in Figure 49, pancreatic islets from cyclospo ⁇ ne treated animals
  • Islet Apoptosis As shown in Figure 50, pancreatic islets from cyclospo ⁇ ne treated animals (Group-2) showed increased apoptosis compared to vehicle treated animals (Group- 1 ), while co-admimstration with compound 1 (Group-3) reduced the number of apoptotic cells to that of vehicle treated animals
  • Example 54 Compound 1 protects against tacrolimus induced hyperglycemia in rat
  • This study is a 2-week study conducted with male Wistar rats (25 animals, 5 treatment groups, 5 rats/group) 1 1 -week old at the start of compound treatment
  • the animals are maintained (starting at 9-week old) on a 12-hr light and 12-hr dark cycle, and provided with commercial rodent chow Purina 5008 and water ad libitum
  • PO daily orally
  • IP intrape ⁇ toneal dose
  • Treatment-2 as shown in the following table
  • Stock solution (5 mg/ml) of tacrolimus is prepared in HCO-60 in 80% alcohol
  • Dose solution of tacrolimus is prepared from the stock solution by 1 10 dilution with skim milk
  • Predose tail-vein-blood samples are collected from each rat at day 0, 7, and 14, and plasma glucose concentrations are determined Body weights are also measured on the same days Oral glucose (2 g/kg, 5 ml/kg) tolerance test (OGTT) are performed on all animals on day-lS after 12-hr fast TeU vein blood samples are collected pre- glucose challenge and at 15, 30, 60, 90 and 120 min post-glucose challenge.
  • Oral glucose (2 g/kg, 5 ml/kg) tolerance test OGTT
  • TeU vein blood samples are collected pre- glucose challenge and at 15, 30, 60, 90 and 120 min post-glucose challenge.
  • BB 19 cells human BCECs (brain capillary endothelial cells) immortalized with the E6E7 genes of human papilloma virus, were kindly provided from Jacques G PrudAppel, Department of Biology, University of California, Riverside, U S A
  • the cells were cultured as monolayer culture in AmniomaxTM-C 100 basal medium (catalog number 17001 -157) with AmniomaxTM-C l OO supplement (catalog number 12556-049) (Invitrogen, Basel, CH)
  • BB 19 cells were seeded 50'0OO cells/ cm 2 on 96-well plates (Falcon) and incubated under condition described above for 6 days Before starting the assay, cells were washed 2 times with pre-warmed Dulbecco's MEM with Glutamax-I (catalog number 61965) (Invitrogen AG, Basel, CH), supplemented with 1 % non essential amino acids, 1 % sodium pyruvate, 50 ⁇ g/ml gentamycin (Invitrogen AG) (DMEM) Cells were then incubated for 15 min at 37°C and 120 rpm in DMEM with or without the specified concentrations of test compounds under investigation After this pre-incubation, cells were incubated in DMEM containing [propyl- 3 H]-dihydro-FK506 ( 3 H-tacrohmus, 1 ⁇ Ci/ml, 34 nM) and with or without the specified concentrations of test compounds for 1 hour at 37°C and
  • cyclospo ⁇ n uptake assay was performed similarly as described above for tacrolimus uptake assay except that 3 H-cyclospo ⁇ n was used in place of 3 H-tacrolimus
  • Example 57 Phosphonated pyrone analog compound 3 reduce plasma and liver triglyceride in C57BL/6 mice
  • the stock solution of vehicle (HCO-60) is composed of 200 mg of HCO-60 per mL of 80% alcohol Vehicle is prepared by diluting the HCO-60 stock solution 1 10 with saline Compound 3 stock solutions are prepared in HCO-60 stock solution and diluted with saline or vehicle to the appropriate dose concentration [00754]
  • Tail-vein-blood samples are collected from each rat 24 hour after the last treatment (day- 14) for plasma t ⁇ glyce ⁇ de determination Animals are sacrificed to obtain liver for triglyceride determination
  • Plasma triglyceride levels The plasma t ⁇ glyce ⁇ de concentrations of animals treated with vehicle or compound 3 are shown in Figure 54 Daily treatment of compound 3 for 13 days reduces plasma t ⁇ glycende in
  • liver triglyceride levels The liver t ⁇ glyce ⁇ de concentrations of animals treated with vehicle or compound 3 are shown in Figure 55 Compared to vehicle treated controls (Group- 1), daily treatment with 30 mg/kg of compound 3 for 13 days significantly reduces liver t ⁇ glyce ⁇ de of C57BL/6 mice
  • Example 58 Phosphonated pyrone analog compound 3 reduce plasma glucose, plasma triglyceride, plasma cholesterol and liver triglyceride in db/db mice without excessive body weight gain
  • Pre-dose tail-vein-blood samples are collected from each rat at day 0, 7, 14, 21 and 28, and plasma glucose, t ⁇ glyce ⁇ de and cholesterol concentrations are determined Body weights are also measured on the same days Animals are sac ⁇ ficed on day-29 to obtain liver for t ⁇ glyce ⁇ de determination [00759] Plasma glucose levels Plasma glucose level on Day-28 of compound 3 treated mice, similar to those treated with rosiglitazone, are lower than vehicle treated control mice (figure 56) Thus, compound 3 significantly reduced diabetes-associated hyperglycemia in db/db mice after 4 weeks of treatment
  • Plasma triglyceride levels Plasma triglyceride levels on Day-28 of 10 mg/kg compound 3 treated mice are significantly lower than vehicle or rosiglitazone treated mice (figure 57) Thus, compound 3 reduced diabetes- associated hypertriglyceridemia in db/db mice after 4 weeks of treatment
  • Liver Triglyceride Liver triglyceride at sac ⁇ fice (day-29) of 10 mg/kg compound 3 treated mice are significantly lower than vehicle treated mice (figure 59) Thus, compound 3 reduced diabetes-associated fatty liver in db/db mice after 4 weeks of treatment
  • Body Weight gain In contrast to rosiglitazone treatment, body weights of compound 3 treated animals are essentially identical that of vehicle treated animals ( Figure 60) Thus, 4 weeks of daily compound 3 treatments reduce plasma glucose, plasma triglyceride, plasma cholesterol and liver t ⁇ glyce ⁇ de in db/db mice without excessive body weight gain
  • Example 59 Synthesis of Diethyl (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo-4W-chromen-3- yloxy)methylphos-phonate (Compound 9) and Ethyl hydrogen (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-4-oxo- 4//-chromen-3-yloxy)-methylphosphonate (Compound 19)
  • Example 62 Synthesis of (2-(3,4-Dihydroxyphenyl)-4-oxo-4//-chromen-3-yloxy)rnethylphosphonic acid (Compound 20), Diethyl (2-(3,4-dihydroxyphenyl)-4-oxo-4//-chromen-3-yloxy)methylphosphonate (Compound 13), and Ethyl hydrogen (2-(3,4-dihydroxyphenyl)-4-oxo-4W-chromen-3- yloxy)methylphosphonate (Compound 21)
  • Ethyl hydrogen (2-(3,4-dihydroxyphenyl)-4-oxo-4W-chromen-3-yloxy)methylphosphonate (Compound 21): A solution of ethyl (2-(3,4-dihydroxyphenyl)-4-oxo-4W-chromen-3-yloxy)methyl-phosphonate (Compound 13) ( 1 0 g, 2 38 mmol) and chloroform ( 12 mL) was stirred at room temperature, while TMSBr (0 31 mL, 2 38 mmol) was added The reaction mixture was allowed to stir at room temperature for 16 hr and quenched by water (5 mL) Mixture was concentrated under reduced pressure and purified by Analogix (SF 25- 10Og, RP C 18) using gradient of 0-40% methanol in water as eluent to give 140 mg, (15% yield) of ethyl hydrogen (2-(3,4- dihydroxy-phenyl)-4-oxo-4W-chromen
  • Example 63 Synthesis of (3,7-Dihydroxy-4-oxo-2-phenyl-4H-chromen-5-yloxy)methylphosphonic acid (Compound 16) and (3,5-Dihydroxy-4-oxo-2-phenyl-4H-chromen-7-yloxy)methylphosphonic acid (Compound 10) Compound 10
  • Ethyl hydrogen (5-(3,7-dihydroxy-4-oxo-4//-chromen-2-yl)-2-hydroxyphenoxy)methylphosphonate (Compound 12): A solution of ethyl (5-(3,7-dihydroxy-4-oxo-4W-chromen-2-yl)-2-hydroxyphenoxy) methylphosphonate (N) ( 100 mg, 023 mmol) and DMF (6 mL) was stirred at room temperature, while TMSBr (0 12 mL, 0 9 mmol) was added After 16 hrs at room temperature, additional TMSBr (0 12 mL, 09 mmol), the reaction was quenched with methanol (5 mL) and concentrated under reduced pressure The mixture was purified by reverse phase chromagraphy with a gradient of 0- 10 % methanol in water (AnaLogix SFl 5-30 g, RP C- 18), concentrated under reduced pressure and lyophihzed for 2 days to give 15 mg ( 16
  • Example 66 Synthesis of Diethyl (2-hydroxy-5-(3,5,7-trihydroxy-4-oxo-4W-chromen-2-yl)phenoxy) methylphospho-nate (Compound 17) and Ethyl hydrogen (2-hydroxy-5-(3,5,7-trihydroxy-4-oxo-4W-chromen- 2-yl)phenoxy)methyl-phosphonate (Compound 14)
  • Ethyl hydrogen (2-hydroxy-5-(3,5,7-trihydroxy-4-oxo-4W-chromen-2-yl)phenoxy)methyl- phosphonate (Compound 14): A solution of diethyl (2-hydroxy-5-(3,5,7-t ⁇ hydroxy-4-oxo-4W-chromen-2- yl)phenoxy)methylphosphonate (Compound 14) (0 10 g, 0 22 mmol), DMF (6 mL), and TMSBr (0 15 mL, 1 1 1 mmol) was stirred at room temperature for 16 hr Additional TMSBr (0 12 mL, 0 89 mmol) was added and the reaction was allowed to stir at room temperature for 16 hr The reaction was quenched with methanol (5 mL), concentrated under reduced pressure The mixture was purified by reverse phase chromagraphy and eluting with gradient of 0- 10 % methanol in water (AnaLogix SF15-3O g, RP C- 18), concentrated
  • Ethyl hydrogen (7-(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-4-oxo-4//-chromen-3- yloxy)methylphosphonate (S): Diethyl (7-(benzyloxy)-2-(3,4-bis(benzyloxy)phenyl)-4-oxo-4W-chromen-3- yloxy)methylphosphonate (R) (0 50 g, 0 71 mmol) was stirred in chloroform (20 mL) at room temperature, while TMSBr (0 19 mL, 1 41 mmol) was added The reaction was allowed to stir at room temperature for 16 hr, quenched with MeOH ( 10 mL), concentrated under reduced pressure and used directly for the next step [00791] Ethyl hydrogen (2-(3,4-dihydroxyphenyl)-7-hydroxy-4-oxo-4//-chromen-3-yloxy)methyl-phosphonate (Compound 15): A

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Abstract

L'invention porte sur des procédés pour le traitement et la prévention de troubles métaboliques ou autres maladies par administration d'un analogue de pyrone ou d'un dérivé de celui-ci. L'invention porte également sur des procédés pour le traitement et la prévention de troubles métaboliques et autres maladies par administration d'un analogue de pyrone, ou d'un dérivé de celui-ci, en combinaison avec un ou plusieurs agents additionnels tels que, par exemple, des hypolipémiants ou des hypoglycémiants. L'invention porte également sur des procédés pour la modulation de l'activité de transporteur de lipide pour accroître la sortie de lipide d'un compartiment physiologique dans un environnement externe. Les procédés divulgués dans la demande peuvent être utilisés pour évaluer le traitement ou la prévention d'un trouble métabolique à la suite de l'administration d'un analogue de pyrone ou d'un dérivé de celui-ci.
EP10714412A 2009-04-27 2010-04-09 Analogues de pyrone phosphorylés et phosphonés comme agents therapeutiques Withdrawn EP2424541A2 (fr)

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CA2693338A1 (fr) 2007-07-31 2009-02-05 Limerick Biopharma, Inc. Analogues de pyrone phosphoryles et procedes
GB2473150A (en) * 2007-07-31 2011-03-02 Limerick Biopharma Inc Quercetin-3'-O-phosphate
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