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WO2008014299A2 - Méthodes et compositions utiles pour le traitement de l'hyperlipidémie - Google Patents

Méthodes et compositions utiles pour le traitement de l'hyperlipidémie Download PDF

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Publication number
WO2008014299A2
WO2008014299A2 PCT/US2007/074284 US2007074284W WO2008014299A2 WO 2008014299 A2 WO2008014299 A2 WO 2008014299A2 US 2007074284 W US2007074284 W US 2007074284W WO 2008014299 A2 WO2008014299 A2 WO 2008014299A2
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Prior art keywords
agonist
compound
activity
sedating
receptor
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WO2008014299A3 (fr
Inventor
Jyotirmoy X. Kusari
Daniel W. Gil
John E. Donello
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Allergan Inc
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Allergan Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/17—Amides, e.g. hydroxamic acids having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention is directed to methods of treating hyperlipidemia using an agonist of the ⁇ 2B and/or ⁇ 2C adrenergic receptor subtypes that lacks (a) significant ⁇ 2A adrenergic receptor activity or (b) significant ⁇ 1A adrenergic receptor activity, or that lacks both (a) and (b).
  • Diabetes mellitus is a condition involving the presence of abnormally high levels of glucose in the blood (hyperglycemia).
  • a normal range of glucose in the blood is considered between about 70 mg/dl and about 110 mg/dl.
  • Hyperglycemia would comprise a blood glucose level above 110 at a time greater than about 2-3 hours after eating. This condition arises due to reduced or absent production or secretion of insulin (Type 1 or insulin-dependent diabetes), or to a cell's lack of response to the presence of insulin in the extracellular milieu (Type 2 or insulin independent diabetes).
  • hyperlipidemia such as hypertriglyceremia
  • existing anti-diabetic agents able to decrease serum glucose may not have a significant effect on the level of triglycerides in the blood.
  • the most common oral hypoglycemic (antidiabetic) agents are generally described only with regard to their ability to lower blood glucose levels.
  • those agents used to lower serum triglycerides, such as statins may have little or no effect on blood glucose levels.
  • an agent is reported to be useful for the treatment of diabetes, such as type Il diabetes, does not mean that the agent is also effective at lowering the level of serum triglycerides.
  • Non-sedating ⁇ 2 receptor agonist compositions contain agents that have already been characterized in the imidazole, thiourea, imidazoline, and imidazole thione, amino imidazoline, amino oxazoline and amino thiazoline chemical classes. It is to be expected that future non-sedating ⁇ 2 agents (or combinations of agents) will be found in additional chemical classes including phenethylamine, amino thiazine, benzazepine, quinazoline, guanidine, piperazine, yohimbine alkaloid, and phenoxypropanolamine chemical classes.
  • non-sedating ⁇ 2 adrenergic agonist compositions have certain biochemical properties in common, regardless of the chemical structure of the agents contained in the compositions.
  • such compounds in addition to having ⁇ 2 adrenergic agonist activity, particularly but not necessarily exclusively, ⁇ 2B and or ⁇ 2C adrenoreceptor activity, also lack significant ⁇ 1 adrenoreceptor activity.
  • a therapeutic composition comprising a nonsedating ⁇ 2 adrenergic agonist may comprise a combination of an ⁇ 2 adrenergic agonist with an ⁇ 1 adrenergic antagonist.
  • the reduced or absent ⁇ 1 adrenergic activity results in a significant increase in the potency of the ⁇ 2 adrenergic agonist activity with no significant increase in the potency of the sedative activity.
  • the ⁇ 2 adrenergic agonist has little or no sedative effect, particularly as compared to a composition comprising an ⁇ 2 adrenergic agonist at a dosage conferring the same therapeutic effect, but lacking significant ⁇ 1 A inhibitory activity.
  • Potency refers to the concentration of an agonist required to produce a therapeutic effect. Potency is quantified by EC50, the concentration at which half of the maximum therapeutic effect of the agonist is seen. Change in potency, therefore, is quantified by a change in EC50: an increase in potency, for example, results in a decrease in EC50.
  • Efficacy refers to maximum effect of an agonist. Percent efficacy (% E) is determined by comparing the maximum effect of each agonist to the maximum effect of a standard full agonist (phenylephrine for ⁇ -1 receptors and bhmonidine for ⁇ -2 receptors. By "lacking significant ⁇ 1A activity” is meant having an ⁇ 1 A/ ⁇ 2A EC 50 ratio greater than that of bhmonidine (for which this ratio is greater than about 25). In preferred embodiments the ratio is at least 20% greater, or at least 40% greater, or at least 50% greater, or at least 70% greater, or at least 80% greater, or at least 100% greater, or at least 200% greater, or at least 500% greater than that of bhmonidine.
  • the non-sedating ⁇ 2 adrenergic agonist may comprise a adrenergic agonist having selective ⁇ 2B and/or ⁇ 2C agonist activity, but lacking significant alpha 2A activity.
  • An " ⁇ 2 agonist lacking significant ⁇ 2A activity" is an ⁇ 2 agonist that has less than 40% of the efficacy of bhmonidine at the ⁇ 2A receptor and has the ability to produce a therapeutic effect without concomitant sedation upon peripheral administration in genetically unaltered animals.
  • Such a characterization includes ⁇ 2B selective agonists lacking significant ⁇ 2A activity, ⁇ 2C selective agonists lacking significant ⁇ 2A activity, and ⁇ 2B/ ⁇ 2C agonists lacking significant ⁇ 2A activity.
  • Such agonists have an EC50 of less than 1000 nM at the indicated receptor subtype(s)( ⁇ 2B, ⁇ 2C, or ⁇ 2B and ⁇ 2C), or at least 100-fold greater activity at the indicated receptor subtype(s) than at the ⁇ 2A receptor.
  • the agonists have an EC50 value of less than 900 nM, 800 nM, 700 nM, 600 nM, 500 nM, 400 nM, 300 nM, 200 nM, 100 nM, 50 nM, 10 nM or 1 nM at the indicated receptor subtype(s).
  • Agonist selectivity can be characterized using any of a variety of routine functional assays, for example, in vitro cell-based assays which measure the response of an agent proximal to receptor activation.
  • Useful assays include, without limitation, in vitro assays such as cyclic AMP assays or GTP ⁇ S incorporation assays for analyzing function proximal to ⁇ 2 receptor activation (Shimizu et al., J. NEUROCHEM. 16:1609-1619 (1969); Jasper et al., BIOCHEM. PHARMACOL.
  • intracellular calcium assays such as FLIPR assays and detection of calcium pulses by Ca ++ -sensitive fluorescent dyes such as fluo-3 for analyzing function proximal to ⁇ 1 receptor activation
  • Sullivan et al. METHODS MOL. BIOL. 1 14:125-133 (1999); Kao et al., J. BIOL. CHEM. 264:8179-8184 (1989)).
  • ⁇ 2A selectivity assays based on inhibition of forskolin- induced cAMP accumulation in PC12 cells stably expressing an ⁇ 2A receptor, and increases in intracellular calcium in HEK293 cells stably expressing an ⁇ 2A receptor are known and have been described in, for example, U.S. Patent Application Publication No. 2005/0059664, which is incorporated by reference as part of this disclosure in its entirety. Additional useful assays include, without limitation, inositol phosphate assays such as scintillation proximity assays (Brandish et al., ANAL. BIOCHEM. 313:31 1-318 (2003)); assays for ⁇ -arrestin
  • GPCR sequestration such as bioluminescence resonance energy transfer assays (Bertrand et al., J. RECEPTOR SIGNAL TRANSDUC. RES. 22:533-541 (2002)); and cytosensor microphysiometry assays (Neve et al., J. BIOL. CHEM. 267:25748- 25753 (1992)).
  • bioluminescence resonance energy transfer assays Bosset et al., J. RECEPTOR SIGNAL TRANSDUC. RES. 22:533-541 (2002)
  • cytosensor microphysiometry assays Neve et al., J. BIOL. CHEM. 267:25748- 25753 (1992)
  • ⁇ 2 and ⁇ 1 (for example ⁇ 1A) receptor function are routine and well known in the art and are hereby incorporated by reference as part of this specification in their entirety.
  • a GTP ⁇ S assay is an assay useful for determining, for instance, the functional selectivity of an agent for activating an ⁇ 2A receptor as compared to an ⁇ 1A receptor in the methods of the invention.
  • ⁇ 2 adrenergic receptors mediate incorporation of guanosine 5'-0-( ⁇ -thio)- triphosphate ([ 35 S]GTPyS) into G-proteins in isolated membranes via receptor- catalyzed exchange of [ 35 S]GTPyS for GDP.
  • An assay based on [ 35 S]GTPyS incorporation can be performed essentially as described in Jasper et al., supra, 1998.
  • confluent cells treated with an agent to be tested are harvested from tissue culture plates in phosphate buffered saline before centhfuging at 300 x g for five minutes at 4 ° C.
  • the cell pellet is resuspended in cold lysis buffer (5 mM Tris/HCI, 5 mM EDTA, 5 mM EGTA, 0.1 mM PMSF, pH 7.5) using a Polytron Disrupter (setting #6, five seconds), and centhfuged at 34,000 x g for 15 minutes at 4 ° C before being resuspended in cold lysis buffer and centhfuged again as above.
  • membrane buffer 50 mM Tris/HCI, 1 mM EDTA, 5 mM MgCI 2 , and 0.1 mM PMSF, pH 7.4
  • GTP ⁇ S incorporation is assayed using [ 35 S]GTPyS at a specific activity of
  • samples are filtered through glass fiber filters (Whatman GF/B, pretreated with 0.5% bovine serum albumin) in a 96-well cell harvester and rapidly washed four times with four ml of ice-cold wash buffer (50 mM Tris/HCI, 5 mM MgCI 2 , 100 mM NaCI, pH 7.5). After being oven dried, the filters are transferred to scintillation vials containing five ml of Beckman's Ready Protein® scintillation cocktail for counting. The EC50 and maximal effect (efficacy) of the agent to be tested are then determined for the ⁇ 2A receptor.
  • a method for measuring alpha agonist activity and selectivity comprises the RSAT (Receptor Selection and Amplification Technology) assay as reported in Messier et al., High Throughput Assays Of Cloned Adrenergic, Muscarinic, Neurokinin And Neurotrophin Receptors In Living Mammalian Cells, PHARMACOL. TOXICOL. 76:308-1 1 (1995), which has been adapted for use with ⁇ 1 and ⁇ 2 receptors.
  • the assay measures a receptor-mediated loss of contact inhibition that results in selective proliferation of receptor-containing cells in a mixed population of confluent cells.
  • the increase in cell number is assessed with an appropriate transfected marker gene such as ⁇ -galactosidase, the activity of which can be easily measured in a 96-well format.
  • Receptors that activate the G protein, G q elicit this response.
  • Alpha 2 receptors, which normally couple to G, activate the RSAT response when coexpressed with a hybrid Gq protein that has a Gi receptor recognition domain, called Gq/i5.
  • Gq/i5 a transfected marker gene
  • the person of ordinary skill in the art can screen drug libraries such as commercial drug libraries available from companies such as, without limitation, Sigma Aldrich, TimTec, Novascreen and the like to select compounds having ⁇ 2 agonist activity, but lacking significant sedative activity at therapeutic concentrations of the drug.
  • drug libraries such as commercial drug libraries available from companies such as, without limitation, Sigma Aldrich, TimTec, Novascreen and the like to select compounds having ⁇ 2 agonist activity, but lacking significant sedative activity at therapeutic concentrations of the drug.
  • known or unknown ⁇ 2 agonists may be used in a non-sedating ⁇ 2 agonist therapeutic composition comprising an ⁇ 1 (preferably an ⁇ 1 A) antagonist to provide a therapeutic effect, wherein the dosage of the ⁇ 2 agonist necessary to provide a therapeutic effect is substantially lowered in such composition relative to a second composition comprising only the ⁇ 2 agonist as the sole active agent. Due to this increase in potency, the amount of sedation and cardiovascular depression experienced by a mammal to whom said agent is administered, either peripherally or non- peripherally, is greatly decreased at a therapeutically effective dose of the 2 agonist.
  • the ⁇ 1 adrenergic receptor antagonist is selected from the group consisting of prazosin, terazosin, doxazonine, urapidil and 5-methylurapadil.
  • the former two compounds and their syntheses are described in U.S. Patents 3,51 1 ,836, and 4,026,894, respectively; the latter compound is an easily synthesized derivative of urapidil, whose synthesis is described in U.S. Patent 3,957,786.
  • ⁇ 1 receptor antagonists including ⁇ 1A receptor antagonists
  • ⁇ 1A receptor antagonists are well known in the art; many such compounds have been clinically approved. See also Lagu, 26 DRUGS OF THE FUTURE 757-765 (2001 ) and Forray et al., 8 EXP. OPIN. INVEST. DRUGS 2073 (1999), hereby incorporated by reference herein, which provide examples of numerous ⁇ 1 antagonists.
  • the present invention is based in part on the surprising finding that ⁇ 2- receptor agonist compositions are useful in treating hyperglycemia and hyperlipidemia and raising blood insulin levels, rather than in maintaining or causing hyperglycemia and hyperlipidemia, as has previously been observed in studies using ⁇ 2 receptor agonist compounds having sedative activity. This effect is seen using non-sedating ⁇ 2B selective receptor agonists compositions but is also observed using non-sedating ⁇ 2 pan-agonist compositions as well.
  • pan-agonist is meant that the agonist is ⁇ 2 receptor agonist able to stimulate the ⁇ 2A, ⁇ 2B and ⁇ 2C receptor subtypes.
  • ⁇ 2 agonist composition comprises an ⁇ 2 agonist having activity at the ⁇ 2B and/or ⁇ 2C adrenergic receptor subtypes, and either a) lacking significant ⁇ 2A activity, b) lacking significant ⁇ 1A activity, or both a) and b).
  • the ⁇ 2 agonist composition may comprise a non-sedating ⁇ 2 receptor agonist, such as an ⁇ 2 agonist lacking substantial ⁇ 1 A activity or an ⁇ 2 agonist lacking significant ⁇ 2A activity.
  • the ⁇ 2 agonist composition may comprise an ⁇ 2 agonist (either an ⁇ 2B or 2C selective agonist or an ⁇ 2 pan-agonist) having activity at the ⁇ 2B and/or ⁇ 2C adrenergic receptor subtypes plus comprising an additional component selected from the group consisting of an ⁇ 1 receptor antagonist (such as an ⁇ 1 A receptor antagonist) or an alpha 2A receptor antagonist or both.
  • ⁇ 1 receptor antagonist such as an ⁇ 1 A receptor antagonist
  • alpha 2A receptor antagonist alpha 2A receptor antagonist
  • a “therapeutically effective” amount, concentration, or dosage is meant an amount, concentration or dosage that is capable of treating at least one symptom of the indicated medical condition.
  • the present invention is drawn to a method for the treatment of a patient having hyperglycemia or hypertriglyceremia and/or elevated levels of blood insulin comprising administering to said patient a therapeutically effective amount of an ⁇ 2 agonist composition comprising an ⁇ 2 receptor subtype agonist.
  • the invention comprises administering to a patient a therapeutically effective amount of a non-sedating ⁇ 2 agonist composition comprising a ⁇ 2 agonist lacking significant ⁇ 2A activity.
  • Compound 1 illustrated below, is an ⁇ 2 agonist composition that may be used according to the method of the invention:
  • the alpha 2-receptor agonist composition comprises a non- sedating ⁇ 2B selective agonist.
  • alpha 2B selective agonist is meant that i) the efficacy relative to a standard full agonist at the ⁇ 2B receptor subtype is greater than its efficacy relative to a standard full agonist at the ⁇ 2A or ⁇ 2C receptor subtypes and that the relative efficacy at the ⁇ 2A or ⁇ 2C receptor subtypes is ⁇ 0.4; or ii) the potency of the compound at the ⁇ 2B receptor subtype is at least 10 fold greater than at the ⁇ 2A or ⁇ 2C receptor subtypes under the same experimental conditions.
  • the non-sedating ⁇ 2B selective agonist has a chemical structure chosen from:
  • compounds 1 , 2, and 4 are of the imidazole-2- thione class of compounds, while compound 3 belongs to the thiourea chemical class; thus the methods and compositions of the present invention are not limited by structure, but apply equally to all alpha 2 non-sedating compounds.
  • Such compounds have now been characterized in the imidazole, thiourea, imidazoline, and imidazole thione chemical classes.
  • Additional chemical classes which comprise non-sedating ⁇ 2 receptor agonists may include, without limitation, the phenethylamine, amino thiazine, amino imidazoline, benzazepine, amino oxazoline, amino thiazoline, quinazoline, guanidine, piperazine, yohimbine alkaloid, and phenoxypropanolamine chemical classes.
  • sedation is a term that means a reduction in motor activity.
  • an ⁇ 2- selective agonist is administered to a mammal at a dose of 2 mg/kg and reduces blood glucose from 250 mg/dl to 200 mg/dl; the ⁇ 2-selective agonist is "nonsedating" if it produces less than about 30% sedation when administered to the mammal at a dose of at least about 20 mg/kg.
  • the amount of ⁇ 2 receptor agonist required to reduce blood glucose by 20% or more will generally be a "therapeutically effective dose," although in certain circumstances a lower reduction (e.g., 10%) may be desirable.
  • non-sedating or “without concomitant sedation” does not mean that the indicated compound lacks sedative activity at any dosage; rather it is always an indication of lack of sedation relative to a therapeutically effective dose.
  • the dose of the non-sedating ⁇ 2 agonist required to produce about 30% sedation can be at least 25-fold greater than, 50-fold greater than, 100-fold greater than, 250-fold greater than, 500-fold greater than, 1000-fold greater than, 2500-fold greater than, 5000-fold greater than, or 10, 000-fold greater than less than the dose of the same ⁇ 2 agonist required to produce a reduction of blood glucose in a hyperglycemic mammal to 1 10 mg/dl or less.
  • Methods for determining the extent of a reduction in blood glucose, as well as the extent of sedation are described herein and further are well known in the art.
  • the present invention may comprise a composition having anti-hyperglycemic activity comprising a non-sedating ⁇ 2- receptor agonist present at a dosage effective to deliver a therapeutically effective dosage of said agent when administered to a mammal in need thereof.
  • methods of administering a drug may include any means sufficient to deliver an effective dose of the agent.
  • preferred routes of administration for the ⁇ 2 agonist composition of the invention may be peripheral or non-peripheral and include oral, intravenous, intrathecal and epidural administration.
  • Other possible means of administration of the non ⁇ 2 agonist composition include, without limitation, by intrathecal pump, subcutaneous pump, dermal patch, intravenous injection, subcutaneous injection, intramuscular injection, and an oral pill, or a combination of such methods.
  • peripheral means of administration of the non-sedating ⁇ 2 agonist composition are not currently preferred in the treatment of hyperglycemia or hyperlipidemia, the advantages of the instantly claimed methods may be observed in such cases as well, depending at least in part on the bioavailability of the agent or agents comprised in the ⁇ 2 agonist composition.
  • compositions comprising the ⁇ 2 agonist composition useful in the present invention optionally (but preferably) includes an excipient such as a pharmaceutically acceptable carrier or a diluent, which is any carrier or diluent that has substantially no long term or permanent detrimental effect when administered to a subject.
  • An excipient generally is mixed with the active compound(s), or permitted to dilute or enclose the active compound(s).
  • a carrier can be a solid, semi-solid, or liquid agent that acts as an excipient or vehicle for the active compound.
  • solid carriers include, without limitation, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, polyalkylene glycols, talcum, cellulose, glucose, sucrose and magnesium carbonate.
  • Suppository formulations can include, for example, propylene glycol as a carrier.
  • pharmaceutically acceptable carriers and diluents include, without limitation, water, such as distilled or deionized water; saline; aqueous dextrose, glycerol, ethanol and the like. It is understood that the active ingredients can be soluble or can be delivered as a suspension in the desired carrier or diluent, depending upon the means of administration.
  • the ⁇ 2 agonist compositions may also optionally include one or more agents such as, without limitation, emulsifying agents, wetting agents, sweetening or flavoring agents, tonicity adjusters, preservatives, buffers or antioxidants.
  • Tonicity adjustors useful in a pharmaceutical composition include, but are not limited to, salts such as sodium acetate, sodium chloride, potassium chloride, mannitol or glycerin and other pharmaceutically acceptable tonicity adjustors.
  • Preservatives useful in pharmaceutical compositions include, without limitation, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuhc acetate, and phenylmercuric nitrate.
  • a pharmaceutical composition including, but not limited to, acetate buffers, citrate buffers, phosphate buffers and borate buffers.
  • anti-oxidants useful in pharmaceutical compositions are well known in the art and include, for example, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene. It is understood that these and other substances known in the art of pharmacology can be included in a pharmaceutical composition useful in the methods of the invention. See, for example, Remington's Pharmaceutical Sciences Mack Publishing Company, Easton, Pa. 16.sup.th Edition 1980.
  • an ⁇ 2 agonist composition may be administered in conjunction with one or more other therapeutic substances, in the same or different pharmaceutical composition and by the same or different routes of administration.
  • the active agents in the ⁇ 2 agonist composition are administered in an effective amount.
  • Such an effective amount generally is the minimum dose necessary to achieve the desired prevention or reduction in severity of hyperglycemia or hyperlipidemia.
  • Such a dose generally is in the range of 0.1- 1000 mg/day and can be, for example, in the range of 0.1-500 mg/day, 0.5-500 mg/day, 0.5-100 mg/day, 0.5-50 mg/day, 0.5-20 mg/day, 0.5-10 mg/day or 0.5-5 mg/day, with the actual amount to be administered determined by a physician taking into account the relevant circumstances including the severity and type of stress-associated condition, the age and weight of the patient, the patient's general physical condition, and the pharmaceutical formulation and route of administration.
  • Suppositories and extended release formulations also can be useful in the methods of the invention, including, for example, dermal patches, formulations for deposit on or under the skin and formulations for intramuscular injection.
  • a pharmaceutical composition useful in the methods of the invention can be administered to a subject by a variety of means depending, for example, on the type of condition to be treated, the pharmaceutical formulation, and the history, risk factors and symptoms of the subject. Routes of administration suitable for the methods of the invention include both systemic and local administration.
  • a pharmaceutical composition useful in the method of the invention can be administered orally; parenterally; by pump, for example a subcutaneous pump; by dermal patch; by intravenous, intra-articular, subcutaneous or intramuscular injection; by topical drops, creams, gels or ointments; as an implanted or injected extended release formulation; by subcutaneous minipump or other implanted device; by intrathecal pump or injection; or by epidural injection.
  • pump for example a subcutaneous pump; by dermal patch; by intravenous, intra-articular, subcutaneous or intramuscular injection; by topical drops, creams, gels or ointments; as an implanted or injected extended release formulation; by subcutaneous minipump or other implanted device; by intrathecal pump or injection; or by epidural injection.
  • the ⁇ 2 agonist composition can be incorporated in any pharmaceutically acceptable dosage form such as, without limitation, a tablet, pill, capsule, suppository, powder, liquid, suspension, emulsion, aerosol or the like, and can optionally be packaged in unit dosage form suitable for single administration of precise dosages, or sustained release dosage forms for continuous controlled administration.
  • a method of the invention can be practiced by peripheral administration of the ⁇ 2 agonist composition.
  • peripheral administration or “administered peripherally” means introducing the ⁇ 2 agonist composition into a subject outside of the central nervous system. Peripheral administration encompasses any route of administration other than direct administration to the spine or brain.
  • Peripheral administration can be local or systemic. Local administration results in significantly more of a pharmaceutical composition being delivered to and about the site of local administration than to regions distal to the site of administration. Systemic administration results in delivery of a pharmaceutical composition essentially throughout at least the entire peripheral system of the subject.
  • a pharmaceutical composition useful in the invention can be peripherally administered, for example, orally in any acceptable form such as in a tablet, liquid, capsule, powder, or the like; by intravenous, intraperitoneal, intramuscular, subcutaneous or parenteral injection; by transdermal diffusion or electrophoresis; topically in any acceptable form such as in drops, creams, gels or ointments; and by minipump or other implanted extended release device or formulation.
  • Figure 1 is a graph showing an increase in body weight of prediabetic female Zucker rats given vehicle or selected non-sedating ⁇ 2 agonist compositions from initiation (week 7) to end of the study (week 15). At the 8th week, animals were given high fat diet to raise blood glucose.
  • Figure 2 is a graph showing the effects on blood glucose levels (at weeks 7, 12 and 15) of chronic treatment of prediabetic Zucker rats with either vehicle or non-sedating ⁇ 2 agonist compositions.
  • Figure 3 is a graph showing the effects on blood triglyceride levels (at weeks 7, 12 and 15) of chronic treatment of prediabetic Zucker rats with either vehicle or non-sedating ⁇ 2 agonist compositions.
  • Figure 5 is a graph showing the effects on blood glucose levels (at weeks 6, 7, 9 and 1 1 ) of chronic treatment of prediabetic db/db mice with either vehicle or non-sedating ⁇ 2 agonist compositions.
  • Figure 6 is a graph showing an increase in body weight of prediabetic female Zucker rats given vehicle or selected non-sedating ⁇ 2 agonist compositions different from those in Example 1 , from initiation (week 8) to end of the study (week 14). At the 9th week, animals were given high fat diet.
  • Figure 7 is a graph showing the effects on blood glucose levels (at weeks 8, 12 and 14) of chronic treatment of prediabetic Zucker rats with either vehicle or non-sedating ⁇ 2 agonist compositions different from those in Example 1.
  • Figure 8 is a graph showing the effects on blood triglyceride levels (at weeks 8, 12, and 14) of chronic treatment of prediabetic Zucker rats with either vehicle or non-sedating ⁇ 2 agonist compositions different from those in Example 1.
  • Figure 9 is a graph showing the effects on blood glucose levels (at weeks
  • Figure 10 is a graph showing the effects on blood triglyceride levels (at weeks 8, 10, 12 and 14) of chronic treatment of diabetic Zucker rats with either vehicle or non-sedating ⁇ 2 agonist compositions (Compound 1 ).
  • Figure 1 1 A shows a comparison of insulin levels of female Zucker rats given vehicle control versus those given Compound 1 on week 14.
  • Figure 1 1 B shows a comparison of cholesterol levels of female Zucker rats given vehicle control versus those given Compound 1 on week 14.
  • Figure 1 1 C shows a comparison of low density lipoprotein (LDL) levels of female Zucker rats given vehicle control versus those given Compound 1 on week 14.
  • LDL low density lipoprotein
  • Figure 1 1 D shows a comparison of glucose levels of female Zucker rats given vehicle control versus those given Compound 1 on week 14.
  • Figure 1 1 E shows a comparison of high density lipoprotein (HDL) levels of female Zucker rats given vehicle control versus those given Compound 1 on week 14.
  • HDL high density lipoprotein
  • Figure 1 1 F shows a comparison of FFA (free fatty acid) levels of female Zucker rats given vehicle control versus those given Compound 1 on week 14.
  • Figure 12A shows a line graph showing a comparison of blood glucose levels of female Zucker diabetic fatty rats following a single injection of either vehicle or Compound 3.
  • Figure 12B shows a line graph showing a comparison of blood glucose levels of female Zucker diabetic fatty rats following a single injection of either vehicle or Compound 1 .
  • Figure 12C shows a line graph showing a comparison of blood glucose levels of female diabetic Zucker rats following a single injection of either vehicle or Compound 2.
  • Female Zucker rats are animal models for Type Il diabetes, developing hyperglycemia and hyperthglyceremia after 1 to 2 weeks of being placed on the high fat diet.
  • mice Female Zucker fatty rats (Charles River Laboratories) between 6-7 weeks old were acclimated to the animal research facilities for at least one week. Animals were housed and maintained on a normal diet during the acclimation period.
  • the rats were weighed and tail-snip glucose and triglyceride levels were determined using a One Touch Ultra® Blood Glucose Monitoring system (LIFESCAN, Milpitas, CA) and CardioChek® A analyzer (Polymer Technology Systems, Inc, Indianapolis, IN), respectively. The resulting data were used as a baseline for comparison with later treatment results. The animals were randomized to various treatment groups based on blood glucose, triglycerides and body weight.
  • LIFESCAN Milpitas, CA
  • CardioChek® A analyzer Polymer Technology Systems, Inc, Indianapolis, IN
  • Compound 1 was administered at 100 ⁇ g or 2.4 mg/kg/day.
  • Compound 2 and Compound 3 were administered at 240 ⁇ g or 2.4 mg/kg/day.
  • Non-sedating ⁇ 2 agonists were administered one week prior to the initiation of a high fat diet to the rats, simulating a "pre-diabetic" condition; this diet was continued until the end of the study.
  • Compound 1 was first administered 1 to 2 weeks after the introduction of the high fat diet to the animals, which continued until end of the study. After 1 or two weeks on the high fat diet, the female Zucker rats become diabetic, with blood glucose at or above 200 mg/dl in the absence of any added therapeutic agent.
  • body weight, blood glucose and triglycerides of the animals were measured as described above at different times after treatment with agonists, high fat diet or both.
  • Figure 1 shows that the body weight of the Zucker rats fed the high fat diet increased with time over the period of the study (from age 7 weeks to age 15 weeks), and that the administration of the non-sedating ⁇ 2 agonists and vehicle control had no effect on this increase in body weight. Also as expected, the increase in body weight correlated with an approximately four-fold increase in blood glucose levels (from about 100 mg/dl to about 400 mg/dl by week 12 in rats given vehicle alone, with even higher levels seen at week 15 (Figure 2).
  • Figure 2 also demonstrates that among prediabetic Zucker rats given non-sedating ⁇ 2 agonist compositions (Compound 2, an ⁇ 2B selective agonist lacking substantial ⁇ 2A activity, at 240 ⁇ g/kg/day and 2.4 mg/kg/day, and Compound 1 , an ⁇ 2 pan-agonist lacking substantial ⁇ 1 activity, at 100 ⁇ g/kg/day and 2.4 mg/kg/day, all showed a significant inhibition in the increase in blood glucose relative to the untreated group, with the higher dose of Compound 1 showing the best activity among the groups, lowering blood glucose to about 300 mg/dl at 12 weeks.
  • Compound 2 an ⁇ 2B selective agonist lacking substantial ⁇ 2A activity, at 240 ⁇ g/kg/day and 2.4 mg/kg/day
  • Compound 1 an ⁇ 2 pan-agonist lacking substantial ⁇ 1 activity, at 100 ⁇ g/kg/day and 2.4 mg/kg/day
  • Figure 3 shows that blood triglycerides increased approximately eight-fold in the untreated rats by 12 weeks. All of the dosages of both non-sedating ⁇ 2 agonist compositions tested (Compound 1 and Compound 2) significantly prevented in increase in serum triglyceride levels in the prediabetic Zucker rats, with the higher dosage of Compound 1 again showing the best activity among those therapeutic compositions tested.
  • mice Female db/db mice are considered to be animal models for Type Il diabetes and hypertriglyeremia. These animals are identifiably obese at around 3 to 4 weeks of age. Elevation in plasma insulin occurs at about 10 to 14 days of age and elevation of blood sugar at about 4-8 weeks. These animals carry the db gene, which contains a G to T point mutation for the leptin receptor.
  • mice Five-week-old female db/db mice (Jackson Laboratories) were acclimated to the animal research facilities for one week and housed and maintained on a normal diet until the initiation of the experiment.
  • mice For the study of prediabetic db/db mice after acclimation for one week, the mice (6 weeks old) were weighed and tail-snip glucose levels were determined using One Touch Ultra Blood Glucose Monitoring system (LIFESCAN, Milpitas, CA). The animals were randomized into vehicle, clonidine and Compound 2 groups based on blood glucose and body weight. Body weight and blood glucose of db/db mice at week 6 were considered as base-line values.
  • LIFESCAN One Touch Ultra Blood Glucose Monitoring system
  • mice mice Once the blood glucose levels of the experimental mice mice were above 150 mg/dL in week 6, vehicle (60% Polyethylene Glycol 300, PEG 300), clonidine or Compound 2 in 60% PEG 300 was administered continuously using osmotic pumps (Alzet mini-osmotic pumps Model 2002 (0.5 ⁇ l/hr), Duret Corp., Cupertino, CA), which were inserted subcutaneously on back of the animals.
  • the mice were anesthetized by isoflurane inhalation (5% induction and 2-3% maintenance by nose cone). An area of approximately 1 inch by 1 inch located in the back of the mice was shaved, rinsed with saline solution, cleaned with antiseptic soap solution and wiped with 70% ethanol.
  • a single 0.5 inch incision was made perpendicular to the long axis of the animal in the skin covering the lumbar region of the back. Using blunt scissors, a subcutaneous pocket was made toward the head of the animal.
  • the sterile osmotic pump filled with 0.5 ml vehicle, clonidine (0.21-0.29 ⁇ g/ul) or Compound 2 (5-7 ⁇ g/ul) was placed into the subcutaneous pocket, and the incision was closed with surgical clips.
  • Clonidine and Compound 2 were administered at 100 ⁇ g/kg/day and 2.4 mg/kg/day, respectively. At different times after administration of vehicle, clonidine or Compound 2, body weight and blood glucose of the animals were measured as described above.
  • Figure 4 shows that the body weight of the db/db mice increased steadily from week 6 to week 8 in both control and experimental groups, and similar to the results seen for prediabetic Zucker rats, the increase in body weight of prediabetic db/db mice was unaffected by the administration of 100 ⁇ g/kg/day clonidine or 2.4 mg/kg/day of Compound 2.
  • Clonidine a sedating ⁇ 2 agonist and 11 imidizole receptor agonist, is known to have hypoglycemic activity and was used as a reference.
  • Figure 5 shows that both clonidine and Compound 2 decreased blood glucose in db/db mice beginning at week 9, and that this trend remained until week 1 1 , the end of the study.
  • These results and the Zucker rat results indicate that pre- treatment with ⁇ 2 agonists attenuates the spontaneous increase in blood glucose in pre-diabetic db/db mice, and also in Zucker rats subsequently given a high fat diet.
  • the non-sedating ⁇ 2 agonist compositions are effective in preventing or lessening the extent of hyperglycemia and hypertriglycermia in prediabetic animals.
  • Both Compound 1 and Compound 2 belong to the imidazole-2-thione class of compounds.
  • Compound 3 a benzyl thiourea having ⁇ 2B selective activity was tested in the same manner as Compound 1 and
  • FIG. 12B shows a time course of changes in blood glucose levels following injection of 300 ⁇ g/kg Compound 1 .
  • Figure 12C shows a time course of changes in blood glucose levels following injection of 300 ⁇ g/kg Compound 2.
  • injection of the non-sedating ⁇ 2 agonist composition resulted in a significant decrease in blood glucose levels relative to the vehicle only control animals.

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Abstract

La présente invention concerne une méthode de traitement de l'hyperglycémie ou de l'hyperlipidémie dans laquelle on utilise un agoniste des sous-types du récepteur adrénergique α2B et/ou α2C qui manquent (a) d'une activité significative du récepteur adrénergique α2A et/ou (b) d'une activité significative du récepteur adrénergique α1A.
PCT/US2007/074284 2006-07-27 2007-07-25 Méthodes et compositions utiles pour le traitement de l'hyperlipidémie Ceased WO2008014299A2 (fr)

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