WO2000018389A2 - USE OF A β2 ADRENERGIC RECEPTOR AGONIST IN THE TREATMENT OF CARDIOVASCULAR DISEASE - Google Patents

USE OF A β2 ADRENERGIC RECEPTOR AGONIST IN THE TREATMENT OF CARDIOVASCULAR DISEASE Download PDF

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WO2000018389A2
WO2000018389A2 PCT/US1999/022712 US9922712W WO0018389A2 WO 2000018389 A2 WO2000018389 A2 WO 2000018389A2 US 9922712 W US9922712 W US 9922712W WO 0018389 A2 WO0018389 A2 WO 0018389A2
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treatment
fenoterol
cardiovascular disease
adrenergic receptor
proteins
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PCT/US1999/022712
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French (fr)
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WO2000018389A3 (en
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Rui-Ping Xiao
Edward G. Lakatta
Heping Cheng
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The United States Of America, Represented By The Secretary, Department Of Health And Human Services
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Publication of WO2000018389A2 publication Critical patent/WO2000018389A2/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone

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  • the present invention relates to a method of using a ⁇ 2 -adrenergic receptor agonist that selectively activates G s proteins in the treatment of cardiovascular disease.
  • the present invention relates to a method of using fenoterol to activate selectively G s proteins in the treatment of acute heart failure, chronic heart failure and aging heart.
  • Heart failure is a disease of left ventricular dysfunction accompanied by severely impaired ⁇ -adrenergic receptor-mediated contractile response (Bristow et al., N. Engl. J. Med. 307: 205 (1982); Bristow et al, Circ. Res. 59: 297 (1986); Brodde, Pharmacol. Rev. 43: 203 (1991); Marzo et al., Circ. Res. 69: 1546 (1991); Feldman, Circulation 87 (Suppl.): IV27 (1993); Kiuchi et al, J. Clin. Invest. 91: 907 (19930: Yamamoto et al., J. Mol. Cell. Cardiol.
  • Heart failure can be acute or chronic. Chronic heart failure has been the number one killer in the United States, causing more than 950,000 lives every year in the United States alone.
  • ⁇ -adrenergic receptor ( ⁇ AR) stimulation provides the primary regulatory mechanism on cardiac function.
  • ⁇ AR subtypes namely ⁇ , AR and ⁇ 2 AR, that exist in the myocardium, although ⁇ , AR predominates.
  • ⁇ i AR couples to stimulatory G proteins (G s )
  • ⁇ 2 AR elicits bifurcated signaling pathways mediated by G s and Q, resulting in functionally opposing effects on cardiac function.
  • the overall response to ⁇ AR stimulation is markedly diminished due to a down-regulation of ⁇ ]AR and an up-regulation of Gj proteins.
  • ⁇ AR agonists are used in the treatment of heart failure.
  • most of the ⁇ AR agonists used target ⁇ r adrenergic receptors ( ⁇ - AR) or ⁇ iAR and ⁇ 2 AR and those that target ⁇ 2 AR do not selectively activate G s or G; proteins. This, in part, has led to the prevalent view that ⁇ AR stimulation in failing heart is deleterious - not beneficial.
  • the present invention is predicated on the surprising and unexpected discovery that a ⁇ 2 AR agonist can selectively activate G s proteins.
  • the present invention is further predicated on the surprising and unexpected discovery that selective activation of G s proteins by a ⁇ 2 AR agonist can revive ⁇ AR contractile support in failing hearts.
  • fenoterol U.S. Patent No. 3,341,593
  • fenoterol was known to be a ⁇ 2 AR agonist, it was not known to have selective ⁇ 2 AR G s activation activity and to be useful in the treatment of acute heart failure, chronic heart failure and aging heart; rather, it was known for its bronchodilatory and tocolytic effects (Merck Index) and its use in the treatment of acute circulatory arrest, shock, and acute respiratory insufficiency in status asthmaticus and chronic lung diseases (Schuster et al., Arzneisch-forsch. 19: 1905-1914 (1969)).
  • fenoterol revives ⁇ AR contractile support in failing hearts, but it does so effectively and so selectively for ⁇ AR G s proteins that low doses can be used, thereby minimizing the adverse side effects realized by activation of G ( proteins and high doses of fenoterol.
  • ligands i.e., agonists and antagonists
  • methods for the selective activation and inactivation of a subset of signaling pathways coupled to any given receptor of any cell or tissue type It is another object of the present invention to provide ligands, i.e., agonists and antagonists, and methods for the selective activation and inactivation of a subset of signaling pathways, such as pathways involving G proteins, in particular G s and Gj proteins, coupled to a cardiovascular receptor, such as ⁇ 2 AR, for the treatment of cardiovascular disease.
  • the present invention provides a method of using a ⁇ 2 adrenergic receptor agonist that selectively activates G s proteins in the treatment of cardiovascular disease.
  • the method comprises administering to a mammal, such as a human, in need thereof, a treatment effective amount of the ⁇ 2 adrenergic receptor agonist so as to treat cardiovascular disease.
  • the ⁇ 2 adrenergic receptor agonist is fenoterol or an acid addition salt thereof and the cardiovascular disease is acute heart failure, chronic heart failure, aging heart or the like.
  • the present invention provides a method of using a ⁇ 2 adrenergic receptor agonist that selectively activates G s proteins in the treatment of cardiovascular disease.
  • the method comprises administering to a mammal in need thereof a treatment effective amount of the ⁇ 2 adrenergic receptor agonist so as to treat cardiovascular disease.
  • the present invention provides a method of using the ⁇ 2 adrenergic receptor agonist fenoterol or an acid addition salt thereof in the treatment of acute heart failure, chronic heart failure, aging heart and the like.
  • the method comprises administering to a mammal in need thereof a treatment effective amount of fenoterol or an acid addition salt thereof so as to treat acute heart failure, chronic heart failure, aging heart and the like.
  • Any ⁇ 2 adrenergic receptor agonist that selectively activates G s proteins can be used in the method of the present invention as long as it is safe and efficacious.
  • the agonist is fenoterol or an acid addition salt thereof.
  • a particular ⁇ 2 adrenergic receptor agonist can selectively activate G s proteins can be determined using the methods set forth in the examples.
  • the ⁇ 2 AR agonists zinterol, procaterol and salbutamol, unlike fenoterol, concurrently activated G s and Gj proteins.
  • Fenoterol is commercially available. However, the synthesis of fenoterol and its acid addition salts is described in U.S. Patent No. 3,341,593.
  • the ⁇ 2 adrenergic receptor agonist that selectively activates G s proteins is administered as soon as possible after cardiovascular disease has been diagnosed.
  • suitable methods of administering a ⁇ 2 adrenergic receptor agonist, which selectively activates G s proteins and is useful in the method of the present invention are available.
  • more than one route can be used to administer the agonist, a particular route can provide a more immediate and more effective reaction than another route. Accordingly, the described methods are merely exemplary and are in no way limiting.
  • the dose administered to an animal, particularly a human, in accordance with the present invention should be sufficient to effect the desired response in the animal over a reasonable time frame.
  • dosage will depend upon a variety of factors, including the strength of the particular agonist employed, the age, species, overall condition, and body weight of the animal, as well as the degree of cells or tissues affected, e.g., the degree of cardiac myocytes affected by cardiovascular disease, such as acute heart failure, chronic heart failure or aging heart.
  • the size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side- effects that might accompany the administration of a particular agonist. It will be appreciated by one of ordinary skill in the art that prolonged treatment involving multiple administrations can be required.
  • Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect, e.g., prophylactic or therapeutic treatment, under the circumstances is reached.
  • the present inventive method will typically involve the administration of about 0.001 to about 1000 mg, preferably about 0.01 to about 100 mg, of an agonist per kg treated weight. See, for example, Goldenthal, Toxicol. Appl. Pharmacol. 18: 185-207 (1971), and Kojima et al., Arzneisch-forsch. 30: 959- 964 (1980).
  • compositions for use in the present inventive method preferably comprise a pharmaceutically acceptable carrier and an amount of an agonist sufficient to treat cardiovascular disease.
  • the carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration.
  • the agonist can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
  • the agonist can be formulated as a pharmaceutically acceptable acid addition salt.
  • pharmaceutically acceptable acid addition salts for use in the pharmaceutical composition include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic, for example p-toluenesulphonic, acids.
  • pharmaceutically acceptable excipients described herein for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one that is chemically inert to the agonist and has no detrimental side effects or toxicity under the conditions of use.
  • excipient will be determined in part by the particular agonist, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention.
  • suitable formulations of the pharmaceutical composition of the present invention are merely exemplary and are in no way limiting.
  • Injectable formulations are among those formulations that are preferred in accordance with the present inventive method.
  • the requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art (See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250, (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4 th ed., pages 622-630 (1986)). It is preferred that such injectable compositions be administered intravenously, intramuscularly, subcutaneously or intracardially.
  • Topical formulations are well-known to those of skill in the art and are suitable in the context of the present invention for application to skin.
  • Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions.
  • Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent.
  • Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch.
  • Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients.
  • Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • a flavor usually sucrose and acacia or tragacanth
  • pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
  • the agonist used in the present inventive method can be made into aerosol formulations to be administered via inhalation.
  • aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non- pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations may be used to spray mucosa. Aerosol formulations are not preferred for administration of fenoterol in the treatment of acute heart failure, chronic heart failure, aging heart and the like.
  • Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • the agonist can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-lJ-dioxolane-4- methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or
  • Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.
  • Suitable soaps for use in parenteral formulations include fatty alkali metals, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers
  • the parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile- lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol.
  • HLB hydrophile- lipophile balance
  • parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use.
  • sterile liquid excipient for example, water
  • Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
  • the ⁇ 2 adrenergic receptor agonist that selectively activates G s proteins can be administered alone or in combination with one or more other active ingredients as are known in the art. Furthermore, such ⁇ 2 adrenergic receptor agonists that selectively activate G s proteins are also useful in the research and development of prophylactic and therapeutic treatment of cardiovascular disease, such as acute heart failure, chronic heart failure and aging.
  • Rat cardiac myocytes which were treated with pertussis toxin (PTX) or left untreated, were exposed to the ⁇ 2 AR agonist fenoterol and contractile response was measured.
  • the measurement of contractile response in the presence of PTX is indicative of G s protein activation, whereas the measurement of contractile response in the absence of PTX is indicative of combined G s and G, activation.
  • Fenoterol induced a maximal contractile response of approximately 300% of control in the absence of PTX.
  • the presence of PTX over a wide range of concentrations (10 "8 M to 10 "4 M) did not affect the contractile response induced by fenoterol.
  • This example demonstrates fenoterol selectively activates the ⁇ 2 AR-coupled G s signaling pathway in cardiac myocytes, which are essentially ⁇ 1 AR-free, in vitro.
  • a transgenic murine (TG4) model in which the human ⁇ 2 AR is overexpressed by approximately 200 fold in a cardiac-specfic manner was used.
  • ⁇ -AR is essentially nonfunctional in the hearts of TG4 transgenic mice in vivo (Du et al., Am. J. Physiol. 271 : H630 (1996)), in isolated atria (Bond et al., Nature 374: 272 (1995); and Milano et al.
  • any cellular response to a ⁇ AR agonist is mediated almost exclusively through the nearly homogeneous population of ⁇ 2 AR.
  • Myocytes were isolated from TG4 and wild-type littermates using a slightly modified enzymatic technique of Korzick et al., Am. J. Physiol. 41 : H590 (1997). Aliquots of cells were incubated with PTX (1.5 ⁇ g/ml at 37 °C for at least 3 hr) to abrogate Gj protein function via ribosylation, as previously described (Xiao et al., ibid.
  • Cells were then perfused with Hepes buffer solution consisting of (in mM) 1.0 CaCl 2 , 137 NaCl, 5 KCl, 15 dextrose, 1.3 MgSO 4 , 1.2 NaH 2 PO 4 , and 20 Hepes, pH 7.4, and were electrically stimulated at 0.5 Hz at 23 °C.
  • Cell length was monitored from the brightfield image of the cell by an optical edge-tracking method using a photodiode array (Reticon Model 1024 SAQ) with a 3 ms time resolution. Cell contraction was indexed by the percent reduction of cell length following electrical stimulation.
  • fenoterol (10 "9 M to 10 "4 M) induced a dose-dependent increase in cell contraction.
  • PTX did not potentiate the effect of fenoterol on the contractile response, indicating that an uncoupling of fenoterol stimulated ⁇ 2 AR from Gj proteins still occurs in cardiac myocytes that overexpress ⁇ 2 AR.
  • fenoterol selectively activates the ⁇ 2 AR- coupled G s signaling pathway in isolated cardiac myocytes in vitro.
  • Rat cardiac myocytes which were treated with PTX or left untreated, were exposed to fenoterol and cAMP accumulation was measured.
  • Cardiac membranes from WKY rats (Harlan Bioproducts for Science) were pelleted and incubated in a cAMP reaction buffer to determine cAMP accumulation in the presence or absence of fenoterol and PTX. The measurement of cAMP accumulation in the presence of PTX is indicative of G s activation.
  • Fenoterol induced maximal cAMP accumulation of approximately 250% of control in the absence of PTX.
  • Spontaneous hypertensive rats (SHR; Harlan Bioproducts for Science, Indianapolis, IN; Pfeffer et al., Am. J. Physiol. 237: H461 (1979); and Conrad et al., Am. J. Physiol. 260: H136 (1991)), which represent an animal model of cardiovascular disease, in particular chronic hypertensive heart disease and heart failure, were studied at an age of 18-24 months, when they demonstrate cardiac hypertrophy and physical signs of heart failure (e.g., resting tachycardia, tachypnea, and pleural and/or pericardial effusions; Pfeffer et al., Am. J. Physiol.
  • WKY 180 + 30, p ⁇ 0.05, n 44), and cross- sectional area of cells computed from images of transmitted light microscopy ( ⁇ m 2 , SHR: 296 + 78 vs. WKY: 135 + 58, p ⁇ 0.001, n - 256).
  • ⁇ 2 AR stimulation by fenoterol enhanced the amplitude of contraction in SHR to an extent similar to that observed in age-matched WKY.
  • fenoterol selectively activates the ⁇ 2 AR- coupled G s signaling pathway in intact cells from failing hearts.
  • SR/JrHsd rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) were given normal (0.2 %) or high (8 %) NaCl diets (ICN Pharmaceuticals, Costa Mesa, CA). Starting from week 4 of the high NaCl diet, the rats were given 8 % NaCl diets five days per week and 0.2 % NaCl diets two days per week (days 5 and 7).
  • SBP systolic blood press
  • the heart/body weight ratios in DS on 8 % and 0.2 % NaCl diets were 6.9 + 0.9 and 3.1 + 0.1 (p ⁇ 0.01).
  • the lung/body weight ratios were 11.4 + 0.8 and 4.1 + 0.3 (p ⁇ 0.01), respectively.
  • heart/body and lung/body weight ratios were 4.0 + 0.1 and 3.9 + 0.1 (p ⁇ 0.01 vs. DS on 8 % diet for both parameters).

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Abstract

The present invention provides a method of using a β2 adrenergic receptor agonist that selectively activates GS proteins in the treatment of cardiovascular disease. More particularly, the present invention provides a method of using fenoterol or an acid addition salt thereof to activate β2AR GS proteins selectively in the treatment of acute heart failure, chronic heart failure, aging heart and the like.

Description

F A β2 ADRENERGIC RECEPTOR AGONIST IN THE TREATMENT OF CARDIOVASCULAR DISEASE
TECHNICAL FIELD OF THE INVENTION
The present invention relates to a method of using a β2-adrenergic receptor agonist that selectively activates Gs proteins in the treatment of cardiovascular disease. In particular, the present invention relates to a method of using fenoterol to activate selectively Gs proteins in the treatment of acute heart failure, chronic heart failure and aging heart.
BACKGROUND OF THE INVENTION
Heart failure is a disease of left ventricular dysfunction accompanied by severely impaired β-adrenergic receptor-mediated contractile response (Bristow et al., N. Engl. J. Med. 307: 205 (1982); Bristow et al, Circ. Res. 59: 297 (1986); Brodde, Pharmacol. Rev. 43: 203 (1991); Marzo et al., Circ. Res. 69: 1546 (1991); Feldman, Circulation 87 (Suppl.): IV27 (1993); Kiuchi et al, J. Clin. Invest. 91: 907 (19930: Yamamoto et al., J. Mol. Cell. Cardiol. 26: 617 (1994); and Brodde et al., J. Cardiovasc. Pharmacol. 31: 585 (1998)) associated with a selective down-regulation of the β, adrenergic receptor (higher β2/β- ratio) (Bristow et al. (1982), supra; Bristow et al. (1986), supra; Brodde (1991), supra; Marzo et al. (1991), supra; and Feldman (1993), supra) and increases in inhibitory G protein (G mRNA level, protein abundance and activity (Feldman et al., J. Clin. Invest. 82: 189 (1988); Neumann et al., Lancet 2: 936 (1988); Eschenhagen et al., Circ. Res. 70: 688 (1992); Bohm et al., Hypertension 22: 715 (1993); Spinale et al, Cardiovasc. Res. 28: 1243 (1994); Ping et al., Am. J. Physiol. 267: H2079 (1994); Steinberg et al., Circulation 91: 2824 (1995); and Shi et al, Am. J. Physiol. 269: H1073 (1995)). Heart failure can be acute or chronic. Chronic heart failure has been the number one killer in the United States, causing more than 950,000 lives every year in the United States alone. Consequently, billions of dollars are spent every year in the treatment of chronic heart failure - at a cost to families and the U.S. government. Therefore, the treatment of this disease has become extremely important for health care and economic reasons. Also important for the same reasons is the treatment of the aging heart, which, given the ever increasing elderly population, is becoming increasingly costly. In the heart, β-adrenergic receptor (βAR) stimulation provides the primary regulatory mechanism on cardiac function. There are at least two βAR subtypes, namely β, AR and β2AR, that exist in the myocardium, although β, AR predominates. While βi AR couples to stimulatory G proteins (Gs), β2AR elicits bifurcated signaling pathways mediated by Gs and Q, resulting in functionally opposing effects on cardiac function. In failing and aged hearts, the overall response to βAR stimulation is markedly diminished due to a down-regulation of β]AR and an up-regulation of Gj proteins. βAR agonists are used in the treatment of heart failure. However, most of the βAR agonists used target βradrenergic receptors (β- AR) or βiAR and β2AR and those that target β2AR do not selectively activate Gs or G; proteins. This, in part, has led to the prevalent view that βAR stimulation in failing heart is deleterious - not beneficial.
The present invention is predicated on the surprising and unexpected discovery that a β2AR agonist can selectively activate Gs proteins. The present invention is further predicated on the surprising and unexpected discovery that selective activation of Gs proteins by a β2AR agonist can revive βAR contractile support in failing hearts.
The present invention is further predicated on the surprising and unexpected discovery that fenoterol (U.S. Patent No. 3,341,593), otherwise known as 5-[l- hydroxy-2-[[2-(4-hydroxyphenyl)- 1 -methylethyl]amino]ethyl]- 1 ,3-benzenediol or 3,5-dihydroxy-α-[[(p-hydroxy-α-methylphenethyl)amino]methyl]benzyl alcohol or 1- (3,5-dihydroxyphenyl)-l-hydroxy-2-[(4-hydroxy-phenyl)isopropylamino]ethane or 1- (p-hydroxyphenyl)-2-[[β-hydroxy-β-(3',5'-dihydroxyphenyl)]ethyl]aminopropane, activates β2AR Gs proteins without activating β2AR Gi proteins and consequently revives βAR contractile support in failing hearts. While fenoterol was known to be a β2AR agonist, it was not known to have selective β2AR Gs activation activity and to be useful in the treatment of acute heart failure, chronic heart failure and aging heart; rather, it was known for its bronchodilatory and tocolytic effects (Merck Index) and its use in the treatment of acute circulatory arrest, shock, and acute respiratory insufficiency in status asthmaticus and chronic lung diseases (Schuster et al., Arzneimittel-forsch. 19: 1905-1914 (1969)). Not only does fenoterol revive βAR contractile support in failing hearts, but it does so effectively and so selectively for βAR Gs proteins that low doses can be used, thereby minimizing the adverse side effects realized by activation of G( proteins and high doses of fenoterol.
In view of the above, it is an object of the present invention to provide ligands, i.e., agonists and antagonists, and methods for the selective activation and inactivation of a subset of signaling pathways coupled to any given receptor of any cell or tissue type. It is another object of the present invention to provide ligands, i.e., agonists and antagonists, and methods for the selective activation and inactivation of a subset of signaling pathways, such as pathways involving G proteins, in particular Gs and Gj proteins, coupled to a cardiovascular receptor, such as β2AR, for the treatment of cardiovascular disease. It is yet another object of the present invention to provide a method of using a β2AR agonist to activate selectively Gs proteins in the treatment of cardiovascular disease. It is still yet another object of the present invention to provide a method of using fenoterol (or a pharmaceutically acceptable salt thereof) to activate selectively Gs proteins in the treatment of acute heart failure, chronic heart failure, aging heart and the like. These and other objects and advantages, as well as additional inventive features, of the present invention will become apparent to one of ordinary skill in the art upon reading the detailed description of the present invention provided herein.
BRIEF SUMMARY OF THE INVENTION The present invention provides a method of using a β2 adrenergic receptor agonist that selectively activates Gs proteins in the treatment of cardiovascular disease. The method comprises administering to a mammal, such as a human, in need thereof, a treatment effective amount of the β2 adrenergic receptor agonist so as to treat cardiovascular disease. Preferably, the β2 adrenergic receptor agonist is fenoterol or an acid addition salt thereof and the cardiovascular disease is acute heart failure, chronic heart failure, aging heart or the like.
DETAILED DESCRIPTION OF THE INVENTION The present invention provides a method of using a β2 adrenergic receptor agonist that selectively activates Gs proteins in the treatment of cardiovascular disease. The method comprises administering to a mammal in need thereof a treatment effective amount of the β2 adrenergic receptor agonist so as to treat cardiovascular disease.
In a preferred embodiment, the present invention provides a method of using the β2 adrenergic receptor agonist fenoterol or an acid addition salt thereof in the treatment of acute heart failure, chronic heart failure, aging heart and the like. The method comprises administering to a mammal in need thereof a treatment effective amount of fenoterol or an acid addition salt thereof so as to treat acute heart failure, chronic heart failure, aging heart and the like.
Any β2 adrenergic receptor agonist that selectively activates Gs proteins can be used in the method of the present invention as long as it is safe and efficacious.
Preferably, the agonist is fenoterol or an acid addition salt thereof. Whether or not a particular β2 adrenergic receptor agonist can selectively activate Gs proteins can be determined using the methods set forth in the examples. In this regard, the β2AR agonists zinterol, procaterol and salbutamol, unlike fenoterol, concurrently activated Gs and Gj proteins.
Fenoterol is commercially available. However, the synthesis of fenoterol and its acid addition salts is described in U.S. Patent No. 3,341,593.
Desirably, the β2 adrenergic receptor agonist that selectively activates Gs proteins is administered as soon as possible after cardiovascular disease has been diagnosed. One skilled in the art will appreciate that suitable methods of administering a β2 adrenergic receptor agonist, which selectively activates Gs proteins and is useful in the method of the present invention, are available. Although more than one route can be used to administer the agonist, a particular route can provide a more immediate and more effective reaction than another route. Accordingly, the described methods are merely exemplary and are in no way limiting.
The dose administered to an animal, particularly a human, in accordance with the present invention should be sufficient to effect the desired response in the animal over a reasonable time frame. One skilled in the art will recognize that dosage will depend upon a variety of factors, including the strength of the particular agonist employed, the age, species, overall condition, and body weight of the animal, as well as the degree of cells or tissues affected, e.g., the degree of cardiac myocytes affected by cardiovascular disease, such as acute heart failure, chronic heart failure or aging heart. The size of the dose also will be determined by the route, timing and frequency of administration as well as the existence, nature, and extent of any adverse side- effects that might accompany the administration of a particular agonist. It will be appreciated by one of ordinary skill in the art that prolonged treatment involving multiple administrations can be required.
Suitable doses and dosage regimens can be determined by conventional range- finding techniques known to those of ordinary skill in the art. Generally, treatment is initiated with smaller dosages, which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect, e.g., prophylactic or therapeutic treatment, under the circumstances is reached. The present inventive method will typically involve the administration of about 0.001 to about 1000 mg, preferably about 0.01 to about 100 mg, of an agonist per kg treated weight. See, for example, Goldenthal, Toxicol. Appl. Pharmacol. 18: 185-207 (1971), and Kojima et al., Arzneimittel-forsch. 30: 959- 964 (1980). Compositions for use in the present inventive method preferably comprise a pharmaceutically acceptable carrier and an amount of an agonist sufficient to treat cardiovascular disease. The carrier can be any of those conventionally used and is limited only by chemico-physical considerations, such as solubility and lack of reactivity with the compound, and by the route of administration. It will be appreciated by one of skill in the art that, in addition to the following described pharmaceutical composition, the agonist can be formulated as inclusion complexes, such as cyclodextrin inclusion complexes, or liposomes.
The agonist can be formulated as a pharmaceutically acceptable acid addition salt. Examples of pharmaceutically acceptable acid addition salts for use in the pharmaceutical composition include those derived from mineral acids, such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulfuric acids, and organic acids, such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, and arylsulphonic, for example p-toluenesulphonic, acids.
The pharmaceutically acceptable excipients described herein, for example, vehicles, adjuvants, carriers or diluents, are well-known to those who are skilled in the art and are readily available to the public. It is preferred that the pharmaceutically acceptable carrier be one that is chemically inert to the agonist and has no detrimental side effects or toxicity under the conditions of use.
The choice of excipient will be determined in part by the particular agonist, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of the pharmaceutical composition of the present invention. The following formulations for oral, aerosol, parenteral, subcutaneous, intravenous, intramuscular, intracardiac and interperitoneal administration are merely exemplary and are in no way limiting.
Injectable formulations are among those formulations that are preferred in accordance with the present inventive method. The requirements for effective pharmaceutical carriers for injectable compositions are well known to those of ordinary skill in the art (See Pharmaceutics and Pharmacy Practice, J.B. Lippincott Company, Philadelphia, PA, Banker and Chalmers, eds., pages 238-250, (1982), and ASHP Handbook on Injectable Drugs, Toissel, 4th ed., pages 622-630 (1986)). It is preferred that such injectable compositions be administered intravenously, intramuscularly, subcutaneously or intracardially.
Topical formulations are well-known to those of skill in the art and are suitable in the context of the present invention for application to skin.
Formulations suitable for oral administration can consist of (a) liquid solutions, such as an effective amount of the compound dissolved in diluents, such as water, saline, or orange juice; (b) capsules, sachets, tablets, lozenges, and troches, each containing a predetermined amount of the active ingredient, as solids or granules; (c) powders; (d) suspensions in an appropriate liquid; and (e) suitable emulsions. Liquid formulations may include diluents, such as water and alcohols, for example, ethanol, benzyl alcohol, and the polyethylene alcohols, either with or without the addition of a pharmaceutically acceptable surfactant, suspending agent, or emulsifying agent. Capsule forms can be of the ordinary hard- or soft-shelled gelatin type containing, for example, surfactants, lubricants, and inert fillers, such as lactose, sucrose, calcium phosphate, and corn starch. Tablet forms can include one or more of lactose, sucrose, mannitol, corn starch, potato starch, alginic acid, microcrystalline cellulose, acacia, gelatin, guar gum, colloidal silicon dioxide, croscarmellose sodium, talc, magnesium stearate, calcium stearate, zinc stearate, stearic acid, and other excipients, colorants, diluents, buffering agents, disintegrating agents, moistening agents, preservatives, flavoring agents, and pharmacologically compatible excipients. Lozenge forms can comprise the active ingredient in a flavor, usually sucrose and acacia or tragacanth, as well as pastilles comprising the active ingredient in an inert base, such as gelatin and glycerin, or sucrose and acacia, emulsions, gels, and the like containing, in addition to the active ingredient, such excipients as are known in the art.
The agonist used in the present inventive method, alone or in combination with other suitable components, can be made into aerosol formulations to be administered via inhalation. These aerosol formulations can be placed into pressurized acceptable propellants, such as dichlorodifluoromethane, propane, nitrogen, and the like. They also can be formulated as pharmaceuticals for non- pressured preparations, such as in a nebulizer or an atomizer. Such spray formulations may be used to spray mucosa. Aerosol formulations are not preferred for administration of fenoterol in the treatment of acute heart failure, chronic heart failure, aging heart and the like.
Formulations suitable for parenteral administration include aqueous and non- aqueous, isotonic sterile injection solutions, which can contain anti-oxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives. The agonist can be administered in a physiologically acceptable diluent in a pharmaceutical carrier, such as a sterile liquid or mixture of liquids, including water, saline, aqueous dextrose and related sugar solutions, an alcohol, such as ethanol, isopropanol, or hexadecyl alcohol, glycols, such as propylene glycol or polyethylene glycol, dimethylsulfoxide, glycerol ketals, such as 2,2-dimethyl-lJ-dioxolane-4- methanol, ethers, such as poly(ethyleneglycol) 400, an oil, a fatty acid, a fatty acid ester or glyceride, or an acetylated fatty acid glyceride with or without the addition of a pharmaceutically acceptable surfactant, such as a soap or a detergent, suspending agent, such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose, or emulsifying agents and other pharmaceutical adjuvants. Oils, which can be used in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral.
Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters. Suitable soaps for use in parenteral formulations include fatty alkali metals, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides, (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulfates, and sulfosuccinates, (c) nonionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-β-aminopropionates, and 2-alkyl-imidazoline quaternary ammonium salts, and (e) mixtures thereof.
The parenteral formulations will typically contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more nonionic surfactants having a hydrophile- lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.
In view of the above, the β2 adrenergic receptor agonist that selectively activates Gs proteins can be administered alone or in combination with one or more other active ingredients as are known in the art. Furthermore, such β2 adrenergic receptor agonists that selectively activate Gs proteins are also useful in the research and development of prophylactic and therapeutic treatment of cardiovascular disease, such as acute heart failure, chronic heart failure and aging.
EXAMPLES The following examples serve to illustrate further the present invention and are not intended to limit the scope of the present invention.
Example 1
This example demonstrates that fenoterol selectively activates the β2AR- coupled Gs signaling pathway in isolated cardiac myocytes in vitro.
Rat cardiac myocytes, which were treated with pertussis toxin (PTX) or left untreated, were exposed to the β2AR agonist fenoterol and contractile response was measured. The measurement of contractile response in the presence of PTX is indicative of Gs protein activation, whereas the measurement of contractile response in the absence of PTX is indicative of combined Gs and G, activation. Fenoterol induced a maximal contractile response of approximately 300% of control in the absence of PTX. The presence of PTX over a wide range of concentrations (10"8 M to 10"4M) did not affect the contractile response induced by fenoterol. These results indicate that fenoterol selectively activates the β2AR-coupled Gs signaling pathway. Similar selective activation results were obtained in mouse cardiac myocytes. Preliminary data also show similar contractile response to fenoterol (10"9M to 10"6M) in isolated, failing human myocytes.
Example 2
This example demonstrates fenoterol selectively activates the β2AR-coupled Gs signaling pathway in cardiac myocytes, which are essentially β1AR-free, in vitro. A transgenic murine (TG4) model in which the human β2AR is overexpressed by approximately 200 fold in a cardiac-specfic manner (Milano et al., Science 264: 582 (1994)) was used. β-AR is essentially nonfunctional in the hearts of TG4 transgenic mice in vivo (Du et al., Am. J. Physiol. 271 : H630 (1996)), in isolated atria (Bond et al., Nature 374: 272 (1995); and Milano et al. (1994), supra) and in PTX- treated and untreated cardiac cells. Accordingly, any cellular response to a βAR agonist is mediated almost exclusively through the nearly homogeneous population of β2AR. Myocytes were isolated from TG4 and wild-type littermates using a slightly modified enzymatic technique of Korzick et al., Am. J. Physiol. 41 : H590 (1997). Aliquots of cells were incubated with PTX (1.5 μg/ml at 37 °C for at least 3 hr) to abrogate Gj protein function via ribosylation, as previously described (Xiao et al., ibid. 47: 322 (1995); Xiao et al., J. Clin Ivest. 101: 1273 (1998); and Zhou et al., Am. J. Physiol. 273: H1611 (1997)). After PTX treatment, cells were kept at room temperature for the rest of the experimental day (approximately 6-8 hr). PTX-treated cells were compared with myocytes from the same heart that had been kept at 37 °C in the absence of PTX for an equal time. Cells were then perfused with Hepes buffer solution consisting of (in mM) 1.0 CaCl2, 137 NaCl, 5 KCl, 15 dextrose, 1.3 MgSO4, 1.2 NaH2PO4, and 20 Hepes, pH 7.4, and were electrically stimulated at 0.5 Hz at 23 °C. Cell length was monitored from the brightfield image of the cell by an optical edge-tracking method using a photodiode array (Reticon Model 1024 SAQ) with a 3 ms time resolution. Cell contraction was indexed by the percent reduction of cell length following electrical stimulation.
In PTX-treated and untreated TG4 myocytes, fenoterol (10"9 M to 10"4 M) induced a dose-dependent increase in cell contraction. In fact, PTX did not potentiate the effect of fenoterol on the contractile response, indicating that an uncoupling of fenoterol stimulated β2AR from Gj proteins still occurs in cardiac myocytes that overexpress β2AR.
Example 3
This example demonstrates that fenoterol selectively activates the β2AR- coupled Gs signaling pathway in isolated cardiac myocytes in vitro. Rat cardiac myocytes, which were treated with PTX or left untreated, were exposed to fenoterol and cAMP accumulation was measured. Cardiac membranes from WKY rats (Harlan Bioproducts for Science) were pelleted and incubated in a cAMP reaction buffer to determine cAMP accumulation in the presence or absence of fenoterol and PTX. The measurement of cAMP accumulation in the presence of PTX is indicative of Gs activation. Fenoterol induced maximal cAMP accumulation of approximately 250% of control in the absence of PTX. The presence of PTX did not affect c AMP accumulation induced by fenoterol over a wide range of concentrations (10"8M to 10"4M). These results indicate that fenoterol selectively activates the β2AR- coupled Gs signaling pathway. Example 4
This example demonstrates that fenoterol selectively activates the β2AR- coupled Gs signaling pathway in intact cells isolated from failing hearts.
Spontaneous hypertensive rats (SHR; Harlan Bioproducts for Science, Indianapolis, IN; Pfeffer et al., Am. J. Physiol. 237: H461 (1979); and Conrad et al., Am. J. Physiol. 260: H136 (1991)), which represent an animal model of cardiovascular disease, in particular chronic hypertensive heart disease and heart failure, were studied at an age of 18-24 months, when they demonstrate cardiac hypertrophy and physical signs of heart failure (e.g., resting tachycardia, tachypnea, and pleural and/or pericardial effusions; Pfeffer et al., Am. J. Physiol. 237: H461 (1979); and Conrad et al., Am. J. Physiol. 260: H136 (1991)) and were compared to age-matched Wistar-Kyoto rats (WKY; Harlan Bioproducts for Science) as a control. Blood pressures were measured weekly in every animal by the tail-cuff method in conscious non-sedated animals pre-warmed to 37 °C. At three months of age, SHR were clearly hypertensive and had systolic blood pressures of 182 + 21 mm Hg (vs. WKY: 121 + 11 mm Hg, p < 0.05, n = 21). Cardiac hypertrophy was confirmed by significant increases in heart weight (wet)/ body weight (mg/g; SHR: 5.10 + 0.8 vs. WKY: 3.8 + 0.5, p < 0.05, n = 13), echocardiographic measurements of left ventricular wall thickness (e.g., posterior wall thickness, mm; SHR: 2.1 + 0.3 vs. WKY: 1.6 + 0.3, p < 0.05, n = 10), electrically determined measurements of cell capacitance (pF; SHR: 270 + 43 vs. WKY 180 + 30, p < 0.05, n = 44), and cross- sectional area of cells computed from images of transmitted light microscopy (μm2, SHR: 296 + 78 vs. WKY: 135 + 58, p < 0.001, n - 256). β2AR stimulation by fenoterol enhanced the amplitude of contraction in SHR to an extent similar to that observed in age-matched WKY.
Example 5
This example demonstrates that fenoterol selectively activates the β2AR- coupled Gs signaling pathway in intact cells from failing hearts. Six week old Dahl salt-sensitive (DS; SS/JrHsd) and salt-resistant (DR;
SR/JrHsd) rats (Harlan Sprague Dawley, Inc., Indianapolis, IN) were given normal (0.2 %) or high (8 %) NaCl diets (ICN Pharmaceuticals, Costa Mesa, CA). Starting from week 4 of the high NaCl diet, the rats were given 8 % NaCl diets five days per week and 0.2 % NaCl diets two days per week (days 5 and 7). At baseline, systolic blood press (SBP) in 12 DS and 12 DR was 106 + 2 and 108 + 2 mm Hg, respectively. In DS on 8 % NaCl diet, SBP gradually rose and reached a plateau on week 2 (161 + 7 mm Hg, n = 6, p < 0.001 vs. baseline). In DR after 2 weeks of 8 % NaCl diet SBP was 118 + 4 mm Hg (n=6, p O.001 vs. DS at week 2). SBP in DS after 2 weeks of 0.2 % NaCl diet was 114 + 3 mm Hg (n = 6, p < 0.001 vs. DS on 8 % NaCl diet). On week 8 of high NaCl diet, DS exhibited symptoms of congestive heart failure, i.e., rapid and labored respiration, loss of physical activity and decrease of body weight. When sacrificed, pathological examination revealed pleural effusion and ascites. The heart/body weight ratios in DS on 8 % and 0.2 % NaCl diets were 6.9 + 0.9 and 3.1 + 0.1 (p < 0.01). The lung/body weight ratios were 11.4 + 0.8 and 4.1 + 0.3 (p < 0.01), respectively. In DR on 8 % NaCl diet, heart/body and lung/body weight ratios were 4.0 + 0.1 and 3.9 + 0.1 (p < 0.01 vs. DS on 8 % diet for both parameters).
Contractile response to fenoterol remained intact in DS myocytes relative to age-matched DR myocytes.
All of the references cited herein, including patents, patent applications, and publications, are hereby incorporated in their entireties by reference.
While this invention has been described with an emphasis upon preferred embodiments, it will be apparent to those of ordinary skill in the art that variations in the preferred embodiments can be prepared and used and that the invention can be practiced otherwise than as specifically described herein. The present invention is intended to include such variations and alternative practices. Accordingly, this invention includes all modifications encompassed within the spirit and scope of the invention as defined by the following claims.

Claims

WHAT IS CLAIMED IS:
1. A method of using a β2 adrenergic receptor agonist that selectively activates Gs proteins in the treatment of cardiovascular disease, which method comprises administering to a mammal in need thereof a treatment effective amount of the β2 adrenergic receptor agonist so as to treat cardiovascular disease.
2. The method of claim 1, wherein said cardiovascular disease is acute heart failure.
3. The method of claim 1, wherein said cardiovascular disease is chronic heart failure.
4. The method of claim 1, wherein said cardiovascular disease is aging heart.
5. The method of any of claims 1-4, wherein said β2 adrenergic receptor agonist is fenoterol or an acid additional salt thereof.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1755581A1 (en) * 2004-04-23 2007-02-28 Northern Sydney and Central Coast Area Health Service Methods and compositions for the treatment of myocardial conditions
US8703826B2 (en) 2006-08-10 2014-04-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Preparation of (R,R)-fenoterol and (R,R)-or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US9492405B2 (en) 2010-03-10 2016-11-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
WO2019112913A1 (en) * 2017-12-04 2019-06-13 The Board Of Trustees Of The Leland Stanford Junior University Beta-2 selective adrenergic receptor agonists

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; AN: 132:317813, XP002142848 & ZHANG, S. ET AL: "Signaling selective beta2-adrenergic stimulation: therapeutic implications in chronic heart failure" HENAN YIKE DAXUE XUEBAO, vol. 35, no. 1, 2000, pages 37-45, *
DATABASE CHEMABS [Online] CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; AN: 132:318239, XP002142849 & ZHANG, S. ET AL: "Agonist directed sorting of beta2-adrenergic receptor signaling and its therapeutic implications in heart" HENAN YIKE DAXUE XUEBAO, vol. 35, no. 1, 2000, pages 37-45, *
IRMER, M. ET AL: "Behandlung der schweren Herzinsuffizienz mit dem Beta-Stimulator Fenoterol" KLINISCHE WOCHENSCHRIFT, vol. 59, no. 12, 1981, pages 639-645, XP000924969 *
KRUMINS, A.M. ET AL: "The stability of the agonist beta2-adrenergic receptor-Gs complex: Evidence for agonist-specific states" MOLECULAR PHARMACOLOGY, vol. 52, no. 1, 1997, pages 144-154, XP000924993 *
M]GGE, A. ET AL: "Effects of the beta2-adrenoceptor agonists fenoterol and salbutamol on force of contraction in isolated human ventricular myocardium" KLINISCHE WOCHENSCHRIFT, vol. 63, no. 1, 1985, pages 26-31, XP000924974 *
MARZO, K.P. ET AL: "beta-Adrenergic receptor-G protein-adenylate cyclase complex in experimental canine heart failure produced by rapid ventricular pacing" CIRCULATION RESEARCH, vol. 69, no. 6, 1991, pages 1546-1556, XP000924985 cited in the application *
RASCHE, K. ET AL: "Pulmo cardialis: Effekt inhalativer Bronchodilatatoren auf den Atemwegswiderstand bei akuter linksventrikulärer Funktionsstörung" PNEUMOLOGIE, vol. 44, no. suppl. 1, 1990, pages 533-535, XP000924970 *
SHI, B. ET AL: "Dynamic changes in G-alpha-i-2 levels in rat hearts associated with impaired heart function after myocardial infarction" AMERCAN JOURNAL OF PHYSIOLOGY, vol. 269, no. 3, 1995, pages H1073-H1079, XP000924991 cited in the application *
STEINFATH, M. ET AL: "Reduced effects of alpha1- and beta2-adrenoceptor-mediated positive intropic effects in human end-stage heart failure" BRITISH JOURNAL OF PHARMACOLOGY, vol. 105, no. 2, 1992, pages 463-469, XP000924806 *

Cited By (13)

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EP1755581A1 (en) * 2004-04-23 2007-02-28 Northern Sydney and Central Coast Area Health Service Methods and compositions for the treatment of myocardial conditions
US10308591B2 (en) 2006-08-10 2019-06-04 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US8703826B2 (en) 2006-08-10 2014-04-22 The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services, National Institutes Of Health Preparation of (R,R)-fenoterol and (R,R)-or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US9522871B2 (en) 2006-08-10 2016-12-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preparation of (R,R)-fenoterol and (R,R)-or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US9908841B2 (en) 2006-08-10 2018-03-06 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US10562843B2 (en) 2006-08-10 2020-02-18 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Preparation of (R,R)-fenoterol and (R,R)- or (R,S)-fenoterol analogues and their use in treating congestive heart failure
US9492405B2 (en) 2010-03-10 2016-11-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
US10130594B2 (en) 2010-03-10 2018-11-20 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
US10617654B2 (en) 2010-03-10 2020-04-14 The Usa, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
US10925840B2 (en) 2010-03-10 2021-02-23 The Usa, As Represented By The Secretary, Department Of Health And Human Services Use of fenoterol and fenoterol analogues in the treatment of glioblastomas and astrocytomas
WO2019112913A1 (en) * 2017-12-04 2019-06-13 The Board Of Trustees Of The Leland Stanford Junior University Beta-2 selective adrenergic receptor agonists
US11590089B2 (en) 2017-12-04 2023-02-28 The Board Of Trustees Of The Leland Stanford Junior University Beta-2 selective adrenergic receptor agonists

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