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US20020012946A1 - Method of identifying partial agonists of the A2A receptor - Google Patents

Method of identifying partial agonists of the A2A receptor Download PDF

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US20020012946A1
US20020012946A1 US09/792,617 US79261701A US2002012946A1 US 20020012946 A1 US20020012946 A1 US 20020012946A1 US 79261701 A US79261701 A US 79261701A US 2002012946 A1 US2002012946 A1 US 2002012946A1
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cvt
adenosine
agonist
coronary
agonists
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Luiz Belardinelli
Brent Blackburn
Zhenhai Gao
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Gilead Sciences Inc
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CV Therapeutics Inc
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Priority to US09/792,617 priority Critical patent/US20020012946A1/en
Assigned to CV THERAPEUTICS, INC. reassignment CV THERAPEUTICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BELARDINELLI, LUIZ, BLACKBURN, BRENT K., GAO, ZHENHAI
Publication of US20020012946A1 publication Critical patent/US20020012946A1/en
Priority to US10/614,702 priority patent/US20040137533A1/en
Priority to US11/070,768 priority patent/US7582617B2/en
Priority to US12/435,176 priority patent/US8071566B2/en
Assigned to GILEAD PALO ALTO, INC. reassignment GILEAD PALO ALTO, INC. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: APEX MERGER SUB, INC., CV THERAPEUTICS, INC.
Assigned to GILEAD SCIENCES, INC. reassignment GILEAD SCIENCES, INC. MERGER (SEE DOCUMENT FOR DETAILS). Assignors: GILEAD PALO ALTO, INC.
Priority to US13/525,223 priority patent/US8536150B2/en
Priority to US14/014,169 priority patent/US9163057B2/en
Abandoned legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
    • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
    • C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
    • C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
    • C07H19/16—Purine radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/08—Vasodilators for multiple indications
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5082—Supracellular entities, e.g. tissue, organisms
    • G01N33/5088—Supracellular entities, e.g. tissue, organisms of vertebrates
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)

Definitions

  • This invention relates to a method of identifying compounds that are selective partial A 2A -adenosine receptor agonists, preferably with a short duration of action. Such compounds provide coronary dilation in mammals without causing corresponding significant peripheral vasodilation. The invention also relates to a method of using such compounds as adjuncts in cardiac imaging.
  • MPI Myocardial perfusion imaging
  • a diagnostic technique useful for the detection and characterization of coronary artery disease.
  • Perfusion imaging uses materials such as radionuclucides to identify areas of insufficient blood flow.
  • blood flow is measured at rest, and the result compared with the blood flow measured during exercise on a treadmill (cardiac stress testing), such exertion being necessary to stimulate blood flow.
  • cardiac stress testing such exertion being necessary to stimulate blood flow.
  • many patients are unable to exercise at levels necessary to provide sufficient blood flow, due to medical conditions such as peripheral vascular disease, arthritis, and the like.
  • a pharmacological agent that increases CBF for a short period of time would be of great benefit, particularly one that did not cause peripheral vasodilation.
  • Vasodilators for example dipyridamole, have been used for this purpose in patients prior to imaging with radionuclide. Dipyridamole is an effective vasodilator, but side effects such as pain and nausea limit the usefulness of treatment with this compound.
  • Adenosine a naturally occurring nucleoside, also is useful as a vasodilator. Adenosine exerts its biological effects by interacting with a family of adenosine receptors characterized as subtypes A 1 , A 2A , A 2B , and A 3 .
  • AdenoScan® (Fujisawa Healthcare Inc.) is a formulation of a naturally occurring adenosine. AdenoScan has been marketed as an adjuvant in perfusion studies using radioactive thallium-201. However, its use is limited due to side effects such as flushing, chest discomfort, the urge to breathe deeply, headache, throat, neck, and jaw pain.
  • AdenoScan is contraindicated in many patients including those with second-or third-degree block, sinus node disease, bronchoconstructive or bronchospastic lung disease, and in patients with known hypersensitivity to the drug.
  • MRE-0470 Medco
  • WRC-0470 Medco
  • adenosine A 2A agonist used as an adjuvant in imaging.
  • a 2A receptor agonists are well known; for example, see Provisional patent applications Ser. Nos. 60/1844296 and 60/21987.
  • the compounds disclosed therein have a high specificity for the adenosine A 2A receptor subtype but are not necessarily selective to heart.
  • the invention relates to a method for identifying compounds useful as adjuncts in MPI, comprising the steps;
  • Such compounds are selective partial A 2A -adenosine receptor agonists, which produce coronary dilation in mammals without causing corresponding peripheral vasodilation at significant levels. They are low affinity compounds having a short duration of action.
  • the invention in a second aspect, relates to a method of measuring coronary blood flow (CBF) in a mammal, comprising administering to a a mammal low doses of an A 2A agonist referred to as CVT-3033, or CVT-3146.
  • CBF coronary blood flow
  • FIG. 1 Competititive radiolabeling binding assays of of adenosine receptor agonists for A 2A and A 1 binding sites
  • Membranes prepared from HEK-293 expressing human A 2A adenosine receptors were incubated with [ 3 H]ZM241385 (1.5-5 M) and from 10 ⁇ 9 M-10 ⁇ 5 M of the various agonists (FIG. 1A).
  • Membranes from CHO-K1 cells expressing human A 1 adenosine receptors were incubated with [ 3 H]CPX (2.5-3.0 M) and from 10 ⁇ 9 M-10 ⁇ 5 M of the various agonists (FIG. 1B).
  • FIG. 2 Competititive radiolabeling binding assays of of adenosine receptor agonists for A 2b and A 3 binding site.
  • Membranes suspensions from HEK-293 cells expressing A 2b adenosine receptors were incubated with [ 3 H]DPCPX (1.5-5 M) and from 10 ⁇ 8 M-10 ⁇ 5 M of the various agonists (FIG. 2A).
  • Membranes from CHO-K1 cells expressing A 3 adenosine receptors were incubated with [ 125 I]ABMECA (2.5-3.0 M) and from 10 ⁇ 8 M-10 ⁇ 5 M of the various agonists (FIG. 2B). The cells were incubated for two hours at room temperature in 50 mmol/L Tris-HCl buffer (pH 7.4) containing ADA (1U/mL). Each point represents the mean ⁇ SEM of triplicates pooled from three experiments.
  • FIG. 3 Effects of adenosine receptor agonists on cAMP content in intact PC12 cells.
  • FIG. 3A PC12 cells were incubated for 10 minutes with various concentrations of adenosine receptor agonists in the presence of 50 ⁇ mol/L rolipram. Cyclic AMP levels were determined as described under “Methods”. Values represent mean ⁇ SEM of results of triplicate samples from three experiments.
  • FIG. 3B Effect of CVT-3033 (1 ⁇ M) on CGS21680 stimulated increase cAMP accumulation in PC12 cells. PC12 cells were stimulated for 10 minutes with various concentrations of CGS21680 in the absence or presence of the partial agonist CVT-3033 (1 ⁇ M). Values represent mean ⁇ SEM of triplicate determinants from one representative experiment.
  • FIG. 4 Effect of CVT-3146 and CVT-3033 on cAMP content in HEK-293 cells.
  • HEK-293cells were incubated for 10 minutes with various concentrations of CVT-3146 or CVT-3033 in the presence of 50 ⁇ mol/L rolipram.
  • Cyclic AMP levels were determined as described under “Methods”. Values represent mean ⁇ SEM of triplicate samples from three experiments.
  • FIG. 5 Time course of the decline in agonist stimulated cAMP following addition of an A 2A adenosine receptor antagonist SCH58261.
  • FIG. 5A PC12 cells were stimulated with various adenosine receptor agonists in the presence of 50 ⁇ mol/L rolipram at 37° C. After a 10 minute incubation, SCH58261 (20 ⁇ mol/L) was added and cAMP content was determined at the times indicated.
  • FIG. 5B Linear regression analysis of the relationship between the T 1 ⁇ 2 (min) and pK i for the agonists. Binding affinities were determined by measurement of the displacement of specific binding of [ 3 H] ZM241385 from membranes prepared from PC12 cells using the data from Table 2
  • FIG. 7A Effect of CPX and ZM241385 on CVT-3146 (10 nM) on CPP by isolated rat hearts.
  • FIG. 7B Effect of concentration of ZM241385 on CVT-3146 stimulation of CC by isolated rat hearts.
  • FIG. 8 Functional selectivity of CVT-3146 and CVT-3033 for adenosine receptor subtypes.
  • FIG. 8A Effect of concentration on AV conduction time and coronary conductance in isolated rat hearts. Symbols and error bars represent means ⁇ SEM of single determinations from each of three hearts.
  • FIG. 8B FIG. 9. Effect of adenosine receptor agonists on coronary perfusion pressure (CCP) in isolated rat hearts. Decreases in CPP caused by infusion of CVT-3146 (10 nM, 4 min) or CGS21680 (100 nM, 4 min) (FIG. 9A and FIG. 9B). Decrease in CPP caused by the infusion of CVT-3146 (10 nM) with or without additional infusion of CGS21680 (100 nM).
  • FIG. 10 Reversal of effect of agonist stimulation on CC.
  • CVT-3033, CGS21680 and adenosine were given as boluses by iv infusion to isolated rat hearts and then. CC was measured at 8, 16 and 24 minutes after administration (FIG. 10A).
  • CVT-3146, WRC 0470 and adenosine were given as boluses by iv infusion to isolated rat hearts and then CC was measured at 8, 16 and 24 minutes after administration (FIG. 10B).
  • Linear regression analysis of the relationship between the pK i (data from Table 2) and the reversal time (t 0.9 ) of coronary vasodilation are given in FIG. 10C and D. Each data point represents the mean ⁇ SEM of pK i and T 0.9 values.
  • R and N are the correlation coefficient and number of agonists, respectively.
  • FIG. 11 Increases in CBF caused by CVT-3146 and adenosine in conscious dogs. Each data point is mean ⁇ SEM of the peak effect in CBF from 6 dogs. *: p ⁇ 0.05, ⁇ : p ⁇ 0.01 and ⁇ : p ⁇ 0.001. Adenosine: (O) and CVT-3146 (O).
  • FIG. 12 Time course of changes in average peak coronary (O) and peripheral (O) artery blood flow velocity after an IV bolus injection of CVT-3146 (1 ug/kg) (A) and adenosine (200-300 ⁇ g/kg).(B). Each point represents the changes in average peak flow velocity ( ⁇ APV) in comparison with the baseline values and represent the mean ⁇ SEM of single determinations.
  • This invention provides methods for identifying partial adenosine A 2A receptor agonists, which are particularly useful in MPI.
  • Compounds that act as A 2A agonists produce a variety of effects that depend on both the characteristics of the agonist, its receptor, and the tissue bearing A 2A receptors.
  • Factors relate to agonist properties are the intrinsic efficacy (E) and the equilibrium dissociation constant of the agonist-receptor complex (K d ).
  • Intrinsic efficacy is the maximum effect that an agonist can produce if the dose is taken to its maximum. Efficacy is determined mainly by the nature of the receptor and its associated effector system. By definition, partial agonists have a lower maximal efficacy than full agonists.
  • the K d of a drug is obtained from data generated from a saturation experiment analyzed according to a Scatchard plot (B/F versus F), which leads to a linear curve.
  • the K d is estimated as the negative reciprocal of the slope of the line of best fit, and B max by the abscissa intercept of the line.
  • the reciprocal of K d measures the affinity constant (K a ) of the radioligand for the receptor.
  • K a affinity constant
  • B max is expressed as pmol or fmol per mg tissue or protein.
  • IC 50 is a measure of the inhibitor or affinity constant (Ki) of the displacer for the receptor. IC 50 and K i are linked as follows if the displacement is of the competitive type then
  • K i IC 50 /(1+[ C*]/K d *
  • the potency is the dose or concentration required to bring about some fraction of a compound's maximal effect (i.e., the amount of compound needed to produce a given effect).
  • the effect usually chosen is 50% of the maximum effect and the dose causing the effect is called the EC 50 .
  • Dose-response ratios using EC 50 values for an agonist for a given receptor in the absence and presence of various concentrations of an antagonist for the same receptor are determined and used to construct a Schild plot from which the K b and p A 2 (-log 10 K b ) values are determined.
  • IC 50 concentration of antagonist that causes 50% inhibition.
  • IC 50 is used to determine the K b , the equilibriumdissociation constant for the antagonist-receptor complex.
  • K b [IC 50 ]/1+[ A]/K A
  • K A equilibrium dissociation constant for an agonist binding to a receptor (concentration of agonist that causes occupancy of 50% of the receptors) and [A] is the concentration of agonist.
  • a compound may be potent but have less intrinsic activity than another compound.
  • Relatively potent therapeutic compounds are preferable to weak ones in that lower concentrations produce the desired effect while circumventing the effect of concentration dependent side effects.
  • tissue specific factors that determine the effect of an agonist are the number of viable specific receptors in a particular tissue [RT] and the efficiency of the mechanisms that convert a stimulus (S) into an effector response.
  • a response to a drug is a function of both the stimulus produced by agonist interaction with the receptor and the efficiency of the transduction of that stimulus by the tissue.
  • Stimulus is proportional to the intrinsic efficacy of the agonist and the number of receptors. Consequently, variation in receptor density in different tissues can affect the stimulus for response.
  • some tissues have very efficiently coupled receptors and other relatively inefficient coupled receptors. This has been termed ‘receptor reserve’ (or spare receptor) since in the first case, a maximum effect can be achieved when a relatively small fraction of the receptor is apparently occupied and further receptor occupancy can produce no additional effect.
  • spare receptors in a tissue increases sensitivity to an agonist.
  • An important biologic consequence of spare receptors is that they allow agonists with low efficacy for receptors to produce full responses at low concentrations and therefore elicit a selective tissue response.
  • a drug may be designed to elicit a maximal effect in a desired tissue but elicit a less than maximal effect in other tissues when such action of a drug would lead to undesirable side effects.
  • the invention provides a method of identifying drugs by first determining their efficacy compared to a known full agonist. Then, the binding affinity of the compound is determined. Compounds identified by this method will demonstrate partial agonist effects in the cAMP assays and a low K i as determined by affinity binding assays.
  • One preferred compound of the invention that is a selective partial A 2A -adenosine receptor agonist with a short duration of action is a compound of the formula:
  • CVT-3033 is particularly useful as an adjuvant in cardiological imaging.
  • the preparation of CVT-3033 and related compounds is described in U.S. patent application Ser. No. 09/338185, filed on Jun. 22, 1999, the specification of which is incorprated herein by reference.
  • Another preferred compound of the invention that is a selective partial A 2A -adenosine receptor agonist with a short duration of action is a compound of the formula:
  • Compounds identified by the method of the invention are partial A 2A agonists that increase CBF but do not significantly increase peripheral blood flow. That is, the stimulation of blood flow in the periphery is less than 50% of the increase of that in the heart.
  • Preferred compounds identified by the method of the invention have a duration of less than 5 seconds but longer than the effect produced by adenosine.
  • the compounds identified by the method of the invention are useful A 2A agonists that may be used as adjuncts in cardiac imaging when added either prior to dosing with an imaging agent or simultaneously with an imaging agent.
  • Suitable imaging agents are 201 “Thallium or 99m Technetium-Sestamibi, 99mTc teboroxime, and 99mtc (III).
  • compositions may be administered orally, intravenously, through the epidermis or by any other means known in the art for administering therapeutic agents.
  • the method of treatment of comprises the administration of an effective quantity of the chosen compound, preferably dispersed in a pharmaceutical carrier.
  • Dosage units of the active ingredient are generally selected from the range of 0.3 to 103 ⁇ g/kg, but will be readily determined by one skilled in the art depending upon the route of administration, age and condition of the patient. These dosage units may be administered one to ten times daily for acute or chronic disorders. No unacceptable toxicological effects are expected when compounds of the invention are administered in accordance with the present invention.
  • compositions including the compounds of this invention, and/or derivatives thereof may be formulated as solutions or lyophilized powders for parenteral administration. Powders may be reconstituted by addition of a suitable diluent or other pharmaceutically acceptable carrier prior to use. If used in liquid form the compositions of this invention are preferably incorporated into a buffered, isotonic, aqueous solution. Examples of suitable diluents are normal isotonic saline solution, standard 5% dextrose in water and buffered sodium or ammonium acetate solution. Such liquid formulations are suitable for parenteral administration, but may also be used for oral administration.
  • compositions including compounds of this invention may be desirable to add excipients such as polyvinylpyrrolidinone, gelatin, hydroxy cellulose, acacia, polyethylene glycol, mannitol, sodium chloride, sodium citrate or any other excipient known to one of skill in the art to pharmaceutical compositions including compounds of this invention.
  • the pharmaceutical compounds may be encapsulated, tableted or prepared in an emulsion or syrup for oral administration.
  • Pharmaceutically acceptable solid or liquid carriers may be added to enhance or stabilize the composition, or to facilitate preparation of the composition.
  • Liquid carriers include syrup, peanut oil, olive oil, glycerin, saline, alcohols and water.
  • Solid carriers include starch, lactose, calcium sulfate, dihydrate, teffa alba, magnesium stearate or stearic acid, talc, pectin, acacia, agar or gelatin.
  • the carrier may also include a sustained release material such as glycerol monostearate or glycerol distearate, alone or with a wax.
  • the amount of solid carrier varies but, preferably, will be between about 20 mg to about 1 gram per dosage unit.
  • the pharmaceutical dosages are made using conventional techniques such as milling, mixing, granulation, and compressing, when necessary, for tablet forms; or milling, mixing and filling for hard gelatin capsule forms.
  • a liquid carrier When a liquid carrier is used, the preparation will be in the form of a syrup, elixir, emulsion or an aqueous or non-aqueous suspension. Such a liquid formulation may be administered directly or filled into a soft gelatin capsule.
  • cAMP cyclic adenosine monophosphate
  • APV average peak velocity
  • CBF coronary blood flow
  • CHO-Ki Choinese hamster ovary cell line
  • HEK-293 human cell line
  • CPP coronary perfusion pressure
  • CR coronary resistence
  • HR heart rate
  • im intramuscular
  • iv intravenous
  • LVSP left ventricle systolic pressure
  • MAP mean arterial pressure
  • PBF peripheral blood flow.
  • Adenosine deaminase was purchased from Boehringer Mannheim Biochemicals Indianapolis, Ind.).
  • ZM241385 was purchased from Tocris Cookson Ltd (Langford, Bristol, UK).
  • CPX was from New England Nuclear (Boston, Mass.).
  • HENECA CGS21680, adenosine, NECA, R-PIA, phenylephrine, DMSO, rolipram and HEK-hA 2A AR membranes were obtained from Sigma-RBI (Natick, Mass.). Nitroglycerin was obtained from Parke-Davis, Morris Plains, N.J. Aminophylline was obtained from Abbott Laboratories, Chicago, Ill.
  • HENECA was a gift from Professor Gloria Cristalli of the University of Camerino, Italy.
  • Drug stock solutions (10 mmol/L) were prepared in DMSO.
  • Sprague Dawley rats were purchased from Simonsen Laboratories (Gilroy, Calif.).
  • Ketamine was purchased from Fort Dodge Animal Health (Fort Dodge, Iowa) and xylazine from Bayer (Shawnee Mission, Kans.).
  • Succinyl cAMP-tyrosyl methyl ester (ScAMP-TME) was purchased from Sigma and iodinated in the presence of chloramine T.
  • Examples 1 and 2 demonstrate the selectivity and binding affinity of the compounds of the invention to adenosine receptors on cells obtained as follows.
  • Rat pheochromocytoma PC12 cells were obtained from the American Type Culture Collection and grown in DMEM with 5% fetal bovine serum, 10% horse serum, 0.5 mmol/L L-glutamine, 100 U/mL penicillin, 0.1 mg/mL streptomycin, and 2.5 ⁇ g/mL amphotericin.
  • HEK-293 cells stabily expressing recombinant human A 2 B adenosine receptors were grown in DMEM supplemented with 10% fetal bovine serum and 0.5 mg/mL G-418.
  • CHO-K1 cells stabily expressing the recombinant human A, adenosine receptors (CHO-hA 1 adenosine receptors) or A 3 adenosine receptors (CHO-hA 3 adenosine receptors) were grown as monolayers on 150-mm plastic culture dishes in Ham's F-12 media supplemented with 10% fetal bovine serum in the presence of 0.5 mg/mL G-418. Cells were cultured in an atmosphere of 5% CO 2 /95% air and maintained at 37° C.
  • Cell membranes were harvested from the cell lines by detaching cells from the culture plates into ice-cold 50 mmol/L Tris-HCl buffer (pH 7.4). The cell suspensions were homogenized and centrifuged at 48,000 g for 15 minutes. The pellets were washed three times by re-suspension in ice-cold Tris-HCl buffer and centrifugation. The final pellet was re-suspended in Tris-HCl, aliquoted and frozen at ⁇ 80° C. until used for receptor binding assays. The protein concentration of membrane suspensions was determined using the Bradford (Bradford, M. M. (1976. Anal. Biochem. 72, 248) with bovine serum albumin as standard.
  • Membranes were also obtained from porcine striatial cells as follows. Porcine striatum was obtained from Pel Freeze Inc. Striatum was minced and homogenized in 10 volumes of ice-cold 50 mmol/L Tris HCl buffer (pH7.4). The homogenate was filtered through cotton gauze and centrifuged at 48,000g for 15 minutes at 4° C. The supernatant was discarded, and the membrane pellet was suspended in 10 volumes of 50 mmol/L Tris-HCl buffer (pH 7.4) and washed three times by centrifugation and resuspended in fresh buffer. The final pellet was frozen at ⁇ 80° C. until used for receptor binding assays.
  • [ 3 H]-ZM241385 ( ⁇ 1.5 to 5 nmol/L) was added to membranes from cells expressing A 2A
  • [ 3 H]-CPX ( ⁇ 2.5 to 3.0 nmol/L) was added to membranes from cells expressing A 1
  • [ 3 H]-CPX (30 nM) was added to membranes from cells expressing A 2B
  • [ 125 I]ABMECA (1 nM) ⁇ was added to membranes from cells expressing A 3 .
  • the competing agents that is the agonists (10 ⁇ 9 -10 ⁇ 4 M) were also added along Gpp (NH) p (100 ⁇ g) which stabilizes the receptor in the low affinity state thereby obviating the complication of multiple affinity states (Gao., Z.
  • K d the equilibrium dissociation constant for [ 3 H]ZM241385 binding that were used in calculations of K 1 values were 0.5, 0.5 and 0.8 nM for pig striatum, PC12 and HEK-hA 2A AdoR cells, respectively.
  • Example 3 demonstrates the ability of the compounds of the invention to stimulate cAMP levels, a measure of the intrinsic efficacy of the agonists.
  • PC12 cells were rinsed three times with Hanks' balanced saline solution (HBSS), detached using a cell lifter, and pelleted by centrifugation at 500 g for 5 minutes. Aliquots of the cell suspension (0.1 to 0.2 mg protein) were placed in microfuge tubes with 250 ⁇ L of HBSS containing rolipram (50 ⁇ mol/L) to inhibit phosphodiesterases that degrade cAMP_and warmed to 37° C. Appropriate drugs were added to the cell suspensions, and incubations were allowed to continue for 10 minutes.
  • HBSS Hanks' balanced saline solution
  • Tubes were placed in a boiling water bath for 5 minutes to terminate the incubation. The samples were then cooled to room temperature, diluted by the addition of 1 mL of 10 mmol/L Tris-HCl buffer at pH 7.4, and then centrifuged for 2 minutes at 13000 g.
  • the cAMP content of the supernatant was determined by modification of a radioimmunoassay method described by Harper and Brooker (1975. J. Cyclic nucleotide Res 1:207). Briefly, an aliquot of the supernatant (0.01 mL) was mixed with 0.04 mL of HBSS, 0.05 mL of 50 mmol/L sodium acetate buffer (pH 6.2) containing 10 mmol/L CaCl 2 , [ 125 I]ScAMP-TME (12500 dpm), and 0.05 mL of anti-cAMP antibody (1:2000 dilution with 0.1% bovine serum albumin in distilled water). The samples were then incubated at 4° C. for 16 hours.
  • PC12 cells cultured in DMEM at 37° C. were treated with WRC0470, CGS21680, CVT-2995, CVT-3146, CVT-3033 and R-PIA each at a concentration of 1 ⁇ M in the presence of rolipram (50 ⁇ M) for 10 minutes. Then, an A 2A antagonist, SCH58261 (20 ⁇ M), was added and cAMP content was determined at various periods.
  • FIG. 5A shows the time-course of the decline of agonist-stimulated cAMP accumulation following the addition of SCH58261when compared to the control cultures (CGS2160 incubated without SCH58261).
  • the calculated values of t 0.5 from these experiments are presented in Table 3.
  • the apparent t 0.5 values of agonists were inversely related to their affinities for A 2A adenosine receptors, that is, the greater the agonist affinity, the lower the rate of decline of cAMP content upon application of the A 2A adenosine receptors antagonist SCH58261 (FIG. 5A).
  • FIG. 5B the relationship between the apparent t 0.5 and pK i for the agonists was best fit by linear regression with a correlation coefficient (r value) of 0.84.
  • the aorta was cannulated and the heart was perfused at a flow rate of 10 ml/min with modified K-H solution.
  • the K-H solution (pH 7.4) was gassed continuously with 95% O 2 and 5% CO 2 and warmed to 35 ⁇ 0.5° C.
  • the heart was electrically paced at a fixed cycle length of 240 ms (250 beats/min) using a bipolar electrode placed in the left atrium.
  • the electrical stimuli were generated by a Grass stimulator (Model S48, W.
  • Warwick, R.I. Warwick, R.I.
  • Stimuli Isolation Unit Model SIU5, Astro-Med, Inc., N.Y.
  • Square-wave pulses of 3-msec in duration and with an amplitude of at least twice the threshold intensity.
  • the potencies (EC 50 values) of adenosine, CGS21680, WRC0470 and the CVT compounds are summarized in Table 4.
  • the low affinity agonist CVT-3146 was found to be approximately 10-fold more potent than adenosine but 10-fold less potent than the high affinity agonists CGS21680 and WRC0470 with respect to increasing coronary conductance.
  • Coronary vasodilatory effect of CVT-3146 in the absence and presence of adenosine receptor antagonists were also demonstrated.
  • the identity of the adenosine receptor subtype (A 1 or A 2A ) mediating the coronary vasodilation was determined.
  • CVT-3146 significantly increased coronary conductance to 0.22 ⁇ 0.01 ml mm Hg ⁇ 1 min ⁇ 1 from a baseline value of 0.16 ⁇ 0.02 ml mm Hg ⁇ 1 min ⁇ 1 .
  • This increase in coronary conductance caused by CVT-3146 was not affected by 60 nM CPX but was completely reversed by 60 nM ZM241385.
  • the inhibition by ZM241385 of an increase of coronary conductance caused by CVT-3146 was concentration-dependent (FIG. 7B).
  • a 1 adenosine receptor-mediated depression of A-V nodal conduction time by CVT-3033 and CVT-3146 was measured using atrial and ventricular surface electrograms as described by Jenkins and Belardinelli (Circ Res 63:97).
  • CVT-3146 and CVT-3033 increased coronary conductance in a concentration-dependent manner, but did not prolong A-V nodal conduction time
  • Coronary perfusion pressure was measured using a pressure transducer that was connected to the aortic cannula via a T-connector positioned approximately 3 cm above the heart.
  • CPP was monitored throughout an experiment and recorded either on a chart recorder (Gould Recorder 2200S,Valley View, Ohio) or a computerized recording system (PowerLab/4S, ADInstruments Pty Ltd, Australia). Only hearts with CPP ranging from 60 to 85 mmHg (in the absence of drugs) were used in the study.
  • CC conductance in ml/min/mmHg was calculated as the ratio between coronary perfusion rate (10 ml/min) and CPP.
  • FIG. 9A the extent of the decrease in coronary perfusion pressure (an index of the coronary vasodilation) caused by CVT-3146 was similar to that caused by a supramaximal concentration of CGS21680 (FIG. 9B). Both 10 nM CVT-3146 and 100 nM CGS21680 decreased coronary perfusion pressure by 23 mmHg. In addition, in the presence of 10 nM CVT-3146, CGS21680 (100 nM) did not cause a further decrease of the coronary perfusion pressure (FIG. 9C). Thus, CVT-3146 is a full agonist with respect to coronary artery conductance.
  • the duration of the effect of adenosine was the shortest followed by those of CVT-3033 and CVT-3146.
  • the effects of CGS21680 and WRC0470 had the longest duration (FIG. 10).
  • the duration of the coronary vasodilation in isolated rat hearts caused by adenosine, the CVT compounds, and other agonists measured as the time to 50% and 90% (t 0.5 and t 0.9, respectively) reversal of the increases in coronary conductance after termination of drug administration are summarized in Table 4.
  • the reversal time of coronary vasodilation correlated with the affinity of the adenosine derivatives for the A 2A receptors. As shown in FIG.
  • Lactate Ringers solution was administered via an ear or femoral vein as an initial bolus of 300-400 ml followed by a continuous infusion at a rate of 5-7 ml/kg/hr.
  • a catheter was inserted into the femoral artery to monitor arterial blood pressure.
  • LVP Left ventricular pressure
  • LAD left anterior descending coronary artery
  • a 24-gauge modified angiocatheter was inserted for intracoronary infusions. All hemodynamic data were continuously displayed on a computer monitor and fed through a 32-bit analog to digital converter into an online data acquisition computer with customized software (Augury, Coyote Bay Instruments, Manchester, N.H.).
  • a 2A adenosine receptors agonists were dissolved in DMSO to produce stock concentrations of 1-5 mM, which were diluted in 0.9% saline and infused at rates of 1-1.5 ml/min via the catheter. The A 2A adenosine receptors agonists were administered intracoronary.
  • a solid-state pressure gauge (P6.5, Konisberg Instrument, Inc) was placed in the apex of the left ventricle for the measurement of the left ventricular systolic pressure (LVSP) and calculation of first derivative of left ventricular pressure (LV dP/dt).
  • LVSP left ventricular systolic pressure
  • LV dP/dt first derivative of left ventricular pressure
  • a Doppler transducer (Craig Hartley) was placed on the left circumflex coronary artery for measurement of CBF.
  • An hydraulic coronary occluder (In Vivo Metric, Inc) was implanted in 4 dogs around the left circumflex coronary artery. The chest was closed in layers and the catheters and wires were run subcutaneously and exited in the interscapular area. The dogs were allowed 10 to 14 days to recover fully from the surgery and were trained to lie on a laboratory table. The protocols were approved by the Institutional Animal Care and Use Committee of New York Medical College and conform to the “Guiding Principles for the
  • MAP mean arterial pressure
  • LV pressure was measured from the solid-state pressure gauge, and LV dP/dt was calculated using a microprocessor set as a differentiator and having a frequency response flat to 700 Hz (LM 324, National Semiconductor).
  • Left circumflex CBF was measured using a pulsed Doppler flowmeter (System 6, Triton technology), and mean CBF was derived using a 2-Hz low-pass filter.
  • Mean CR was calculated as the quotient of MAP and CBF.
  • Heart rate was monitored from the pressure pulse interval using a cardiotachometer (Beckman Instruments).
  • the lead-2 of the electrocardiogram was recorded during the experiments in order to examine the alterations in the AV nodal conduction (PR interval). All signals were recorded on a direct-writing oscillograph (Gould 2800).
  • the duration of coronary vasodilation was determined using two different injection protocols: 1) an iv infusion of 10 ml in 10 seconds and; 2) iv infusion of 10 ml in 30 seconds.
  • the time to the peak effect in mean CBF increase and the duration during which CBF remained at least 2 fold above baseline.
  • a dose-response curve of the effect of CVT-3146 on CBF is shown in FIG. 11.
  • An IV bolus injection of CVT-3146 caused a dose-dependent increase in mean CBF, with a ED 50 of 0.34 ⁇ 0.08 ⁇ g/kg and a maximal increase of 154 ⁇ 16 ml/min from baseline (45 ⁇ 3 ml/min).
  • the maximal increase in mean CBF stimulated by CVT-3146 and adenosine were similar.
  • CVT-3146 produced a maximal decrease in CR of 73 ⁇ 2% and 75 ⁇ 2% at 2.5 ⁇ g/kg at 5 ⁇ g/kg, respectively.
  • Adenosine produced a maximal decrease of 73 ⁇ 1% at 267 ⁇ g/kg (data not shown).
  • Example 7 demonstrates the differential effects of CVT-3146 on blood flow velocity in coronary and peripheral arteries, systemic arterial blood pressure and heart rate in anesthetized dogs.
  • Vascular arterial angiography was performed using Hypaque-76 contrast fluid (Bracco Diagnostics, Inc., Princeton, N.J.; Lot #9H28899) and a mobile fluoroscopic unit (Philips, BV 29). Systemic arterial blood pressure was measured using an electronic transducer-tipped catheter (Millar). The following pharmacologic agents were used: CVT-3146 (CV Therapeutics; Lot #315-53), heparin (Solopak Laboratories, Inc., Elk Grove Village, Ill.; Lot #960211) and sodium pentobarbital (lot #9700), and acepromazine (lot #3960960), obtained from JA Webster (Fort Dodge, Iowa).
  • Dogs were sedated with acepromazine (0.25 mg/kg), anesthetized with sodium pentobarbital (30 mg/kg+additional doses (1 mg/kg) given as necessary to maintain the level of anesthesia), intubated with endotracheal tube and artificially ventilated with room air using a respirator.
  • acepromazine (0.25 mg/kg
  • sodium pentobarbital (30 mg/kg+additional doses (1 mg/kg) given as necessary to maintain the level of anesthesia
  • endotracheal tube was artificially ventilated with room air using a respirator.
  • the pressure transducer-tipped catheter was introduced through the left femoral artery and positioned in the descending aorta.
  • the Doppler FloWire was introduced through the right femoral artery.
  • a peripheral vein was cannulated for the administration of all drugs.
  • Doses of 1 ⁇ g/kg of CVT-3146 and 300 or 200 ⁇ g/kg adenosine (Adenosine) were given multiple times, once or twice when the Doppler catheter was positioned in a coronary artery and again when the catheter was positioned in the cranial circumflex humeral artery.
  • the sequence of positioning of the Doppler catheter was reversed in consecutive experiments.
  • baseline values of measured parameters were recorded following a stabilization period of 20 minutes, and CVT-3146 and Adenosine were given as intravenous bolus injections ( ⁇ 0.5 ml) followed by a physiologic saline solution flush (10 ml); the time required for both injections of each drug was ⁇ 15 sec.
  • BP Systemic arterial blood pressure
  • ECG electrocardiograms
  • Gould Data Acquisition System model 13-4615-65A
  • a video cassette recorder Teac, XR 5000
  • a chart recorder Astromed, 9600.
  • the following parameters were monitored and recorded: Average peak coronary and peripheral artery blood flow velocity (APV), mean arterial blood pressure (MAP) (mmHg), and sinus cycle length (SCL; msec). Differences in measure parameters were tested for statistical significance using ANOVA and Student's t test corrected for multiple measurements. Data are expressed as the mean ⁇ SEM.
  • CVT-3146 increased APV in the coronary vasculature by 2.6 ⁇ 0.2-fold while its increase of APV in the peripheral arteries was only 1.1 ⁇ 0.1 -fold (Table 7).
  • the vasodilatory action of adenosine was similar in the two vascular beds: specifically, adenosine increased APV in the coronary vasculature by 2.5 ⁇ 0.3-fold while its increase of APV in the periopheral arteries was 2.0 ⁇ 0.4-fold.

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US20090317331A1 (en) 2009-12-24
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CA2439222C (fr) 2009-07-14
US20050175535A1 (en) 2005-08-11
US20120251440A1 (en) 2012-10-04
US7582617B2 (en) 2009-09-01
US9163057B2 (en) 2015-10-20
US8071566B2 (en) 2011-12-06
US8536150B2 (en) 2013-09-17
CA2439222A1 (fr) 2001-08-30

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