WO2004105751A1 - Traitement de pathologie cardiovasculaire - Google Patents

Traitement de pathologie cardiovasculaire Download PDF

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WO2004105751A1
WO2004105751A1 PCT/US2004/016720 US2004016720W WO2004105751A1 WO 2004105751 A1 WO2004105751 A1 WO 2004105751A1 US 2004016720 W US2004016720 W US 2004016720W WO 2004105751 A1 WO2004105751 A1 WO 2004105751A1
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pde4
cardiovascular pathology
inhibitor
mammal
mass
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Frank C. Barone
Robert W. Coatney
Jeffrey J. Legos
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Glaxo Group Ltd
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Glaxo Group Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil

Definitions

  • the present invention relates to a method and pharmaceutical composition for reducing cardiovascular pathology in mammals.
  • Cardiac hypertrophy is an increase in myocardial (heart) muscle mass where wall thickness increases in size because the heart has to work harder to maintain normal physiologic function. Cardiac hypertrophy may be caused by both hemodynamic stresses and non-hemodynamic factors. Included in the hemodynamic stresses that contribute to increased wall thickness (e.g., cardiac hypertrophy) are pressure overload from hypertension/arteriosclerosis or volume overload from sodium and water retention. Non- hemodynamic factors that contribute to developing pathology may include activation of the renin-angiotensin-aldosterone system (which also increases volume and pressure overload) and the level of fibrosis or stiffness in the myocardium. These events may lead to increased wall thickness and decreased ventricular chamber diameter.
  • CVF congestive heart failure
  • myocardial infarction cardiovascular complications which are associated with a significant increase in mortality.
  • Reducing or reversing cardiac hypertrophy to levels that are approaching that of healthy patients has been associated with reduced arrhythmias, improved cardiac function, and reduced risk of heart failure including congestive heart failure and an improvement in coronary blood flow reserves enabling patients to live healthier, longer lives.
  • mice have been commonly used as experimental models of cardiac hypertrophy, myocardial infarction, and heart failure to mimic pathology observed in humans.
  • the aorta is constricted approximately 30%, which causes an increase in blood pressure (e.g., pressure overload) and sympathatetic activation of the renin-angiotensin- aldosterone system (e.g., volume overload).
  • blood pressure e.g., pressure overload
  • sympathatetic activation of the renin-angiotensin- aldosterone system e.g., volume overload
  • /- hypertrophy represents an adequate model to assess the pharmacologic effects of novel agents on left ventricular mass.
  • Phosphodiesterases comprise a large, divergent family of enzymes that catalyze the catabolism of cAMP and cGMP to AMP and GMP, respectively. Eleven members of this family have been identified to date based on substrate specificity, kinetic properties, sensitivity to specific inhibitors, tissue distribution, and primary sequences (Manganiello, VC et al., Arch Biochem Biophys, 322 (1): 1-13, (1995); Fawcett, L et al., ProcNatlAcadSci USA, 91(1): 3702-3707 (2000)). Recognition of these differences has greatly stimulated interest in PDEs as drug targets. In particular, the cAMP specific PDE, termed PDE4, that is found in nearly all immune and inflammatory cells has been an attractive target for novel anti-asthmatic and anti-inflammatory therapies.
  • PDE4 inhibitors have a property of reducing cardiac hypertrophy in mammals suffering from cardiac hypertrophy.
  • a method for reducing cardiovascular pathology in a mammal comprising administering an effective amount of a phosphodiesterase 4 (PDE4) inhibitor to reduce said cardiovascular pathology.
  • PDE4 phosphodiesterase 4
  • a pharmaceutical formulation comprising a PDE4 inhibitor in an amount effective to reduce cardiovascular pathology in a mammal.
  • the instant invention provides a method for reducing cardiovascular pathology in a mammal suffering from cardiovascular pathology, comprising administering an effective amount of a phosphodiesterase 4 (PDE4) inhibitor to reduce said cardiovascular pathology.
  • PDE4 phosphodiesterase 4
  • reduce refers to a decrease in the severity of or cessation of a cardiovascular pathology.
  • the severity of cardiovascular pathology may be decreased by reducing the left ventricular muscle mass of an animal to any extent, including but not limited to reducing left ventricular muscle mass equivalent to that observed at baseline or to left ventricular muscle mass considered to be within normal range for a healthy animal of the same species and having similar physical characteristics.
  • baseline left ventricular mass refers to left ventricular muscle mass of an animal prior to receiving any therapeutic method or compound of the invention.
  • normal left ventricular mass refers to: (1) the amount of left ventricular mass in a healthy animal of the same species and having similar physical characteristics including but not limited to gender, age, weight, height, blood pressure, and underlying disease, and/or (2) the amount of left ventricular mass in a animal of the same species and having similar physical characteristics including but not limited to gender, age, weight, height, blood pressure, and underlying disease prior to treatment using a method or compound of the invention.
  • a “healthy animal” as used herein refers to an animal that does not show thickening of the left ventricular wall above normal. Healthy animals typically do not show signs or symptoms of cardiovascular pathology, and are typically free from any other underlying disease or gross morbidity.
  • cardiac pathology refers to a cardiovascular complication or risk thereof and may include but is not limited to cardiac hypertrophy, coronary heart disease, arrhythmia, restricted coronary blood flow, arteriosclerosis, heart failure, congestive heart failure (CHF), myocardial infarction, as well as others.
  • cardiac hypertrophy refers to increased left ventricular mass above normal. Cardiac hypertrophy may manifest as heart wall growth that causes a narrowing of the ventricular chambers.
  • increased left ventricular muscle mass refers to growth or thickening of the left ventricular wall upon the onset of one or more cardiovascular pathology.
  • hemodynamic stress refers to any factors contributing to pressure, viscosity and/or volume overload of the cardiac system. Hemodynamic stress that may contribute to pressure overload may include but is not limited to hypertension/arteriosclerosis. Hemodynamic stress that may contribute to volume overload may include but is not limited to sodium and water retention. Hemodynamic stress contributes to increased left ventricular wall thickness (e.g., cardiac hypertrophy).
  • non-hemodynamic factors refers to any factors contributing to pressure and/or volume overload of the cardiac system.
  • Non-hemodynamic factors may include but are not limited to activation of the renin-angiotensin-aldosterone system, and increased fibrosis or stiffness in the myocardium.
  • inhibitor(s) or “inhibiting,” as it relates to PDE4, means a compound that causes or is related to a change in an amount, and/or quality, and/or effect of a particular response and/or activity of PDE4.
  • alkyl refers to a straight or branched chain hydrocarbon having from one to twelve carbon atoms, optionally substituted with substituents selected from the group that includes, but is not limited to, -C ⁇ alkyl, -C ⁇ alkoxy, C ⁇ -C 6 alkylsulfanyl, -C ⁇ alkylsulfenyl, Ci-C ⁇ alkylsulfonyl, oxo, hydroxy, mercapto, amino optionally substituted by alkyl, carboxy, carbamoyl optionally substituted by alkyl, aminosulfonyl optionally substituted by a substituent selected from the group including alkyl, nitro, cyano, halogen and lower perfluoroalkyl, multiple degrees of substitution being allowed.
  • alkyl as used herein may include, but are not limited to, methyl, ethyl, n-butyl, n-pentyl, isobutyl, isopropyl and the like.
  • alkoxy refers to the group R ⁇ O-, where Rg is alkyl.
  • aryl refers to a 6 to 10 carbon aromatic moiety.
  • Examples of "aryl” as used herein may include, but are not limited to, phenyl, pyridyl, pyrimidyl, pyridazyl, pyrazyl, and triazyl.
  • aryloxy refers to the group R a O-, where R * is aryl.
  • halogen refers to the group fluorine, chlorine, bromine, and iodine.
  • the term "agent” is understood to mean a substance that produces a desired effect in a intracellular component, cell, tissue, system, animal, mammal, human, or other subject.
  • the method of the present invention includes administering a specific PDE4 inhibitor agent.
  • PDE4 inhibitor agents may include, but are not limited to, rolipram and rolipram derivatives, or rolipram mimetic compounds; and fused ring compounds such as benzopyrazoles, benzimidazoles, benzofurans, diazepinio-indoles, quinolines, quinolones, nitraquazone derivatives, purines and xanthines, and losartan analogues.
  • PDE4 inhibitors are described, for instance, in "PDE4 inhibitors 1998", Norman, Peter; Exp. Opin. Ther. Patents (1998) 8(7); and “Chronic Pulmonary Inflammation and Other Therapeutic Applications of PDErV Inhibitors", Stafford, Jeffrey A. and Feldman, Paul L., Ch. 8 Annual Reports In Medicinal Chemistry Ch. 8, 71-80 (1996) which references are herein incorporated by reference to the extent of their disclosure of PDE4 inhibitor compounds.
  • Rj is -(CR, R 5 ) n C(0)0(CR 4 R 5 ) m s, -(CR, R 5 ) radical C(0)NR4 (CR 4 R 5 ) m R5, -(CR 4 5 ) n 0(CR 4 R 5 ) m Rg, or --(CR 4 R 5 ) r Re wherein the alkyl moieties may be optionally substituted with one or more halogens; m is 0 to 2; n is 0 to 4; r is 0 to 6;
  • R 4 and R 5 are independently selected from hydrogen or a -2 alkyl;
  • Re is hydrogen, methyl, hydroxyl, aryl, halo substituted aryl, aryloxy C ⁇ 3 alkyl, halo substituted aryloxy C ⁇ -3 alkyl, indanyl, indenyl, C 7- ⁇ polycycloalkyl, tetrahydrofuranyl, furanyl, tetrahydropyranyl, pyranyl, tetrahydrothienyl, thienyl, tetrahydrothiopyranyl, thiopyranyl, C 3-6 cycloalkyl, or a C . ⁇ cycloalkyl containing one or two unsaturated bonds, wherein the cycloalkyl and heterocyclic moieties may be optionally substituted by 1 to 3 methyl groups or one ethyl group; provided that: when Re is hydroxyl, then m is 2; or when R ⁇ is
  • X is YR 2 , halogen, nitro, NR R 5 , or formyl amine; Y is O or S(0) m *; m' is O, 1, or 2; X 2 is O or NRs ; X 3 is hydrogen or X; X 4 is
  • C(Z')NHRi5, CR (NOC(0)R 16 ), or X 5 is H, R 9 , OR,, CN, C(0)Rg, C(0)ORs, C(0)NRg R & or NRg R 8 ;
  • R 2 is independently selected from the group consisting of -CH 3 and ⁇ CH 2 CH 3 optionally substituted by 1 or more halogens;
  • R 2 ' is a hydrogen, halogen, or OR ⁇ ; s is 0 to 4; R 3 ' and R 4 ' are each independently -(CH2) t X 6 ; t is 0, 1, 2, or 3; v is 0, 1, 2, or 3; ,
  • X ⁇ is a mono- or bicyclic aryl group optionally containing one or more heteroatoms selected from sulfur, oxygen, or nitrogen;
  • R 5 ' and g' are each independently hydrogen or an optionally substituted alkyl;
  • R 3 is hydrogen, halogen, C 1-4 alkyl, CH 2 NHC(0)C(0)NH 2 , halo-substituted C M alkyl, -
  • CH CR s 'R g ', cyclopropyl optionally substituted by R 8 ', CN, ORg, CH 2 ORg, NRg io,
  • Z' is O, S, NRs, NORs, NCN, C(-CN) 2 , CRgCN, CR 8 N0 2 , CR 8 C(0)OR 8 , CR 8 C(0)ONR 8 8 , C(-CN)N0 2 , C(-CN)C(0)OR 9 , C(-CN)C(0)NR 8 Rs;
  • Z is C(Y')Ri4, C(0)O i4, C(Y')NR 10 R I4 , C(NR 10 )NR 10 R M , CN, C(NOR 8 )R 14 , C(0)NR 8
  • R 7 is --(CR 4 R 5 ) q R ⁇ 2 or Ci- ⁇ alkyl wherein the R i2 or d -6 alkyl group is optionally substituted one or more times by C 1-2 alkyl optionally substituted by one to three fluorines, - -F, ⁇ Br, -CI, -N0 2 , -NRio Rn, ⁇ C(0)Rs, ⁇ C(0)ORs, --ORg, -CN, -C(O)NR 10 R meaning, ⁇ OC(O)NR 10 Ru, ⁇ OC(0)Rs, -NRio C(O)NR ⁇ 0 Ru, -NRio C(0)R ceremoni, -NRio C (0)OR 9 , ⁇ NR 10 C(0)Ri 3 , -C(NR ⁇ o)NR 10 Rn, ⁇ C(NCN)NR ⁇ o R n , ⁇ C(NCN)SR 9 , -NRio C (NCN)SR 9 , -NRi
  • R ⁇ is hydrogen, or CM alkyl optionally substituted by one to three fluorines; or when Rio and Ru are as NRio Ru they may together with the nitrogen form a 5 to 7 membered ring optionally containing at least one additional heteroatom selected from O/N/or S;
  • R ⁇ 3 is oxazolidinyl, oxazolyl, thiazolyl, pyrazolyl, triazolyl, tetrazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, isoxazolyl, oxadiazolyl, or thiadiazolyl, and each of these heterocyclic rings is connected through a carbon atom and each may be unsubstituted or substituted by one or two C ⁇ -2 alkyl groups;
  • R 14 is hydrogen or R 7 ; or when Rio and R ]4 are as NRio R 14 they may together with the nitrogen form a 5 to 7 membered ring optionally containing one or more additional heteroatoms selected from O, N, or S;
  • R 15 is optionally substituted pyridyl, pyrazinyl, pyrimidinyl, isoxazolyl; or an N-oxide thereof; or a optionally substituted phenyl, wherein s optional substituents are one or more selected from the group consisting of halogen, haloalkyl, aryl, aiylalkyl, alkoxy, aryloxy, alkylthio, arylthio, alkoxycarbonyl, alkanoyl, aroyl, alkylsulphonyl, arylsulphonyl, alkylsulphinyl, arylsulphinyl, hydroxy, hydroxyalkyl, formyl, alkanoylamino, aroylamino, cyano, and nitro;
  • Ri 6 is amino, C C 6 alkylamino, arylamino, C ⁇ -C 6 alkoxy, or aryloxy;
  • R ⁇ is hydrogen, or optionally substituted alkyl, alkenyl, alkoxyalkyl, or alkanoyl, or a formyl, carboxamido, or thiocarboxamido;
  • Still another group of Formula I PDE4 inhibitor compounds that may be usefully employed in the process of the present invention includes (+/-)-4-[2-(3-cyclopentyloxy-4- methoxyphenyl)-2-phenylethyl]pyridine (CDP-840), represented by Figure 10(b) of WO 01/93909, and related compounds. These compounds are described, as well as the synthesis thereof, in International Patent Applications WO 94/14742; 97/23460; 97/23461 ; 97/38976; 97/42172; and 98/12178.
  • Additional PDE4 inhibitors that may be utilized in the present invention include, but are not limited to:
  • denbufylline i.e., 7-acetonyl,l,3dibutylxanthine, made by SmithKline Beecham and depicted in Figure 11(b) of WO 01/93909;
  • a PDE4 inhibitor agent is a compound of Formula I.
  • a PDE4 inhibitor is c «-4-cyano-4-[3-(cyclopentyloxy)-4- methoxyphenyl]cyclohexane-l-carboxylic acid or salt thereof; N-(3,5-dichloropyrid-4-yl)-3- cyclopentyloxy-4-methoxybenzamide; l-[3-cyclopentyloxy)-4-methoxyphenyl] ethanone (E)-0- ⁇ aminocarbonyl ⁇ oxime; (+/-)-4-[2-(3 -cyclopentyloxy-4-methoxyphenyl)-2- phenylethyl]pyridine; SB200473; or roflumilast.
  • PDE4 inhibitors of the present invention are PDE4 specific inhibitors.
  • PDE4 specific inhibitors they are meant that activities of inhibitors against PDE TV enzyme is at least 400 times or more potent in terms of IC50 as compared to activities against other PDE isoenzymes, e.g. PDE I, II, HI, or V.
  • PDE I, II, HI, or V activities against other PDE isoenzymes
  • flumilast, rolipram and cilomilast (ARIFLO) against PDE TV are more than 400 times potent against PDE I, ⁇ , DJ and V. (J Pharmacol Exp Ther 2001 Apr;297(l):267-79).
  • PDE4 inhibitors to reduce left ventricular wall mass are not limited to human use, but includes veterinary use as well. However, it is well understood that the effectiveness of a particular PDE4 inhibitor in a particular species is limited, such as, by its bioavailability in that species. Which PDE4 inhibitor is more effective in a particular species may be readily ascertained by conventional pharmacological methods.
  • one aspect of the present invention is a method of reducing cardiovascular pathology in a mammal, comprising administering an amount effective for reducing said cardiovascular pathology with a phosphodiesterase 4 (PDE4) inhibitor.
  • the cardiovascular pathology is cardiac hypertrophy, heart failure, and/or CHF.
  • the mammal is suffering from hypertension and/or arteriosclerosis.
  • the PDE4 inhibitor is PDE4 specific inhibitor.
  • a PDE4 specific inhibitor may be rolipram or roflumilast, among others.
  • PDE4 specific inhibitors may be administered separately or in combination with one another or with other pharmaceutical agents.
  • this invention provides a pharmaceutical formulation comprising a PDE4 inhibitor in an amount effective to reduce cardiovascular pathology in a mammal suffering from cardiovascular pathology.
  • the cardiovascular pathology is cardiac hypertrophy, heart failure, and/or CHF.
  • the mammal is suffering from hypertension and/or arteriosclerosis.
  • a PDE4 inhibitor is PDE4 specific inhibitor.
  • a PDE4 specific inhibitor may be rolipram or roflumilast among others. These PDE4 inhibitors may be administered separately or in combination with one another or with other pharmaceutical agents.
  • PDE4 inhibitors of the present invention may be administered by any appropriate route.
  • Suitable routes may include, but are not limited to, oral, rectal, nasal, topical (including, but not limited to, buccal and sublingual), vaginal, and parenteral (including, but not limited to, subcutaneous, intramuscular, intraveneous, intradermal, intrathecal, and epidural). It will be appreciated that a route of administration may vary with, for example, the condition of the recipient.
  • compositions adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; chewable gum; or oil-in-water liquid emulsions or water-in-oil liquid emulsions, among others.
  • an active drug component may be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like.
  • Powders may be prepared by comminuting a compound to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent may also be present.
  • Capsules may be made, for example, by preparing a powder mixture as described above, and filling formed gelatin sheaths.
  • Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol may be added to a powder mixture before a filling operation.
  • a disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate may also be added to improve the availability of a medicament when a capsule is ingested.
  • suitable binders may include, but are not limited to, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like.
  • Lubricants used in these dosage forms may include, but are not limited to, sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators may include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets may be formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture may be prepared by mixing a compound, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quaternary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate, among others.
  • a powder mixture may be granulated by wetting with, for example, a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a powder mixture may be run through a tablet machine forming imperfectly formed slugs broken into granules.
  • Granules may be lubricated to prevent sticking to tablet-forming dies by means of addition of stearic acid, a stearate salt, talc or mineral oil, among others.
  • a lubricated mixture may then be compressed into tablets.
  • Compounds of the present invention may also be combined, for example, with free flowing inert carrier and compressed into tablets directly without going through granulating or slugging steps.
  • a clear or opaque protective coating consisting of, for example, a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax may be provided. Dyestuffs or other compounds may be added to these coatings to distinguish different unit dosages.
  • Oral fluids such as solution, syrups and elixirs may be prepared in dosage unit form so that a given quantity contains a predetermined amount of the compound.
  • Syrups may be prepared by dissolving a compound in a suitably flavored aqueous solution, while elixirs are prepared through the, use of a non-toxic alcoholic vehicle.
  • Suspensions may be formulated by dispersing a compound in a non-toxic vehicle.
  • Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like may also be added.
  • dosage unit formulations for oral administration may be microencapsulated.
  • a formulation may also be prepared to prolong or sustain release as for example by coating or embedding particulate material in polymers, wax or the like.
  • oral formulation may be in the form of a chewable gum.
  • compositions adapted for transdermal administration may be presented as discrete patches intended to remain in intimate contact with the epidermis of the recipient for a prolonged period of time.
  • an active ingredient may be delivered from a patch by iontophoresis as generally described in Pharmaceutical Research, 3(6), 318 (1986).
  • compositions adapted for rectal administration may be presented as suppositories or as enemas, among others.
  • compositions adapted for parenteral administration may include, but are not limited to, aqueous and non-aqueous sterile injection solutions that may contain anti-oxidants, buffers, bacteriostats and solutes that render a formulation isotonic with the blood of an intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickening agents.
  • Formulations may be presented in unit- dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only addition of a sterile liquid carrier, for example water for injections, immediately prior to use.
  • Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.
  • formulations may include, but are not limited to, other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non- toxic salts of the compounds of this invention that are prepared, for example, by reacting a free base with a suitable organic or inorganic acid or by reacting an acid with a suitable organic or inorganic base.
  • a therapeutically effective amount of a PDE4 inhibitor of the present invention will depend upon a number of factors including, for example, age and weight of a mammal, at least one precise condition requiring treatment, severity of a condition, nature of a formulation, and route of administration. Ultimately, a therapeutically effective amount will be at the discretion of an attendant physician or veterinarian.
  • CMC carboxymethylcellulose
  • Enalapril as the gold standard to validate murine model of cardiac hypertrophy
  • Male CD-I mice (n 6 to 8 per group), 20-25 g in weight, were used for the experiment. Each mouse's aorta was exposed between the two renal arteries and was surgically constricted using a 30-gauge needle and 6.0 suture to induce heart growth. Seven days after surgery, baseline echocardiography was performed on each mouse to establish left ventricular mass ("LV mass").
  • Enalapril the gold standard in treating cardiac hypertrophy, was orally administered to the mice at the dose of 10 mg/kg beginning on day 11 (4 days after baseline) and was continued once daily for 10 days. The control group was administered with the vehicle. Repeat echocardiography was conducted on mice 14 and 21 days post surgery.
  • mice in the vehicle group and the enalapril group had mean ⁇ SE LV masses of 98.2 ⁇ 3.3 mg and 96.1 ⁇ 4.8 mg, respectfully.
  • the vehicle group had a mean ⁇ SE LV mass of 117.0 ⁇ 5.6 mg and the enalapril group had a mean ⁇ SE mass of 91.9 ⁇ 3.4 mg.
  • the vehicle group had a mean ⁇ SE LV mass of 123.2 ⁇ 8.3 mg and the enalapril group have a mean ⁇ SE mass of 84.1+4.1 mg.
  • the aorta was exposed between the renal arteries of the mice and was surgically constricted using a 30-gauge needle and 6.0 suture to induce heart growth as discussed in Example 2. Seven days after surgery, baseline echocardiography was performed on each mouse to establish LV mass.
  • Rolipram suspended in 1% CMC was orally administered to the mice at the doses of 10-100 mg/kg.
  • the control group was administered with vehicle (1% CMC).
  • mice were administered a single oral dose of PDE4 inhibitor or vehicle and dosing was continued once daily for ten days. Seven mice were used in each dose group. Repeat echocardiography was conducted on each mouse 14 and 21 days after surgery.
  • Table 1 shows LV mass of mice treated with vehicle, rolipram, and enalapril at baseline (7 days after surgery), 14 and 21 days after surgery.
  • mice Male CD-I mice, 20-25 g in weight, were used for the experiment.
  • the aorta was exposed between the renal arteries of the mice and was surgically constricted using a 30- gauge needle and 6.0 suture to induce heart growth as discussed in Example 2.
  • Roflumilast was suspended in 1% carboxymethylcellulose (vehicle) and was orally administered to the mice at the doses of 3-30 mg/kg.
  • the control group was administered with vehicle.
  • mice were administered a single oral dose of PDE4 inhibitor or vehicle and dosing was continued once daily for ten days. Seven mice were used in each dose group.
  • Repeat echocardiography was conducted on each mouse 14 and 21 days after surgery. t Fourteen days after surgery, a statistically significant reduction in LV mass was observed in mice treated with 3 mg/kg of roflumilast compared with vehicle at the same timepoint as shown in Table 2.
  • mice Twenty-one days after surgery, a statistically significant reduction in LV mass was observed in mice that received 3, 10 and 30 mg/kg of roflumilast compared with vehicle at the same timepoint also shown in Table 2.
  • Table 2 shows LV mass of mice treated with vehicle, roflumilast, and enalapril at baseline (7 days after surgery), 14 and 21 days after surgery.
  • Table 2 Mean ⁇ SE LV Mass of mice treated with vehicle roflumilast or enalapril

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Abstract

La présente invention concerne un procédé de réduction de la pathologie cardiovasculaire chez un mammifère à l'aide d'un inhibiteur de phosphodiestérase 4 (PDE4).
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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006111495A1 (fr) * 2005-04-19 2006-10-26 Nycomed Gmbh Utilisation de roflumilast pour traiter l'hypertension pulmonaire
EP3165224A1 (fr) 2015-11-09 2017-05-10 Albert-Ludwigs-Universität Freiburg Utilisation d'inhibiteurs de pde4 pour la prophylaxie et/ou la thérapie de la dyslipoproteinémie et des troubles apparentés

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US6331543B1 (en) * 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use

Patent Citations (1)

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Publication number Priority date Publication date Assignee Title
US6331543B1 (en) * 1996-11-01 2001-12-18 Nitromed, Inc. Nitrosated and nitrosylated phosphodiesterase inhibitors, compositions and methods of use

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006111495A1 (fr) * 2005-04-19 2006-10-26 Nycomed Gmbh Utilisation de roflumilast pour traiter l'hypertension pulmonaire
EA016037B1 (ru) * 2005-04-19 2012-01-30 Никомед Гмбх Рофлумиласт для лечения лёгочной гипертензии
US8648100B2 (en) 2005-04-19 2014-02-11 Takeda Gmbh Roflumilast for the treatment of pulmonary hypertension
EP3165224A1 (fr) 2015-11-09 2017-05-10 Albert-Ludwigs-Universität Freiburg Utilisation d'inhibiteurs de pde4 pour la prophylaxie et/ou la thérapie de la dyslipoproteinémie et des troubles apparentés
WO2017080919A1 (fr) * 2015-11-09 2017-05-18 Albert-Ludwigs-Universität Freiburg Utilisation d'inhibiteurs de pde4 pour la prophylaxie et/ou le traitement de la dyslipoprotéinémie et de troubles associés

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