WO2020178443A1 - Méthodes de traitement ou de prévention de l'insuffisance cardiaque et de réduction du risque d'insuffisance cardiaque - Google Patents

Méthodes de traitement ou de prévention de l'insuffisance cardiaque et de réduction du risque d'insuffisance cardiaque Download PDF

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WO2020178443A1
WO2020178443A1 PCT/EP2020/056102 EP2020056102W WO2020178443A1 WO 2020178443 A1 WO2020178443 A1 WO 2020178443A1 EP 2020056102 W EP2020056102 W EP 2020056102W WO 2020178443 A1 WO2020178443 A1 WO 2020178443A1
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phenyl
isopentylcyclohexanecarbonylamino
mant
dimethylthiopropionate
ant
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PCT/EP2020/056102
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English (en)
Inventor
Jean-Claude Tardif
Eric Rhéaume
Nolwenn MERLET
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Dalcor Pharma Uk Ltd., Leatherhead, Zug Branch
Montreal Heart Institute
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Application filed by Dalcor Pharma Uk Ltd., Leatherhead, Zug Branch, Montreal Heart Institute filed Critical Dalcor Pharma Uk Ltd., Leatherhead, Zug Branch
Priority to KR1020217025686A priority Critical patent/KR20210137442A/ko
Priority to BR112021014677-6A priority patent/BR112021014677A2/pt
Priority to CA3126323A priority patent/CA3126323A1/fr
Priority to SG11202107468YA priority patent/SG11202107468YA/en
Priority to AU2020232350A priority patent/AU2020232350A1/en
Publication of WO2020178443A1 publication Critical patent/WO2020178443A1/fr

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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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/426—1,3-Thiazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A61K31/7076—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines containing purines, e.g. adenosine, adenylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • LDL low-density lipoproteins
  • statin drugs which lower LDL, such as Crestor, Lipitor, Pravachol, and Zocar are widely used and among the most prescribed drugs.
  • HDL High-density lipoproteins
  • niacin and CETP inhibitors such as torcetrapib, anacetrapib, evacetrapib and dalcetrapib.
  • Cholesteryl ester transfer protein also called plasma lipid transfer protein is a hydrophobic glycoprotein that is synthesized in several tissues but mainly in the liver.
  • CETP promotes bidirectional transfer of cholesteryl esters and triglyceride between all plasma lipoprotein particles.
  • the first evidence of the effect of CETP activity on plasma lipoproteins was provided by observations in people with genetic deficiencies of CETP.
  • the first CETP mutation was identified in Japan in 1989 as a cause of markedly elevated HDL-C.
  • Ten mutations associated with CETP deficiency have since been identified in Asians and one in Caucasians. It was found in Japan that 57% of subjects with levels of HDL-C > 100 mg/dL have mutations of the CETP gene.
  • CETP inhibitors have been under development for some time with the expectation that they will be useful for treating or preventing atherosclerosis.
  • a number of classes of CETP inhibitor drugs have been shown to increase HDL, decrease LDL in humans and to have therapeutic effects for treating atherosclerosis and cardiovascular disease including dalcetrapib, torcetrapib, anacetrapib, evacetrapib, BAY 60-5521 and others.
  • these drugs may not be safe and effective in all patients.
  • torcetrapib was terminated in Phase III due to incidence of mortality in patient to whom torcetrapib and atorvastatm were administered concomitantly compared to patients treated with atorvastatin alone.
  • the clinical trial for dalcetrapib was also halted in Phase III in this case due to a lack of efficacy relative to statins alone.
  • the dalcetrapib mortality and morbidity trial was a double-blind, randomized, placebo-controlled, parallel group, multi-centre study in stable CHD patients recently hospitalized for acute coronary syndrome (ACS).
  • the study was conducted to test the hypothesis that CETP inhibition will reduce the risk of recurrent cardiovascular events in patients with recent ACS by raising levels of HDL-C through CETP inhibition.
  • Eligible patients entered a single-blind placebo run-in period of approximately 4 to 6 weeks to allow for patients to stabilize and for completion of planned revascularization procedures.
  • a pharmacogenomic study of the dal-OUTCOMES study population was conducted to study the inter-individual variation in dalcetrapib response and to identify genetic markers for predicting therapeutic response to dalcetrapib, or other CETP inhibitors, for patient stratification and for treatment selection. It was discovered that the effects of dalcetrapib on atherosclerotic outcomes are determined by correlated polymorphisms in the Adenylate Cyclase Type 9 (ADCY9) gene.
  • ADCY9 Adenylate Cyclase Type 9
  • SNPs that occur in the ADCY9 gene on chromosome 16 including rs11647778, rs1967309, rs12595857, rs2239310, rs11647828, rs8049452, rsl2935810, rs74702385, rs17136707, rs8061182, rs111590482, rs4786454, rs2283497, rs2531967, rs3730119, rs2531971, rs2238448, rsl1599911, rs12920508, and rsl3337675 were found to be associated with response to a CETP inhibitor, dalcetrapib.
  • This finding was disclosed in WO2014154606A1, WO2016016157A1, Tardif et al., Circulation: Cardiovascular Genetics, (2015) 8:372-382, and Tardif et al., Circulation: Cardiovascular Genetics, (2016) 9:340-348, each of which is incorporated by reference herein.
  • ADCYs Adenylate cyclases catalyze the formation of cyclic adenosine-3 ⁇ ,5 ⁇ - monophosphate (cAMP), the universal second messenger, from adenosine triphosphate (ATP).
  • cAMP cyclic adenosine-3 ⁇ ,5 ⁇ - monophosphate
  • ATP adenosine triphosphate
  • ADCY9 is the ninth, least well characterized and widely distributed isoform of adenylate cyclase. Polymorphisms in the ADCY9 gene have been shown to affect individual response to inhaled therapy in patients with asthma. (Kim et al., J Clin Pharm Ther.
  • One aspect of the invention provides methods for treating or preventing congestive heart failure, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • Another aspect of the invention provides methods for treating or preventing congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • Another aspect of the invention provides methods for reducing risk of diastolic heart failure, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the congestive heart failure is systolic heart failure.
  • the congestive heart failure is diastolic heart failure.
  • Another aspect of the invention provides methods for reducing the risk of diastolic heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.
  • Another aspect of the invention provides methods for reducing risk of systolic heart failure, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the congestive heart failure is systolic heart failure.
  • the congestive heart failure is diastolic heart failure.
  • Another aspect of the invention provides methods for reducing risk of systolic heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the congestive heart failure is systolic heart failure.
  • the congestive heart failure is diastolic heart failure.
  • Another aspect of the invention provides methods for treating or preventing ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • Another aspect of the invention provides methods for treating or preventing ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • Another aspect of the invention provides methods for reducing risk of ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • Another aspect of the invention provides methods for reducing risk of ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • Another aspect of the invention provides methods for treating or preventing ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • Another aspect of the invention provides methods for treating or preventing ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • Another aspect of the invention provides methods for reducing risk of ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • Another aspect of the invention provides methods for reducing risk of ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • Another aspect of the invention provides methods for treating or preventing heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • Another aspect of the invention provides methods for treating or preventing heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • Another aspect of the invention further provides methods for reducing risk of heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • Another aspect of the invention further provides methods for reducing risk of heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • FIG. 1A shows that Adcy9 mRNA expression (analyzed by RT-qPCR) in the heart was decreased by 50% in Adcy9 WT/Gt mice and by at least 90% in Adcy9 Gt/Gt mice compared to WT (wild type).
  • FIG. 1E shows that ADCY9 protein expression was abolished in Adcy9 Gt/Gt mice compared to WT in the skeletal muscle.
  • FIG.1B shows the plasma PCSK9 concentration of WT and Adcy9 Gt/Gt mice infected with AAV8-Pcsk9 D377Y at baseline, one week after infection and before the start of the atherogenic diet, after 8 weeks and 12 weeks of atherogenic diet.
  • FIG. 1C shows that PCSK9 D377Y induced a reduction of 90% in hepatic LDL receptor expression that was similar in WT and Adcy9 Gt/Gt .
  • FIG. 1D shows the plasma cholesterol levels of WT and Adcy9 Gt/Gt mice infected with AAV8-Pcsk9 D377Y at baseline, one week after infection and before the start of the atherogenic diet, after 4 weeks, 8 weeks and 12 weeks of atherogenic diet.
  • FIG. 2A and FIG. 2B show the lipoprotein profile by chromatography of WT (FIG. 2A) and Adcy9 Gt/Gt (FIG.2B) mice at baseline and after 16 weeks of atherogenic diet.
  • FIG. 3A shows that 11.3 ⁇ 2.1% of the surface of the intima covered with atherosclerotic lesions in WT mice compared to 3.8 ⁇ 0.6% in Adcy9 Gt/Gt mice at sacrifice. Atherosclerosis lesions were quantified on whole aorta dissected en face.
  • FIG. 3D shows atherosclerotic lesions in the aorta of WT and Adcy9 Gt/Gt mice as revealed by Oil Red O staining.
  • FIG. 3B shows that the cross-sectional quantification of plaque area all along the aortic root of WT and Adcy9 Gt/Gt mice.
  • FIG.3E shows the atherosclerotic lesions in cross-sections of the aortic valve of WT and Adcy9 Gt/Gt mice.
  • FIG.3C and FIG.3F show that all WT animals had plaques in the brachiocephalic arteries in contrast to Adcy9 Gt/Gt mice (100%, versus 50%, P ⁇ 0.05). The plaques in WT mice were also larger and presented more frequently fibrin deposits at their surface (P ⁇ 0.05) and cap ruptures compared to Adcy9 Gt/Gt mice.
  • FIG.4A shows that CD68-positive foam cells, a key constituent of atherosclerotic plaques, represented 19.0 ⁇ 1.9% and 11.4 ⁇ 2.1% of the lesion area in WT and Adcy9 Gt/Gt mice, respectively (P ⁇ 0.05).
  • FIG. 4D shows immune-fluorescent detection of CD68-positive macrophages (foam cells).
  • FIG.4B shows in situ hybridization analysis of Adcy9 expression in atherosclerotic lesions at sites of foam cell accumulation in WT and Adcy9 Gt/Gt mice.
  • FIG. 4C and FIG. 4E show immunofluorescence detection of Ki67 which revealed that proliferation of CD68-positive foam cells was significantly decreased in Adcy9 Gt/Gt compared to WT (P ⁇ 0.05).
  • FIG.5A shows that endothelial-dependent vasodilatation to ACh in untreated animals (no AAV8-Pcsk9 D377Y and no atherogenic diet) was potentiated in the femoral arteries of Adcy9 Gt/Gt mice compared to WT (P ⁇ 0.01); in contrast, endothelial-independent vasodilation to the nitric oxide donor SNP was similar in both groups (FIG.5E).
  • FIG. 5C and FIG.5F show that in femoral arteries from atherosclerotic animals (AAV8- Pcsk9 D377Y and atherogenic diet) both endothelial-dependent (Ach) and endothelial-independent vasodilatation (SNP) were increased in Adcy9 Gt/Gt mice compared to WT mice (P ⁇ 0.05).
  • FIG. 5D and FIG. 5G show that the relaxant dose response to ACh (FIG. 5D) and SNP (FIG. 5G) of aorta of animals treated with the AAV8-Pcsk9 D377Y and atherogenic diet when comparing Adcy9 Gt/Gt to WT mice.
  • FIG. 6A and FIG. 6D show that the nitric oxide synthase blocker L-NNA inhibited significantly ACh-induced vasodilatation both in WT and Adcy9 Gt/Gt mice (P ⁇ 0.01), but flow- mediated vasodilatation was numerically reduced only in Adcy9 Gt/Gt mice.
  • FIG.6B and FIG.6E show that the cyclooxygenase blocker meclofenamate or the cocktail of endothelial-dependent hyperpolarization blockers (TRAM-34 and apamin), inhibited ACh- induced endothelial-dependent vasodilatation in Adcy9 Gt/Gt mice (P ⁇ 0.01 for both pathways) but not in WT mice.
  • TAM-34 and apamin endothelial-dependent hyperpolarization blockers
  • FIG. 6C shows the specificity of the Adcy9 mRNA signal by in situ hybridization in the femoral artery wall was confirmed by absence of dots with the negative control probe.
  • FIG. 7A shows that Adcy9 Gt/Gt mice gained more weight than WT animals during the 16 weeks of atherogenic diet, to reach weights of 45.1 ⁇ 2.4 g and 33.5 ⁇ 1.2 g respectively (P ⁇ 0.01).
  • FIG. 7B shows that MRI performed at week 14 showed that Adcy9 Gt/Gt mice presented more adipose tissue than WT mice.
  • FIG.7C shows a doubling of total body adipose tissue volume in Adcy9 Gt/Gt mice (9.4 ⁇ 1.2 cm 3 ) compared to WT (4.3 ⁇ 0.4 cm 3 , P ⁇ 0.01).
  • FIG. 7D shows larger inguinal, perirenal, epididymal and interscapular fat depots in Adcy9 Gt/Gt mice compared to WT.
  • FIG. 7E and FIG.7F show histological sections showing that Adcy9 inactivation resulted in hypertrophic adipocytes in epididymal white adipose tissue (FIG.7E) and larger lipid droplets in interscapular brown adipose tissue (FIG.7F).
  • FIG. 8A shows that with the atherogenic diet, Adcy9Gt/Gt mice showed a significant increase in feed efficiency (1.2 ⁇ 0.1 g/100 kCal) compared to WT (0.6 ⁇ 0.1 g/100 kCal, P ⁇ 0.01).
  • pNN(6) which represents the percentage of RR intervals exceeding preceding ones by 6 ms or more and reflects parasympathetic nervous system activity17, was increased during the night period in Adcy9Gt/Gt mice (21.6 ⁇ 2.4%) compared to WT (14.5 ⁇ 2.2%, P ⁇ 0.05).
  • FIG. 9B shows percentage of lesion area in the whole aorta in WT, Adcy9 Gt/Gt , CETP WT and CETP Gt mice.
  • FIG. 10A shows vasodilatation to ACh in femoral arteries from atherosclerotic CETP WT and CETP Gt mice.
  • FIG. 10B shows vasodilatation to SNP in femoral arteries from atherosclerotic CETP WT and CETP Gt mice.
  • FIG.11A shows progression of body weight upon atherogenic treatment in WT, Adcy9 Gt/Gt , CETP WT and CETP Gt mice.
  • FIG.11B shows adipose tissue volumes on MRI in WT, Adcy9 Gt/Gt , CETP WT and CETP Gt mice.
  • FIG. 12A depicts mice model of myocardial infarction. These mice have four different genotypes: WT (wild-type mice); Adcy9 Gt / Gt (Adyc9 gene-trapped mice); tgCETP +/- (transgenic mice carrying a copy of CETP gene); and Adcy9 Gt / Gt - tgCETP +/- (Adyc9 gene-trapped mice carrying a copy of CETP gene). All mice were have a C57BL/6J genetic background.
  • FIG. 12B is a diagram showing ligation of the left ventricular anterior descending (LAD) artery using a suture, used to mimic the myocardial infarction caused by plaque formation.
  • FIG. 12C depicts a surgical timeline of a mouse infarction model by ligating the LAD. Echocardiography (“Echo”) was performed at baseline, at 24 hours, at 1 week, and before 4 weeks postoperatively.
  • Echocardiography (“Echo”) was performed at baseline, at 24 hours, at 1 week, and before 4 weeks postoperatively.
  • FIG.13A shows Kruskal-Wallis tests of the age of the mice with the four genotypes at day 0.
  • FIG.13B shows Kruskal-Wallis tests of the body weight (“BW”) of the mice with the four genotypes at day 0.
  • FIG.13C shows survival of the mice in 28 days. No differences in survival among the mice with the four genotypes were observed.
  • FIG.14A all mice and FIG.14B (alive mice only) show echocardiographic wall motion score index (WMSI) analysis that was performed at 24 hours post-LAD-ligation for sham or myocardial-infarction-induced (“MI”) mice with the four genotypes (WT, Adcy9Gt/Gt, tgCETP +/- and Adcy9Gt/Gt - tgCETP +/- ).
  • WMSI echocardiographic wall motion score index
  • FIG.15 shows WMSI correlated with serum cardiac troponin ⁇ I (cTn-I) at 24 hours.
  • FIG. 16A shows that the reduced WMSI for Adcy9 Gt/Gt mice observed at 24 hours post- LAD-ligation is maintained over-time.
  • FIG. 16B shows two-way repeated ANOVA analysis for myocardial-infarction-induced (“MI”) mice with the four genotypes (WT, Adcy9 Gt / Gt , tgCETP +/- and Adcy9 Gt / Gt - tgCETP +/- ) (p ⁇ 0.001).
  • MI myocardial-infarction-induced
  • FIG.17A shows how the portion of ischemic myocardium was calculated.
  • FIG.17B shows proportion of ischemic myocardium in mice with the four genotypes.
  • FIG. 18A shows how the hearts of the mice with the four genetic backgrounds were sectioned for histological analysis.
  • FIG.18B shows Masson's trichrome staining of the heart for infarct size estimation.
  • FIG.19A and FIG.19B show infarct-size-reduction in mice with the four genotypes (WT, Adcy9 Gt / Gt , tgCETP +/- and Adcy9 Gt / Gt - tgCETP +/- ).
  • FIG. 19C shows that Adcy9 Gt / Gt MI mice had a lower WMSI compared to the mice with the other genotypes.
  • An“effective amount,” when used in connection with a CETP inhibitor and an ADCY inhibitor, is the total amount of CETP inhibitor and ADCY inhibitor that is effective for treating or preventing a cardiovascular disorder or reducing risk of a cardiovascular event in a subject.
  • A“gene” is an ordered sequence of nucleotides located in a particular position on a particular chromosome that encodes a specific functional product and may include untranslated and untranscribed sequences in proximity to the coding regions. Such non-coding sequences may contain regulatory sequences needed for transcription and translation of the sequence or introns etc. or may as yet to have any function attributed to them beyond the occurrence of the SNP of interest.
  • genotyping refers to the determination of the genetic information an individual carries at one or more positions in the genome.
  • genotyping may comprise the determination of which allele or alleles an individual carries for a single SNP or the determination of which allele or alleles an individual carries for a plurality of SNPs.
  • the nucleotides may be an A in some individuals and a G in other individuals. Those individuals who have an A at the position have the A allele and those who have a G have the G allele.
  • the individual will have two copies of the sequence containing the polymorphic position so the individual may have an A allele and a G allele or alternatively, two copies of the A alleles or two copies of the G allele.
  • Those individuals who have two copies of the G allele are homozygous for the G allele, those individuals who have two copies of the A allele are homozygous for the A allele, and those individuals who have one copy of each allele are heterozygous.
  • the alleles are often referred to as the A allele, often the major allele, and the B allele, often the minor allele.
  • the genotypes may be AA (homozygous A), BB (homozygous B) or AB (heterozygous).
  • the term“about” when used in connection with a referenced numeric indication means the referenced numeric indication plus or minus up to 10% of that referenced numeric indication.
  • the language“about 50” means from 45 to 55.
  • the term“subject,” as used herein unless otherwise defined, is a mammal, e.g., a human, mouse, rat, guinea pig, dog, cat, horse, cow, pig, or non-human primate, such as a monkey, chimpanzee, or baboon.
  • the subject is a human.
  • the subject is an adult human.
  • the subject is a pediatric human.
  • the term“adult human” refers to a human that is 18 years or older.
  • the term“pediatric human” refers to a human that is 1 year to 18 years old.
  • CETP inhibitors that are useful in the compositions and methods of the invention include small molecules, anti-CETP antibodies and peptides that inhibit or suppress CETP activity.
  • CETP inhibitors that are useful in the compositions and methods of the invention include, but are not limited to, dalcetrapib, anacetrapib, evacetrapib, torcetrapib, BAY 60-5521, obicetrapib, BMS-795311, CP-800,569, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19- 4789, BAY 38-1315, DLBS-1449 (Dexa Medica) and ATH-03 (Affris), and pharmaceutically acceptable salts of any of the foregoing.
  • “Dalcetrapib” refers to S-[2-( ⁇ [1-(2-Ethylbutyl)cyclohexyl]carbonyl ⁇ amino)phenyl]-2- methylpropanethioate, and is also known as JTT-705 or CAS 211513-37-0. Dalcetrapib has the structure:
  • “Anacetrapib” refers to (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3- ⁇ [4'-fluoro-2'- methoxy-5'- (propan-2-yl)-4-(trifluoromethyl)[1,l'-biphenyl]-2-yl]methyl ⁇ -4-methyl-1,3- oxazolidin-2-one, and is also known as (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-( ⁇ 2-[4- fluoro-2-methoxy-5-(propan-2-yl)phenyl]-5-(trifluoromethyl)phenyl ⁇ methyl)-4-methyl-1,3- oxazolidin-2-one; MK-0859; or CAS 875446-37-0.
  • Anacetrapib has the structure:
  • “Evacetrapib” refers to trans-4-( ⁇ (5S)-5-[ ⁇ [3,5-bis(trifluoromethyl)phenyl]methyl ⁇ (2- methyl-2H-tetrazol-5-yl)amino]-7,9-dimethyl-2,3,4,5-tetrahydro-lH-benzazepin-l- yl ⁇ methyl)cyclohexanecarboxylic acid, and is also known as LY2484595 or CAS 1186486-62-3.
  • Evacetrapib has the structure:
  • Torcetrapib refers to (2R,4S)-4-[(3,5-bistrifluoromethylbenzyl) methoxycarbonylamino]-2-ethyl-6-trifluoromethyl-3,4-dihydro-2H-quinoline-l-carboxylic acid ethyl ester, and is also known as Ethyl (2R,4S)-4-( ⁇ [3,5- bis(trifluoromethyl)phenyl]methyl ⁇ (methoxycarbonyl)amino)-2-ethyl-6-(trifluoromethyl)- 1,2,3,4-tetrahydroquinoline-1-carboxylate; CP-529,414; or CAS 262352-17-0. Torcetrapib has the structure:
  • BAY 60-5521 refers to (S)-4-cyclohexyl-2-cyclopentyl-3-((S)-fluoro(4- (trifluoromethyl)phenyl)methyl)-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, and is also known as CAS 893409-49-9.
  • BAY 60-5521 has the structure:
  • “Obicetrapib” refers to 4-((2-((3,5-bis(trifluoromethyl)benzyl)((2R,4S)-1- (ethoxycarbonyl)-2-ethyl-6-(trifluoromethyl)-1,2,3,4-tetrahydroquinolin-4-yl)amino)pyrimidin- 5-yl)oxy)butanoic acid, and is also known as AMG-899, DEZ-001, TA-8995 or CAS 866399-87- 3.
  • Obicetrapib has the structure:
  • BMS795311 refers to (R)-N-(1-(3-cyclopropoxy-4-fluorophenyl)-1-(3-fluoro-5- (2,2,3,3-tetrafluoropropanoyl)phenyl)-2-phenylethyl)-4-fluoro-3-(trifluoromethyl)benzamide, and is also known as CAS 939390-99-5.
  • BMS795311 has the structure:
  • CP-800,569 refers to (2R)-3-[3-(4-chloro-3-ethylphenoxy)-n-[[3-(1,1,2,2- tetrafluoroethoxy)phenyl]methyl]anilino]-1,1,1-trifluoropropan-2-ol.
  • CP-800,569 has the structure:
  • DRL-17822 refers to CAS 1454689-50-9 and is disclosed in WO 2014128564 and WO 2014076568. DRL-17822 has the structure:
  • JNJ-28545595 refers to 1,1,1-Trifluoro-3-[2-[3-(1,1,2,2-tetra-fluoroethoxy)phenyl]-5- (3-trifluoromethoxyphenyl)-3,4-dihydro-2H-quinolin-1-yl]-propan-2-ol.
  • JNJ-28614872 refers to 1,1,1-Trifluoro-3-[3-[3-(1,1,2,2-tetrafluoro-ethoxy)-phenyl]-8- (3-trifluoromethoxy-phenyl)-2,3-dihydro-benzo[1,4]oxazin-4-yl]-propan-2-ol.
  • JNJ-28545595 and JNJ-28614872 are set forth below:
  • Additional CETP inhibitors useful in the compositions and methods of the invention include those disclosed in WO 2016/086453 or Chen et al., European Journal of Medicinal Chemistry, (2017) 139:201-213, and have the structure:
  • CETP inhibitors useful in the compositions and methods of the invention include, but are not limited to:
  • CETP inhibitors useful in the compositions and methods of the invention include those disclosed in WO 2017/011279, and have the structure:
  • CETP inhibitors useful in the compositions and methods of the invention include those disclosed in WO 2016/018729, and have a structure according to the following:
  • CETP inhibitors useful in the compositions and methods of the invention include, but are not limited to: torcetrapib; dalcetrapib; anacetrapib; evacetrapib; obicetrapib; BMS-79531; CP-800,569; DRL-17822; JNJ-28545595; JNJ-28614872; BAY 19- 4789; BAY 38-1315; 1,1,1-trifluoro-3-((3-phenoxyphenyl)(3-(1,1,2,2- tetrafluoroethoxy)benzyl)amino)propan-2-ol; (R)-3-((4-(4-chloro-3-ethylphenoxy)pyrimidin-2
  • the CETP inhibitor is an antibody or peptide.
  • U.S. Pat. No. 5,519,001 herein incorporated by reference, describes a 36 amino acid peptide derived from baboon apo C-1 that inhibits CETP activity.
  • Cho et al. (Biochim. Biophys. Acta (1998) 1391: 133- 144) describes a peptide from hog plasma that inhibits human CETP.
  • Bonin et al. J. Peptide Res. (1998) 51, 216-225) discloses a decapeptide inhibitor of CETP.
  • a depspeptide fungal metabolite is disclosed as a CETP inhibitor by Hedge et al. in Bioorg. Med. Chem. Lett., (1998) 8:1277-80.
  • An anti-CETP antibody has been described in WO2013075040 A1, herein incorporated by reference.
  • An ADCY inhibitor can be a small molecule, anti-ADCY antibody, or peptide that inhibits or suppresses adenylate cyclase expression or activity.
  • the ADCY inhibitor inhibits or suppresses adenylate cyclase expression or activity of one or more of ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 and ADCY10.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9, or ADCY10 inhibitor.
  • ADCY inhibitors are useful in the methods and compositions of the present invention.
  • Each compound’s structure is depicted at the immediate right of its name.
  • ADCY inhibitors useful in the compositions and methods of the present invention are disclosed in Dessauer et al. Pharmacol Rev, (2017) 69 (2): 93-139, and have the structure:
  • ADCY inhibitors include, but are not limited to: SQ22536 (9-(tetrahydro-2-furanyl)-adenine); 2 ⁇ ,5 ⁇ -dideoxyadenosine, 9- cyclopentyladenine; 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate; 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ - monophosphate; MDL-12330A (cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone; 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone; 4.2-amino
  • Illustrative ADCY inhibitor peptides useful in the compositions and methods of the present invention include, but are not limited to: adrenocorticotropic hormone; brain natriuretic peptide (BNP); and pituitary adenylate cyclase-activating polypeptide.
  • Pharmaceutically acceptable salts include, for example, acid-addition salts and base-addition salts.
  • the acid that forms an acid-addition salt can be an organic acid or an inorganic acid.
  • a base that forms a base-addition salt can be an organic base or an inorganic base.
  • a pharmaceutically acceptable salt is a metal salt.
  • a pharmaceutically acceptable salt is an ammonium salt.
  • Acid-addition salts can arise from the addition of an acid to the free-base form of a compound useful in the compositions and methods of the present invention.
  • the acid is organic.
  • the acid is inorganic.
  • suitable acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, nitrous acid, sulfuric acid, sulfurous acid, a phosphoric acid, nicotinic acid, isonicotinic acid, lactic acid, salicylic acid, 4-aminosalicylic acid, tartaric acid, ascorbic acid, gentisinic acid, gluconic acid, glucaronic acid, saccaric acid, formic acid, benzoic acid, glutamic acid, pantothenic acid, acetic acid, propionic acid, butyric acid, fumaric acid, succinic acid, citric acid, oxalic acid, maleic acid, hydroxymaleic acid, methylmaleic acid, glycolic
  • Non-limiting examples of suitable acid-addition salts include a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a nitrate salt, a nitrite salt, a sulfate salt, a sulfite salt, a phosphate salt, a hydrogen phosphate salt, a dihydrogen phosphate salt, a carbonate salt, a bicarbonate salt, a nicotinate salt, an isonicotinate salt, a lactate salt, a salicylate salt, a 4- aminosalicylate salt, a tartrate salt, an ascorbate salt, a gentisinate salt, a gluconate salt, a glucaronate salt, a saccarate salt, a formate salt, a benzoate salt, a glutamate salt, a pantothenate salt, an acetate salt, a propionate salt, a butyrate salt, a fumarate salt
  • Metal salts can arise from the addition of an inorganic base to a compound having a carboxyl group.
  • the inorganic base can include a metal cation paired with a basic counterion, such as, for example, hydroxide, carbonate, bicarbonate, or phosphate.
  • the metal can be an alkali metal, alkaline earth metal, transition metal, or main group metal.
  • suitable metals include lithium, sodium, potassium, cesium, cerium, magnesium, manganese, iron, calcium, strontium, cobalt, titanium, aluminum, copper, cadmium, and zinc.
  • Non-limiting examples of suitable metal salts include a lithium salt, a sodium salt, a potassium salt, a cesium salt, a cerium salt, a magnesium salt, a manganese salt, an iron salt, a calcium salt, a strontium salt, a cobalt salt, a titanium salt, an aluminum salt, a copper salt, a cadmium salt, and a zinc salt.
  • Ammonium salts can arise from the addition of ammonia or an organic amine to a compound having a carboxyl group.
  • suitable organic amines include triethyl amine, diisopropyl amine, ethanol amine, diethanol amine, triethanol amine, morpholine, N-methylmorpholine, piperidine, N-methylpiperidine, N-ethylpiperidine, dibenzyl amine, piperazine, pyridine, pyrrazole, imidazole, pyrazine, pipyrazine, ethylenediamine, N,N'- dibenzylethylene diamine, procaine, chloroprocaine, choline, dicyclohexyl amine, and N- methylglucamine.
  • Non-limiting examples of suitable ammonium salts include a triethylammonium salt, a diisopropylammonium salt, an ethanolammonium salt, a diethanolammonium salt, a triethanolammonium salt, a morpholinium salt, an N-methylmorpholinium salt, a piperidinium salt, an N-methylpiperidinium salt, an N-ethylpiperidinium salt, a dibenzylammonium salt, a piperazinium salt, a pyridinium salt, a pyrrazolium salt, an imidazolium salt, a pyrazinium salt, an ethylenediammonium salt, an N,N'-dibenzylethylenediammonium salt, a procaine salt, a chloroprocaine salt, a choline salt, a dicyclohexylammonium salt, and a N-methylglucamine salt.
  • the present invention provides methods for treating or preventing a cardiovascular disorder, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the cardiovascular disorder is acute coronary syndrome (ACS), atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial- hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, cardiovascular disease, coronary heart disease, coronary artery disease, hyperlipidemia, hyperlipidoproteinemia or a vascular complication of diabetes, obesity or endotoxemia.
  • ACS acute coronary syndrome
  • atherosclerosis peripheral vascular disease
  • dyslipidemia hyperbetalipoproteinemia, hypoalphalipoproteinemia
  • hypercholesterolemia hypertriglyceridemia
  • familial- hypercholesterolemia familial- hypercholesterolemia
  • angina ischemia
  • cardiac ischemia cardiac ischemia
  • stroke myocardial infarction
  • reperfusion injury angioplastic restenosis
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL- 17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'- monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-amino-7-(4- chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro- 5(6H)-quinazolinone; 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone; 2-amino-7-(2- furanyl)-7,8-dihydro-5(6H)-adenine;
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • Another aspect of the invention provides methods for treating or preventing a cardiovascular disorder, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9. [00130] The activity level of ADCY can be detected using techniques known in the art.
  • adenylate cyclase assays have been disclosed by Salomon et al., (1974) Analytical Biochemistry, 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron, 20:1199-1210.
  • expression level of ADCY is determined at protein expression level.
  • protein expression level of ADCY is analyzed using a specific antibody and a protein assay. Any suitable method or assay can be used to measure the level of ADCY protein expression in the biological sample of a subject. Numerous antibody-based detection formats are well known in the art, and include ELISA (enzyme linked immunosorbent assay), radioimmunoassays, immunoblots, Western blots, flow cytometry, immunofluorescence assays, immunoprecipitation, protein A assays, immunoelectrophoresis assays, and other related techniques.
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled.
  • Many means are known in the art for detecting binding in an immunoassay and are within the scope of the kits, assays and methods described herein.
  • Antibodies specific for ADCY may be provided in a diagnostic kit that incorporates at least one of these procedures to quantitate ADCY expression.
  • the kit may contain other components, packaging, instructions, or other material to aid the quantitation of the protein and use of the kit.
  • Anti-ADCY antibodies as described herein can be obtained commercially or routinely made according to methods such as, but not limited to, inoculation of an appropriate animal with the polypeptide or an antigenic fragment, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or recombinant cells expressing nucleic acid encoding such anti- ADCY antibodies. Immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti- ADCY antibodies. Similarly, immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti-ADCY antibodies.
  • level of ADCY is analyzed at the mRNA level.
  • RT-PCR and a pair of specific primers may be used.
  • mRNA are prepared and analyzed according to well-established protocols.
  • reduced expression or activity level of ADCY in the subject is tissue or cell type specific.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level. In some embodiments, the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the subject of the forgoing methods is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a pediatric human.
  • the cardiovascular disorder is acute coronary syndrome (ACS), atherosclerosis, peripheral vascular disease, dyslipidemia, hyperbetalipoproteinemia, hypoalphalipoproteinemia, hypercholesterolemia, hypertriglyceridemia, familial- hypercholesterolemia, angina, ischemia, cardiac ischemia, stroke, myocardial infarction, reperfusion injury, angioplastic restenosis, hypertension, cardiovascular disease, coronary heart disease, coronary artery disease, hyperlipidemia, hyperlipidoproteinemia or a vascular complication of diabetes, obesity or endotoxemia.
  • ACS acute coronary syndrome
  • atherosclerosis peripheral vascular disease
  • dyslipidemia hyperbetalipoproteinemia, hypoalphalipoproteinemia
  • hypercholesterolemia hypertriglyceridemia
  • familial- hypercholesterolemia familial- hypercholesterolemia
  • angina ischemia
  • cardiac ischemia cardiac ischemia
  • stroke myocardial infarction
  • reperfusion injury angioplastic restenosis
  • the subject has acute coronary syndrome (ACS).
  • ACS acute coronary syndrome
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for treating or preventing a cardiovascular disorder, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, r
  • the invention further provides methods for treating or preventing a cardiovascular disorder, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2
  • the invention further provides methods for treating or preventing a cardiovascular disorder, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, r
  • the present invention further provides methods for reducing risk of a cardiovascular event, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the present invention further provides methods for reducing the risk of a cardiovascular event, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9. Methods to measure the expression or activity level of ADCY are disclosed herein.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the cardiovascular event is coronary heart disease, cardiac arrest, myocardial infarction, ischemic stroke, congestive heart failure, sudden cardiac death, cerebral infarction, syncope, transient ischemic attack, angina or coronary revascularization.
  • the cardiovascular event is an adverse cardiovascular event, e.g., coronary heart disease, death, cardiac arrest, myocardial infarction, ischemic stroke, angina or coronary revascularization.
  • the cardiac arrest is resuscitated cardiac arrest.
  • the myocardial infarction is non-fatal myocardial infarction.
  • the ischemic stroke is non-fatal ischemic stroke.
  • the angina is unstable angina.
  • the coronary revascularization is unanticipated coronary revascularization.
  • the subject has acute coronary syndrome (ACS).
  • ACS acute coronary syndrome
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for reducing risk of a cardiovascular event, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19- 4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA,
  • the invention further provides methods for reducing risk of a cardiovascular event, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19- 4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs
  • the invention further provides methods for reducing risk of a cardiovascular event, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19- 4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG,
  • the present invention provides methods for treating or preventing congestive heart failure, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the congestive heart failure is systolic heart failure.
  • the congestive heart failure is diastolic heart failure.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL- 17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'- monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-amino-7-(4- chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro- 5(6H)-quinazolinone; 2-amino-7-phen
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • Another aspect of the invention provides methods for treating or preventing congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • ADCY activity level of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays have been disclosed by Salomon et al., (1974) Analytical Biochemistry, 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron, 20:1199-1210.
  • expression level of ADCY is determined at protein expression level.
  • protein expression level of ADCY is analyzed using a specific antibody and a protein assay. Any suitable method or assay can be used to measure the level of ADCY protein expression in the biological sample of a subject. Numerous antibody-based detection formats are well known in the art, and include ELISA (enzyme linked immunosorbent assay), radioimmunoassays, immunoblots, Western blots, flow cytometry, immunofluorescence assays, immunoprecipitation, protein A assays, immunoelectrophoresis assays, and other related techniques.
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled.
  • Many means are known in the art for detecting binding in an immunoassay and are within the scope of the kits, assays and methods described herein.
  • Antibodies specific for ADCY may be provided in a diagnostic kit that incorporates at least one of these procedures to quantitate ADCY expression.
  • the kit may contain other components, packaging, instructions, or other material to aid the quantitation of the protein and use of the kit.
  • Anti-ADCY antibodies as described herein can be obtained commercially or routinely made according to methods such as, but not limited to, inoculation of an appropriate animal with the polypeptide or an antigenic fragment, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or recombinant cells expressing nucleic acid encoding such anti- ADCY antibodies. Immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti- ADCY antibodies. Similarly, immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti-ADCY antibodies.
  • level of ADCY is analyzed at the mRNA level.
  • RT-PCR and a pair of specific primers may be used.
  • mRNA are prepared and analyzed according to well-established protocols.
  • reduced expression or activity level of ADCY in the subject is tissue or cell type specific.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the subject of the forgoing methods is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a pediatric human.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for treating or preventing congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA,
  • the invention further provides methods for treating or preventing congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs
  • the invention further provides methods for treating or preventing congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG,
  • the present invention further provides methods for reducing risk of congestive heart failure, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the congestive heart failure is systolic heart failure.
  • the congestive heart failure is diastolic heart failure.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the present invention further provides methods for reducing the risk of congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the congestive heart failure is systolic heart failure. In certain embodiments, the congestive heart failure is diastolic heart failure.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9. Methods to measure the expression or activity level of ADCY are disclosed herein.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, r
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for reducing risk of congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA,
  • the invention further provides methods for reducing risk of congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, r
  • the invention further provides methods for reducing risk of congestive heart failure, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG,
  • the present invention provides methods for treating or preventing ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the ventricular systolic dysfunction is left ventricular systolic dysfunction.
  • the ventricular systolic dysfunction is right ventricular systolic dysfunction.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL- 17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'- monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-amino-7-(4- chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro- 5(6H)-quinazolinone; 2-amino-7-phen
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • Another aspect of the invention provides methods for treating or preventing ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the ventricular systolic dysfunction is left ventricular systolic dysfunction.
  • the ventricular systolic dysfunction is right ventricular systolic dysfunction.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • ADCY activity level of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays have been disclosed by Salomon et al., (1974) Analytical Biochemistry, 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron, 20:1199-1210.
  • expression level of ADCY is determined at protein expression level.
  • protein expression level of ADCY is analyzed using a specific antibody and a protein assay. Any suitable method or assay can be used to measure the level of ADCY protein expression in the biological sample of a subject. Numerous antibody-based detection formats are well known in the art, and include ELISA (enzyme linked immunosorbent assay), radioimmunoassays, immunoblots, Western blots, flow cytometry, immunofluorescence assays, immunoprecipitation, protein A assays, immunoelectrophoresis assays, and other related techniques.
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled.
  • Many means are known in the art for detecting binding in an immunoassay and are within the scope of the kits, assays and methods described herein.
  • Antibodies specific for ADCY may be provided in a diagnostic kit that incorporates at least one of these procedures to quantitate ADCY expression.
  • the kit may contain other components, packaging, instructions, or other material to aid the quantitation of the protein and use of the kit.
  • Anti-ADCY antibodies as described herein can be obtained commercially or routinely made according to methods such as, but not limited to, inoculation of an appropriate animal with the polypeptide or an antigenic fragment, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or recombinant cells expressing nucleic acid encoding such anti- ADCY antibodies. Immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti- ADCY antibodies. Similarly, immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti-ADCY antibodies.
  • level of ADCY is analyzed at the mRNA level.
  • RT-PCR and a pair of specific primers may be used.
  • mRNA are prepared and analyzed according to well-established protocols.
  • reduced expression or activity level of ADCY in the subject is tissue or cell type specific.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level. In some embodiments, the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the subject of the forgoing methods is a human.
  • the subject is an adult human.
  • the subject is a pediatric human.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for treating or preventing ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ- 28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs747023
  • the subject is known to have genotype rs1967309/AA.
  • the ventricular systolic dysfunction is left ventricular systolic dysfunction. In certain embodiments, the ventricular systolic dysfunction is right ventricular systolic dysfunction.
  • the invention further provides methods for treating or preventing ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ- 28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs806118
  • the subject is known to have genotype rs1967309/AG.
  • the ventricular systolic dysfunction is left ventricular systolic dysfunction. In certain embodiments, the ventricular systolic dysfunction is right ventricular systolic dysfunction.
  • the invention further provides methods for treating or preventing ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ- 28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs478645
  • the present invention further provides methods for reducing risk of ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the ventricular systolic dysfunction is left ventricular systolic dysfunction.
  • the ventricular systolic dysfunction is right ventricular systolic dysfunction.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the present invention further provides methods for reducing the risk of ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the ventricular systolic dysfunction is left ventricular systolic dysfunction.
  • the ventricular systolic dysfunction is right ventricular systolic dysfunction.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9. Methods to measure the expression or activity level of ADCY are disclosed herein.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for reducing risk of ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs7470
  • the subject is known to have genotype rs1967309/AA.
  • the ventricular systolic dysfunction is left ventricular systolic dysfunction. In certain embodiments, the ventricular systolic dysfunction is right ventricular systolic dysfunction.
  • the invention further provides methods for reducing risk of ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/
  • the subject is known to have genotype rs1967309/AG.
  • the ventricular systolic dysfunction is left ventricular systolic dysfunction. In certain embodiments, the ventricular systolic dysfunction is right ventricular systolic dysfunction.
  • the invention further provides methods for reducing risk of ventricular systolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786
  • the present invention provides methods for treating or preventing ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction.
  • the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL- 17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'- monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-amino-7-(4- chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro- 5(6H)-quinazolinone; 2-amino-7-phen
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • Another aspect of the invention provides methods for treating or preventing ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction.
  • the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • ADCY activity level of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays have been disclosed by Salomon et al., (1974) Analytical Biochemistry, 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron, 20:1199-1210.
  • expression level of ADCY is determined at protein expression level.
  • protein expression level of ADCY is analyzed using a specific antibody and a protein assay. Any suitable method or assay can be used to measure the level of ADCY protein expression in the biological sample of a subject. Numerous antibody-based detection formats are well known in the art, and include ELISA (enzyme linked immunosorbent assay), radioimmunoassays, immunoblots, Western blots, flow cytometry, immunofluorescence assays, immunoprecipitation, protein A assays, immunoelectrophoresis assays, and other related techniques.
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled.
  • Many means are known in the art for detecting binding in an immunoassay and are within the scope of the kits, assays and methods described herein.
  • Antibodies specific for ADCY may be provided in a diagnostic kit that incorporates at least one of these procedures to quantitate ADCY expression.
  • the kit may contain other components, packaging, instructions, or other material to aid the quantitation of the protein and use of the kit.
  • Anti-ADCY antibodies as described herein can be obtained commercially or routinely made according to methods such as, but not limited to, inoculation of an appropriate animal with the polypeptide or an antigenic fragment, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or recombinant cells expressing nucleic acid encoding such anti- ADCY antibodies. Immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti- ADCY antibodies. Similarly, immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti-ADCY antibodies.
  • level of ADCY is analyzed at the mRNA level.
  • RT-PCR and a pair of specific primers may be used.
  • mRNA are prepared and analyzed according to well-established protocols.
  • reduced expression or activity level of ADCY in the subject is tissue or cell type specific.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level. In some embodiments, the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the subject of the forgoing methods is a human.
  • the subject is an adult human.
  • the subject is a pediatric human.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for treating or preventing ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385
  • the subject is known to have genotype rs1967309/AA.
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction. In certain embodiments, the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • the invention further provides methods for treating or preventing ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG
  • the subject is known to have genotype rs1967309/AG.
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction. In certain embodiments, the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • the invention further provides methods for treating or preventing ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454
  • the present invention further provides methods for reducing risk of ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction.
  • the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the present invention further provides methods for reducing the risk of ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction.
  • the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9. Methods to measure the expression or activity level of ADCY are disclosed herein.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for reducing risk of ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs747023
  • the subject is known to have genotype rs1967309/AA.
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction. In certain embodiments, the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • the invention further provides methods for reducing risk of ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/
  • the subject is known to have genotype rs1967309/AG.
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction. In certain embodiments, the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • the invention further provides methods for reducing risk of ventricular diastolic dysfunction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs478645
  • the ventricular diastolic dysfunction is left ventricular diastolic dysfunction. In certain embodiments, the ventricular diastolic dysfunction is right ventricular diastolic dysfunction.
  • the present invention provides methods for treating or preventing heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL- 17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is 9-(tetrahydro-2-furanyl)-adenine); 2',5'-dideoxyadenosine; 9-cyclopentyladenine; 2',5'-dideoxyadenosine 3'-diphosphate; 2',5'-dideoxyadenosine 3'- monophosphate; cis-N-(2-phenylcyclopentyl)azacyclotridece-1-en-2-amine); 2-amino-7-(4- chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone; 2-amino-7-(4-methoxyphenyl)-7,8-dihydro- 5(6H)-quinazolinone; 2-amino-7-
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • Another aspect of the invention provides methods for treating or preventing heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • ADCY activity level of ADCY can be detected using techniques known in the art. For example, adenylate cyclase assays have been disclosed by Salomon et al., (1974) Analytical Biochemistry, 58(2): 541-548; Wiegn et al., (1993) Anal Biochem. 208(2):217-22; and Storm et al., (1998) Neuron, 20:1199-1210.
  • expression level of ADCY is determined at protein expression level.
  • protein expression level of ADCY is analyzed using a specific antibody and a protein assay. Any suitable method or assay can be used to measure the level of ADCY protein expression in the biological sample of a subject. Numerous antibody-based detection formats are well known in the art, and include ELISA (enzyme linked immunosorbent assay), radioimmunoassays, immunoblots, Western blots, flow cytometry, immunofluorescence assays, immunoprecipitation, protein A assays, immunoelectrophoresis assays, and other related techniques.
  • antibody binding is detected by detecting a label on the primary antibody.
  • the primary antibody is detected by detecting binding of a secondary antibody or reagent to the primary antibody.
  • the secondary antibody is labeled.
  • Many means are known in the art for detecting binding in an immunoassay and are within the scope of the kits, assays and methods described herein.
  • Antibodies specific for ADCY may be provided in a diagnostic kit that incorporates at least one of these procedures to quantitate ADCY expression.
  • the kit may contain other components, packaging, instructions, or other material to aid the quantitation of the protein and use of the kit.
  • Anti-ADCY antibodies as described herein can be obtained commercially or routinely made according to methods such as, but not limited to, inoculation of an appropriate animal with the polypeptide or an antigenic fragment, in vitro stimulation of lymphocyte populations, synthetic methods, hybridomas, and/or recombinant cells expressing nucleic acid encoding such anti- ADCY antibodies. Immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti- ADCY antibodies. Similarly, immunization of an animal using purified recombinant ADCY or peptide fragments thereof, is an example of a method of preparing anti-ADCY antibodies.
  • level of ADCY is analyzed at the mRNA level.
  • RT-PCR and a pair of specific primers may be used.
  • mRNA are prepared and analyzed according to well-established protocols.
  • reduced expression or activity level of ADCY in the subject is tissue or cell type specific.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9.
  • the subject is known to have reduced expression or activity level of ADCY in the subject’s central nervous system compared to a control level. In some embodiments, the subject is known to have reduced expression or activity level of ADCY in the subject’s hypothalamus compared to a control level.
  • the subject of the forgoing methods is a human. In some embodiments, the subject is an adult human. In some embodiments, the subject is a pediatric human. [00313] In certain embodiments, the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT,
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG.
  • the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for treating or preventing heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385
  • the invention further provides methods for treating or preventing heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG,
  • the invention further provides methods for treating or preventing heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454
  • the present invention further provides methods for reducing risk of heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of: a) a CETP inhibitor; and b) an ADCY inhibitor.
  • administering the CETP inhibitor occurs before, concurrently with, or after administering the ADCY inhibitor.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the present invention further provides methods for reducing the risk of heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the subject is known to have reduced expression or activity level of ADCY compared to a control level, wherein the reduced expression or activity level of ADCY is indicative that the subject would benefit from administration of the CETP inhibitor.
  • control level is an expression or activity level of ADCY established based on the expression or activity level of ADCY of subjects who do not respond positively to treatment of a CETP inhibitor in the absence of an ADCY inhibitor.
  • reduced expression or activity level of ADCY in the subject compared to a control level is caused by one or more polymorphisms or mutations in the ADCY gene of the subject.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10.
  • the ADCY is ADCY9. Methods to measure the expression or activity level of ADCY are disclosed herein.
  • the ADCY is ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, or ADCY10
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH- 03, DRL-17822, JNJ-28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY is ADCY9, and wherein the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the CETP inhibitor is BMS795311, CP-800,569, JNJ-28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)-adenine), 2 ⁇ ,5 ⁇ - dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ - dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the ADCY inhibitor is adrenocorticotropic hormone; brain natriuretic peptide (BNP); or pituitary adenylate cyclase-activating polypeptide.
  • the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs74702385/GA, rs74702385/AA, rs8049452/GG, rs8061182/AA, rs2238448/TT, rs12920508/GG, rs2531971/AA, or rs12599911/GG.
  • the subject is known to have genotype rs1967309/AA.
  • the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/AG, rs2238448/TC, rs12920508/CG, rs2531971/AC, or rs12599911/GT.
  • the subject is known to have genotype rs1967309/AG. [00334] In certain embodiments, the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs4786454/GG, rs74702385/GG, rs8049452/AA, rs8061182/GG, rs2238448/CC, rs12920508/CC, rs2531971/CC, or rs12599911/TT.
  • the invention further provides methods for reducing risk of heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ- 28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CC, rs12595857/GG, rs1967309/AA, rs111590482/AG, rs111590482/GG, rs11647828/GG, rs12935810/GG, rs17136707/GG, rs2239310/GG, rs2283497/AA, rs2531967/AA, rs3730119/AA, rs4786454/AA, rs747023
  • the invention further provides methods for reducing risk of heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ- 28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/CG, rs12595857/AG, rs13337675/AG, rs13337675/GG, rs1967309/AG, rs11647828/AG, rs17136707/AG, rs2239310/AG, rs2283497/CA, rs2531967/GA, rs3730119/GA, rs4786454/GA, rs8049452/GA, rs8061182/
  • the invention further provides methods for reducing risk of heart failure with preserved ejection fraction, comprising administering to a subject in need thereof an effective amount of a CETP inhibitor, wherein the CEPT inhibitor is BMS795311, CP-800,569, JNJ- 28545595, JNJ-28614872, BAY 19-4789, or BAY 38-1315, or a pharmaceutically acceptable salt of any of the foregoing and wherein the subject is known to have genotype rs11647778/GG, rs12595857/AA, rs13337675/AA, rs1967309/GG, rs111590482/AA, rs11647828/AA, rs12935810/GA, rs12935810/AA, rs17136707/AA, rs2239310/AA, rs2283497/CC, rs2531967/GG, rs3730119/GG, rs478645
  • the dosage of the CETP inhibitors and ADCY inhibitors of the methods and compositions of the invention can be selected in accordance with a variety of factors including type, species, age, weight, sex and medical condition of the subject; the severity of the disorder to be treated or prevented; the severity of the cardiovascular event; the route of administration; the renal or hepatic function of the subject; or the CETP or ADCY inhibitor to be administered.
  • the daily dosage amount of CETP inhibitor useful in the methods and compositions of the present invention ranges from about 1 mg to about 1000 mg.
  • the daily dosage amount of ADCY inhibitor useful in the methods and compositions of the present invention ranges from about 1 mg to about 1000 mg.
  • the CETP inhibitor is dalcetrapib or a pharmaceutically acceptable salt thereof, wherein dalcetrapib or pharmaceutically acceptable salt thereof is administered orally at a dose of about 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, or 1000 mg daily.
  • the CETP inhibitor is torcetrapib or a pharmaceutically acceptable salt thereof, wherein torcetrapib or pharmaceutically acceptable salt thereof is administered orally at a dose of about 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg daily.
  • the CETP inhibitor is anacetrapib or a pharmaceutically acceptable salt thereof, wherein anacetrapib or pharmaceutically acceptable salt thereof is administered orally at a dose of about 40 mg, 60 mg, 80 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, or 200 mg daily.
  • the CETP inhibitor is evacetrapib a pharmaceutically acceptable salt thereof, wherein evacetrapib or pharmaceutically acceptable salt thereof is administered orally at a dose of about 30 mg, 60 mg, 90 mg, 100 mg, 120 mg, 140 mg, 160 mg, 180 mg, 200 mg, 250 mg, 300 mg, 350 mg, 400 mg, 450 mg, 500 mg, 550 mg, or 600 mg daily.
  • the CETP inhibitor is BAY 60-5521 or a pharmaceutically acceptable salt thereof, wherein BAY 60-5521 or pharmaceutically acceptable salt thereof is administered orally at a dose of about 5 mg, 12.5 mg, 25 mg, 30mg, 40mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, or 100 mg daily.
  • the subject of the forgoing methods is a human.
  • the subject is an adult human.
  • the subject is a pediatric human.
  • compositions comprising a) an effective amount of a CETP inhibitor and an ADCY inhibitor; and b) a pharmaceutically acceptable carrier or vehicle.
  • the CETP inhibitor is dalcetrapib, torcetrapib, anacetrapib, evacetrapib, obicetrapib, BMS795311, CP-800,569, DLBS-1449, ATH-03, DRL-17822, JNJ- 28545595, JNJ-28614872, BAY 19-4789, BAY 38-1315, or BAY 60-5521, or a pharmaceutically acceptable salt of any of the foregoing.
  • the ADCY inhibitor is an ADCY1, ADCY2, ADCY3, ADCY4, ADCY5, ADCY6, ADCY7, ADCY8, ADCY9 or ADCY10 inhibitor.
  • the ADCY inhibitor is SQ22536 (9-(tetrahydro-2-furanyl)- adenine), 2 ⁇ ,5 ⁇ -dideoxyadenosine, 9-cyclopentyladenine, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -diphosphate, 2 ⁇ ,5 ⁇ -dideoxyadenosine 3 ⁇ -monophosphate, MDL-12330A (cis-N-(2- phenylcyclopentyl)azacyclotridece-1-en-2-amine), compounds such as 7,8-dihydro-5(6H)- quinazolinone derivatives disclosed in JP Patent Application No.
  • 2001-153954 (preferably, 2- amino-7-(4-chlorophenyl)-7,8-dihydro-5 (6H)-quinazolinone, 2-amino-7-(4-methoxyphenyl)-7,8- dihydro-5(6H)-quinazolinone, 2-amino-7-phenyl-7,8-dihydro-5(6H)-quinazolinone, 4.2-amino-7- (2-furanyl)-7,8-dihydro-5(6H)-quinazolinone, and 2-amino-7-(2-thienyl)-7,8-dihydro-5(6H)- quinazolinone), MANT-ATP; MANT-ITP; MANT-GTP; MANT-XTP; MANT-CTP; MANT- UTP; 2’-MANT-3’dATP; 3’-MANT-2’dATP; MANT-ATPgS; MANT-ITPgS; MANT-GTPgS
  • the pharmaceutical acceptable carrier or vehicle can be liquids, such as water and oils, including those of petroleum, animal, vegetable, or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the pharmaceutical excipients can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea and the like.
  • auxiliary, stabilizing, thickening, lubricating, and coloring agents can be used.
  • the pharmaceutically acceptable excipients are sterile when administered to a subject. Water is a useful excipient when the CETP inhibitor or ADCY inhibitor is administered intravenously.
  • Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid excipients, specifically for injectable solutions.
  • suitable pharmaceutical excipients also include starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also comprise minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g., those targeted for buccal, sublingual, and systemic absorption, boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration, for example, by subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained release formulation; (3) topical application, for example, as a cream, ointment, or a controlled release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) transdermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets, e.g.
  • compositions of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the compositions may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred percent, this amount will range from about 0.1 percent to about ninety-nine percent of active ingredient, e.g., from about 5 percent to about 70 percent, or from about 10 percent to about 30 percent.
  • a composition of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a CETP inhibitor or ADCY inhibitor.
  • an aforementioned composition renders orally bioavailable a CETP inhibitor or ADCY inhibitor.
  • compositions or compositions include the step of bringing into association a CETP inhibitor or ADCY inhibitor with the carrier and, optionally, one or more accessory ingredients.
  • the compositions are prepared by uniformly and intimately bringing into association a CETP inhibitor or ADCY inhibitor with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • compositions of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a CETP inhibitor or ADCY inhibitor as an active ingredient.
  • a CETP inhibitor or ADCY inhibitor may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants,
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface-active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the CETP inhibitor or ADCY inhibitor include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubil
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • compositions of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by admixing one or both of the CETP inhibitor and ADCY inhibitor with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • compositions of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray compositions containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically- acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a CETP inhibitor or ADCY inhibitor to a subject.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • compositions of this invention suitable for parenteral administration can comprise a CETP inhibitor, an ADCY inhibitor and one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the composition isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable compositions are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • biodegradable polymers such as polylactide-polyglycolide.
  • Depot injectable compositions are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • CETP inhibitor or ADCY inhibitor When administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be administered orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • phrases“parenteral administration” and“administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal and intrasternal injection and infusion.
  • phrases“systemic administration,”“administered systemically,”“peripheral administration” and“administered peripherally” as used herein mean the administration of a compound, drug or other material other than directly into the central nervous system, such that it enters the patient’s system and, thus, is subject to metabolism and other like processes, for example, subcutaneous administration.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracisternally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the CETP inhibitor or ADCY inhibitor which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • compositions of this invention may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular CETP inhibitor or ADCY inhibitor employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian can readily determine and prescribe the effective amount of the pharmaceutical composition.
  • the physician or veterinarian could start doses of the CETP inhibitor or ADCY inhibitor employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a CETP inhibitor or an ADCY inhibitor is that amount of the CETP inhibitor or ADCY inhibitor which is the lowest dose effective to produce a therapeutic effect. Such an effective dose will generally depend upon the factors described above.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms, e.g., one administration per day.
  • kits useful for treating or preventing a cardiovascular disorder or reducing risk of a cardiovascular event as described herein.
  • the kits comprise a CETP inhibitor or an ADCY inhibitor and instructions for its use.
  • each of the CETP inhibitor and ADCY inhibitor is present in a separate composition.
  • the CETP inhibitor and ADCY inhibitor are present in the same composition.
  • the invention also provides a CETP inhibitor and an ADCY inhibitor as described herein and compositions comprising an effective amount of a CETP inhibitor and an ADCY inhibitor as described herein for use in the methods described herein. Examples
  • Adyc9 gene-trapped mice were generated initially from Lexicon Pharmaceuticals (Zambrowicz et al., Proc Natl Acad Sci U S A. (2003)100:14109-14). Cryo- preserved sperm from the B6;129S5-Adcy9 Gt(neo)159Lex /Mmucd strain was imported from the Mutant Mouse Regional Resource Center (MMRRC) and used for in vitro fertilization and oviduct transfer at the Institute for Research in Immunology and Cancer (IRIC) animal facility in a specific-pathogen-free area and their breeding and reproduction was approved by the University de Quebec Deontology Committee on Animal Experimentation.
  • MMRRC Mutant Mouse Regional Resource Center
  • MaxBax accelerated backcrossing and genotyping was performed to achieve >98.6% C57BL/6J genetic background. Procedures involving mice were performed at the Montreal Heart Institute (MHI) Research Center and approved by the local ethics committee for animal research in accordance with the Canadian Council on Animal Care guidelines. Adcy9 Gt/Gt mice were bred by mating Adcy9 WT/Gt animals. Mice hemizygous for transgenic human CETP minigene (CETP WT ) were obtained from Jackson laboratory (Bar Harbor, ME) and were on 100% C57BL/6J genetic background.
  • MHI Montreal Heart Institute
  • CETP WT transgenic human CETP minigene
  • CETP WT mice were first crossed with Adcy9 WT/Gt animals, then mice transgenic for CETP and heterozygote for Adcy9 WT/Gt were crossed with Adcy9 Gt/Gt or Adcy9 WT/Gt animals. All mice were under a C57BL/6J background, males and aged from 8 to 12 weeks. Blood collection was performed after 4 hours of fasting.
  • Example 2 Atherosclerosis model
  • Wild-type (WT) and Adcy9 Gt/Gt male mice (8 to 12-week-old) were injected with a single dose of an AAV8 viral vector expressing gain-of-function Pcsk9 D377Y (AAV8-Pcsk9 D377Y , 6.5x10 11 gene copies) as previously described.
  • a control group was injected with a saline solution in preliminary experiments to confirm the effect of the AAV8-Pcsk9 D377Y infection on LDL receptor expression.
  • mice were fed for 16 weeks with a chow- based (Purina 5015) atherogenic diet (TD, 150545, Envigo, Madison, WI) enriched with 0.75% cholesterol and having the following caloric composition: proteins 20.4%, carbohydrates 42.7% and fats 36.9% (3.9 kcal/g). Food and water were available ad libitum.
  • atherosclerosis development was investigated in the whole aorta, aortic root and brachiocephalic artery by an experienced observer blinded to the mouse genotype.
  • Adcy9 inactivation protects against atherosclerosis
  • RNA quantification and quality were assessed using Agilent RNA 6000 Nano Kit for Bioanalyzer 2100 System (Agilent Technologies, Santa Clara, CA).
  • Primers for Adcy9 were designed using the Beacon designer software v.8 (Premier Biosoft) and obtained from IDT (Coralville, IA). Gapdh was used as the reference gene for normalization.
  • the quantitative PCR (qPCR) was performed with SYBR-Green reaction mix (BioRad, Hercules, CA). The qPCR conditions consisted of an initial denaturation at 95°C for 3 minutes followed with 40 cycles of amplification, each cycle consisting of 95°C for 10 seconds and 60°C for 30 seconds.
  • Adcy9 Gt modified target locus The effect of the Adcy9 Gt modified target locus on Adcy9 expression in Adcy9 Gt/Gt mice was characterized. Using RT-qPCR, it was demonstrated that Adcy9 mRNA expression in the heart was decreased by 50% in Adcy9 WT/Gt mice and by at least 90% in Adcy9 Gt/Gt mice compared to WT (FIG.1A). In the skeletal muscle, where the ADCY9 gene has been reported to be highly expressed, it was observed that protein expression was abolished in Adcy9 Gt/Gt mice compared to WT (FIG.1E).
  • Atherosclerosis lesions were quantified on whole aorta dissected en face. Aortas were fixed in 4% paraformaldehyde (PFA) overnight and then stained with a 0.7% solution of Oil Red O (Sigma-Aldrich) for 1 hour and then counterstained with Nuclear Fast Green at 0.05% (Sigma-Aldrich, F7258) to optimize contrast. Images were captured using a Leica Microsystem (Concord, ON, Canada) stereomicroscope with digital camera (MC170 HD, Leica Microsystem). Atherosclerotic lesions were quantified from the aortic root down to the iliac artery bifurcation using Image-Pro Premier 9.2 (Media Cybernetics, Inc, Rockville, MD). Percent atherosclerotic lesion area was expressed as the percentage of the intima area presenting Oil Red O staining.
  • Atherosclerotic lesion cross-sectional quantification in the aortic root [00397] The base of the heart was embedded in OCT compound and sliced in 10 ⁇ m sections before fixation with 10% cold formalin for five minutes and then rinsed twice with deionized water. Slides were immersed twice in 100% propylene glycol for five minutes. Aortic roots were stained with a 0.7% Oil Red O solution for 48 hours at room temperature. Afterwards, slides were successively immersed in 100% propylene glycol, 85% propylene glycol solution and deionized water baths, using agitation. Slides were counterstained with a hematoxylin solution for a few seconds, rinsed and then mounted using an aqueous medium. Atherosclerosis lesions were quantified at regular distances from the base of the aortic sinuses to 500 ⁇ m more distally in the aortic root. Images were obtained by microscope and quantified by Image-Pro Premier 9.2.
  • aortas showed 11.3 ⁇ 2.1% of the surface of the intima covered with atherosclerotic lesions in WT mice compared to 3.8 ⁇ 0.6% in Adcy9 Gt/Gt mice (P ⁇ 0.01, FIG. 3A and FIG.3D), a reduction of 65%.
  • Brachiocephalic arteries are the site in mice where plaques are more complex and prone to rupture (Rosenfeld et al., Arterioscler Thromb Vasc Biol.
  • FIG.3C shows that all WT animals had plaques in the brachiocephalic arteries in contrast to Adcy9 Gt/Gt mice (100%, versus 50%, P ⁇ 0.05). The plaques in WT mice were also larger and presented more frequently fibrin deposits at their surface (P ⁇ 0.05) and cap ruptures compared to Adcy9 Gt/Gt mice (FIG.3F).
  • Adcy9 inactivation reduces CD68-positive macrophage (foam cell) accumulation and their proliferation in atherosclerotic lesions
  • the base of the heart was embedded in OCT compound and 10 ⁇ m sections were cut with a cryostat. Slides were incubated in PBS to remove the OCT and then immersed in 4% PFA (pH 7.4) for 20 minutes. After fixation, slides were washed in PBS. Permeabilization, blocking and antibody incubation were performed in a Tris solution (in mM): Tris-base 50, NaCl 150, BSA 1%, Triton X-100 0.4% and fetal bovine serum 20% at pH 7.4. Rat antibody against CD68 was diluted 1/200 (BioRad, #MCA19557) and rabbit antibody against Ki67 was used at 1 ⁇ g/mL (Abcam, #ab15580).
  • CD68 was visualized using goat anti-rat antibody labeled with Alexa-647 (Thermo Fisher Scientific, # cat A-21247).
  • Ki67 was visualized with a goat anti-rabbit antibody labeled with Alexa-647 (Thermo Fisher Scientific, #A- 27040).
  • the nuclei were counterstained with DAPI. Images were acquired with a confocal microscope (LSM 710, Zeiss, Peabody, CA).
  • CD68-positive foam cells a key constituent of atherosclerotic plaques, represented 19.0 ⁇ 1.9% and 11.4 ⁇ 2.1% of the lesion area in WT and Adcy9 Gt/Gt mice, respectively (P ⁇ 0.05, FIG.4A).
  • In situ hybridization showed Adcy9 expression in atherosclerotic lesions at sites of foam cell accumulation (FIG. 4B). In situ hybridization was performed according to the manufacturer’s recommended procedure (Advanced Cell diagnostic, Hayward, CA). Staining was performed on 6 ⁇ m-thick sections of paraffin-embedded femoral artery or aortic root. Sections were counterstained with hematoxylin. It was observed that the signal for Adcy9 was specific by comparing tissue sections from Adcy9 Gt/Gt and WT mice (data not shown). Adcy9 probe was Mm- Adcy9 targeting nucleotides 1522-2502 of NM_009624.3. Probe for the bacterial gene dapB was used as a negative control.
  • Endothelial-dependent vasodilatation to ACh in untreated animals was potentiated in the femoral arteries of Adcy9 Gt/Gt mice compared to WT (P ⁇ 0.01, FIG.5A); in contrast, endothelial-independent vasodilation to the nitric oxide donor SNP was similar in both groups (FIG. 5E).
  • Adcy9 Gt/Gt mice are systemically inactivated for Adcy9 making it difficult to identify its role in vascular tissue that could be associated with the observed potentiated endothelial function. Therefore, Adcy9 mRNA expression was studied by in situ hybridization on histological sections and was demonstrated in the femoral artery wall. Specificity of the Adcy9 mRNA signal was confirmed by absence of dots with the negative control probe (FIG.6C).
  • Example 6 Adcy9 inactivation increases body weight and adipose tissue volume
  • Body weight was measured every week from the week of infection with AAV8- Pcsk9 D377Y and for a total of 16 weeks.
  • Feed efficiency the ratio of the weight gain to the caloric intake (g/100kcal), was calculated for a total of 8 weeks during the atherogenic diet.
  • Adcy9 Gt/Gt mice gained more weight than WT animals during the 16 weeks of atherogenic diet, to reach weights of 45.1 ⁇ 2.4 g and 33.5 ⁇ 1.2 g respectively (P ⁇ 0.01, FIG. 7A).
  • MRI performed at week 14 showed that Adcy9 Gt/Gt mice presented more adipose tissue than WT (FIG.7B), with a doubling of total body adipose tissue volume in Adcy9 Gt/Gt mice (9.4 ⁇ 1.2 cm 3 ) compared to WT (4.3 ⁇ 0.4 cm 3 , P ⁇ 0.01, FIG. 7C). This increase was confirmed by the larger inguinal, perirenal, epididymal and interscapular fat depots (FIG. 7D).
  • Adcy9 inactivation resulted in hypertrophic adipocytes in epididymal white adipose tissue and larger lipid droplets in interscapular brown adipose tissue (FIG. 7E and FIG. 7F).
  • No significant change in blood glucose or insulin concentrations was observed in response to the atherogenic diet and increased fat deposits, suggesting that the weight gain in response to Adcy9 inactivation does not modify insulin sensitivity (data not shown).
  • Example 7 Adcy9 inactivation modulates autonomic nervous system activity
  • feed efficiency defined as the ratio of weight gain over energy intake was evaluated over the same period of time.
  • Adcy9 Gt/Gt mice showed a significant increase in feed efficiency (1.2 ⁇ 0.1 g/100 kCal) compared to WT (0.6 ⁇ 0.1 g/100 kCal, P ⁇ 0.01, FIG. 8A). This indicates that the control of energetic balance, which is dependent on the autonomic nervous system, is modified by Adcy9 inactivation. Therefore, autonomic nervous system activity was evaluated by measuring heart rate variability by telemetry in WT and Adcy9 Gt/Gt mice.
  • pNN(6) which represents the percentage of RR intervals exceeding preceding ones by 6 ms or more and reflects parasympathetic nervous system activity 17 , was increased during the night period in Adcy9 Gt/Gt mice (21.6 ⁇ 2.4%) compared to WT (14.5 ⁇ 2.2%, P ⁇ 0.05, FIG.8C).
  • Example 8 Adcy9 inactivation-induced atheroprotection is lost in mice expressing CETP.
  • transgenic mice for the human CETP minigene CETP WT
  • Adcy9 Gt/Gt mice to obtain animals with CETP and inactivated for Adcy9 (CETP Gt ).
  • Both types of mice CETP WT and CETP Gt ) were then subjected to the previously described atherogenic protocol (involving AAV8- Pcsk9 D377Y injection and atherogenic diet).
  • FIG.9B compares percentage of lesion area in the whole aorta in WT, Adcy9 Gt/Gt , CETP WT and CETP Gt to emphasize the absence of atheroprotection in CETP Gt mice compared to Adcy9 Gt/Gt mice (P ⁇ 0.05). These results indicate that Adcy9 does not significantly affect atherosclerosis development in presence of CETP.
  • Example 9 Adcy9 inactivation-induced endothelial function protection is lost in mice expressing CETP
  • Adcy9 inactivation-induced gains in body weight and adipose tissue volume are lost in mice expressing CETP.
  • Anesthesia was maintained with 2.0-3.0% isoflurane in pure oxygen to target a respiration rate between 80 and 120 BPM while heart rate and oxygen saturation were monitored with a pulse oximeter on the right hindpaw and body temperature was maintained at 37.0°C with a rectal probe and a warm air fan (SA Instruments, Stony Brook, NY).
  • Mouse fat was manually quantified using ITK- SNAP (Yushkevich et al., Neuroimage. (2006) 31:1116-28).
  • Example 11 Mice model of myocardial infarction
  • mice have four different genotypes: WT (wild-type mice); Adcy9 Gt / Gt (Adyc9 gene-trapped mice); tgCETP +/- (transgenic mice carrying a copy of CETP gene); and Adcy9 Gt / Gt - tgCETP +/- (Adyc9 gene-trapped mice carrying a copy of CETP gene) (FIG.12A). All mice were in C57BL/6J genetic background.
  • FIG. 12C depicts the surgical timeline of a mouse infarction model by ligating the LAD. Echocardiography (“Echo”) was performed at baseline, at 24 hours, at 1 week, and before 4 weeks postoperatively. The mice were 10 ⁇ 3 week-old at D0 in the timeline.
  • Echo Echocardiography
  • mice with the four genotypes WT (wild-type mice); Adcy9 Gt / Gt (Adyc9 gene-trapped mice); tgCETP +/- (transgenic mice carrying a copy of CETP gene); and Adcy9 Gt / Gt - tgCETP +/- (Adyc9 gene-trapped mice carrying a copy of CETP gene).
  • WT wild-type mice
  • Adcy9 Gt / Gt Adyc9 gene-trapped mice
  • tgCETP +/- transgenic mice carrying a copy of CETP gene
  • Adcy9 Gt / Gt - tgCETP +/- Adcy9 gene-trapped mice carrying a copy of CETP gene
  • Example 13 Wall motion score index (WMSI) analysis
  • WMSI Echocardiographic wall motion score index
  • MI myocardial-infarction-induced mice
  • WT four genotypes
  • Adcy9 Gt / Gt MI mice had a lower WMSI comparing to the mice with the other genotypes. See FIG.14A (all mice) and FIG. 14B (alive mice only).
  • WMSI correlated with serum cardiac troponin ⁇ I (cTn-I) at 24 hours (FIG. 15).
  • FIG. 16A shows The reduced WMSI for Adcy9 Gt/Gt mice observed at 24 hours post-LAD-ligation over-time as shown in FIG. 16A.
  • FIG. 19C Adcy9 Gt / Gt MI mice had a lower WMSI compared to the mice with the other genotypes.
  • FIG.16B shows a two-way repeated ANOVA analysis for myocardial-infarction-induced (“MI”) mice with the four genotypes (WT, Adcy9 Gt / Gt , tgCETP +/- , Adcy9 Gt / Gt - tgCETP +/- ) (p ⁇ 0.001).
  • Adcy9 Gt/Gt mice were significantly lower than the infarct sizes in the wild-type and tgCETP +/- mice.
  • the infarct-size-reduction in Adcy9 Gt/Gt mice was less pronounced in Adcy9 Gt / Gt - tgCETP +/- mice (FIG.19A and FIG.19B).

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Abstract

L'invention concerne des compositions et des méthodes utiles pour traiter ou prévenir une insuffisance cardiaque congestive, une insuffisance systolique ventriculaire, une insuffisance diastolique ventriculaire ou une insuffisance cardiaque à fraction d'éjection préservée, et pour réduire le risque d'insuffisance cardiaque congestive, d'insuffisance systolique ventriculaire, d'insuffisance diastolique ventriculaire ou d'insuffisance cardiaque à fraction d'éjection préservée.
PCT/EP2020/056102 2019-03-07 2020-03-06 Méthodes de traitement ou de prévention de l'insuffisance cardiaque et de réduction du risque d'insuffisance cardiaque WO2020178443A1 (fr)

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BR112021014677-6A BR112021014677A2 (pt) 2019-03-07 2020-03-06 Métodos para tratar ou prevenir a insuficiência cardíaca e reduzir o risco de insuficiência cardíaca
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