WO2008137803A1 - Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase a2 (spla2) inhibitors and spla2 inhibitor combination therapies - Google Patents

Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase a2 (spla2) inhibitors and spla2 inhibitor combination therapies Download PDF

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Publication number
WO2008137803A1
WO2008137803A1 PCT/US2008/062577 US2008062577W WO2008137803A1 WO 2008137803 A1 WO2008137803 A1 WO 2008137803A1 US 2008062577 W US2008062577 W US 2008062577W WO 2008137803 A1 WO2008137803 A1 WO 2008137803A1
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Prior art keywords
inhibitors
spla
administration
plus
cvd
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PCT/US2008/062577
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French (fr)
Inventor
Joaquim Trias
Colin Hislop
Paul Truex
Heather Fraser
Debra Odink
Scott Chadwick
Kenneth Gould
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Anthera Pharmaceuticals, Inc.
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Priority to EP08747605A priority Critical patent/EP2154958A4/en
Priority to BRPI0811486-2A2A priority patent/BRPI0811486A2/en
Priority to CN200880023061A priority patent/CN101742907A/en
Priority to JP2010507578A priority patent/JP2010526152A/en
Priority to EA200971020A priority patent/EA200971020A1/en
Priority to MX2009011925A priority patent/MX2009011925A/en
Priority to AU2008247451A priority patent/AU2008247451A1/en
Priority to CA002686157A priority patent/CA2686157A1/en
Publication of WO2008137803A1 publication Critical patent/WO2008137803A1/en
Priority to IL201897A priority patent/IL201897A0/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • 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
    • 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

Definitions

  • CVD cardiovascular disease
  • CHD coronary heart disease
  • CAD coronary artery disease
  • a variety of therapeutic options are currently employed in the treatment of CVD and conditions associated with CVD Many of these therapeutic options function by lowering cholesterol levels, particularly LDL levels
  • statins a class of compounds that inhibit cholesterol biosynthesis and prevent the build-up of arterial plaque Statin administration has been shown to lower LDL and triglyceride levels and to substantially reduce coronary events and death from CVD
  • statin therapy alone is insufficient to completely treat CVD Therefore, there is a need in the art for more effective methods of treating CVD and conditions associated with CVD SUMMARY
  • methods are provided for treating dyshpidemia in a subject in need thereof by administering a therapeutically effective amount of one or more sPLA 2 inhibitors
  • the one or more sPLA 2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01
  • the one or more SPLA 2 inhibitors comprise A-002 a prodrug of A-O01
  • administration of one or more SPLA 2 inhibitors results in a decrease in cholesterol and/or triglyceride levels
  • administration of one or more SPLA 2 inhibitors results in a decrease in total cholesterol, non-HDL cholesterol LDL, LDL particle, small LDL particle, oxidized LDL, and/or ApoB levels
  • methods are provided for decreasing triglyceride levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA 2 inhibitors
  • the one or more SPtA 2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug salt, polymorph co-crystal, or solvate of A-O01
  • the one or more SPLA 2 inhibitors comprise A-002, a prodrug of A-O01
  • the one or more SPLA 2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more sPLA 2 inhibitors are administered twice per day
  • the one or more SPLA 2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA 2 inhibitors may be administered at a dosage of about
  • methods are provided for treating CVD or a condition associated with CVD in a subject in need thereof by administering a therapeutically effective amount of one or more sPLA 2 inhibitors
  • the one or more SPLA 2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug salt polymorph, co-crystal or solvate of A-O01
  • the one or more SPLA 2 inhibitors comprise A-002, a prodrug of A-O01
  • the one or more SPLA 2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA 2 inhibitors are administered twice per day
  • the one or more SPLA 2 inhibitors may be administered to the subject on a once a day basis
  • the one or more SPLA 2 inhibitors may be administered at a dosage of
  • methods are provided for treating metabolic syndrome in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA 2 inhibitors
  • the one or more SPLA 2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01
  • the one or more SPLA 2 inhibitors comprise A-002 a prodrug of A-O01
  • the one or more SPLA 2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA 2 inhibitors are administered twice per day
  • the one or more SPLA 2 inhibitors may be administered to the subject on a once a day basis
  • the one or more SPLA 2 inhibitors may be administered at a dosage of about 50 to about 500 mg
  • the one or more SPLA 2 inhibitors may be administered at a dosage of about 50 to about 500 mg
  • compositions comprising one or more SPLA 2 inhibitors and one or more compounds used in the treatment of CVD
  • the composition further comprises one or more pharmaceutically acceptable carriers
  • the one or more SPLA 2 inhibitors comprise A-001 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-001
  • the one or more sPLA 2 inhibitors comprise A-002, a prodrug of A-001
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs
  • the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin lovastatin pravastatin, cerivastatin, fluvastatin mevastatin, pravastatin and various salts, solvates, stereoisomers, and prodrug derivatives thereof In certain of these embodiments,
  • methods are provided for decreasing cholesterol levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA 2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD
  • the one or more sPLA 2 inhibitors comprise A-001 or a pharmaceutically acceptable prodrug, salt, polymorph co-crystal, or solvate of A-001
  • the one or more sPLA 2 inhibitors comprise A-002 a prodrug of A-001
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs
  • the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin lovastatin pravastatin cerivastatin, fluvastatin mevastatin, pravastatin, and various salts, solvates, stereoisomers, and prod
  • methods are provided for decreasing triglyceride levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA 2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01
  • the one or more sPLA 2 inhibitors comprise A-002, a prodrug of A-O01
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs
  • the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin fluvastatin, mevastatin, pravastatin, and various salts,
  • methods are provided for increasing HDL levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA 2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt polymorph, co-crystal or solvate of A-O01.
  • the one or more SPLA 2 inhibitors comprise A-002, a prodrug of A-O01
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs
  • the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin.
  • the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine atorvastatin plus CP-529414, atorvastatin plus AP A-01 , simvastatin plus ezetimibe simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fen ofib rate and statin plus TAK-457
  • the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (
  • methods are provided for treating metabolic syndrome in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA 2 inhibitors and one or more compounds used in the treatment of CVD
  • the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01
  • the one or more sPLA 2 inhibitors comprise A-002, a prodrug of A-O01
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs
  • the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, ce ⁇ vastatin, fluvastatin, mevastatin, pravastatin, and various salts solvates, stereoisomers, and prod
  • methods are provided for increasing the effectiveness of a compound used in the treatment of CVD in a subject by administering one or more SPLA 2 inhibitors to said subject
  • the one or more sPLA ? inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01
  • the one or more SPLA 2 inhibitors comprise A-002, a prodrug of A-O01
  • the compound used in the treatment of CVD may be a statin or statin combination drug
  • the statin may be selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin ce ⁇ vastatin, fluvastatin, mevastatin, pravastatin, and various salts, solvates, stereoisomers and prodrug derivatives thereof
  • the statin combination drug may be selected from the group consisting of atorvastatin, simvastatin, rosuvastatin,
  • the use of one or more SPLA 2 inhibitors for preparation of a medicament for treating dyslipidemia, treating CVD and conditions associated with CVD, lowering cholesterol levels lowering triglyceride levels, increasing HDL levels, and improving HDL/LDL ratios in a subject is provided
  • the one or more sPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01
  • the one or more sPLA 2 inhibitors comprise A-002, a prodrug of A-O01
  • the medicament further comprises one or more pharmaceutically acceptable carriers
  • the use of one or more SPLA 2 inhibitors and one or more compounds used in the treatment of CVD for preparation of a medicament for treating dyslipidemia, treating CVD and conditions associated with CVD lowering cholesterol levels lowering triglyceride levels, increasing HDL levels and/or improving HDL/LDL ratios in a subject is provided
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt polymorph, co-crystal, or solvate of A-O01
  • the one or more SPLA 2 inhibitors comprise A-002, a prodrug of A-O01
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments the one or more statins are selected from the group consisting of atorvastatin simvastatin rosuvastatin lovastatin, pravastatin cerivastatin, fluvastatin,
  • Figure 1 Effect of A-002 administration on body weight in mice ApoE ; mice were administered vehicle only 30 mg/kg A-002 or 90 mg/kg A- 002 twice daily over 16 weeks Body weight was measured once a week
  • Figure 2 Effect of A-002 administration on plasma total cholesterol levels in mice ApoE ' mice were administered vehicle only, 30 mg/kg A-002 or 90 mg/kg A-002 twice daily over 16 weeks Total plasma cholesterol levels were measured at 0 4 8 12 and 16 weeks
  • FIG. 3 Effect of A-002 administration on atherosclerotic plaque coverage in mice ApoE 7 mice were administered vehicle only, 30 mg/kg A- 002 or 90 mg/kg A-002 twice daily over 16 weeks At 16 weeks aortic plaque coverage was measured
  • FIG. 4 Effect of A-002 administration on angiotensin ll-mediated atherosclerotic plaque formation and aortic aneurysm
  • ApoE ' mice were administered saline plus water angiotensin Il in water vehicle, angiotensin Il in acacia vehicle or angiotensin Il in acacia vehicle plus 30 mg/kg A-002 At 4 weeks, aortic plaque coverage was measured
  • Figure 5 En face lesions in A-002 and/or statin dosage groups ApoE ' mice on a high fat diet were administered various dosages of A-002 statin, or A-002 plus statin over twelve weeks and en face lesion content was measured using digital imaging methods Lesion size is expressed as percent coverage over entire tissue sample A low dose A-002, B high dose A-002, C statin, D low dose A-002 plus statin, E high dose A-002 plus statin, and F vehicle only
  • FIG. 6 Total plasma cholesterol levels in A-002 and/or statin dosage groups ApoE ' mice on a high fat diet were administered various dosages of A-002, statin, or A-002 plus statin over twelve weeks, and total cholesterol levels were measured A low dose A-002 B high dose A-002, C statin, D low dose A-002 plus statin, E high dose A-002 plus statin and F vehicle only
  • FIG 7 HDL levels in A-002 and/or statin dosage groups ApoE ' mice on a high fat diet were administered various dosages of A-002, statin or A-002 plus statin over twelve weeks, and HDL levels were measured A low dose A-002, B high dose A-002, C statin, D low dose A-002 plus statin E high dose A-002 plus statin, and F vehicle only
  • FIG. 8 A-002/s ⁇ mvastat ⁇ n combination tablet preparation protocol [0028] Figure 9 HPLC profiles A Simvastatin B A-002 C A- 002/s ⁇ mvastat ⁇ n combination tablet #19 D A-002/s ⁇ mvastat ⁇ n combination tablet #27
  • AA arachidonic acid, ACE, angiotensin converting enzyme, Ang, angiotensin, ApoB, apolipoprotein B, ARB, Angiotensin Receptor Blocker, BID, twice daily, BMI, body mass index, CAD, coronary artery disease, CETP, cholesteryl ester transfer protein, cfm, cubic feet per minute, CHD, coronary heart disease, CRP, C-reactive protein, CVD cardiovascular disease, ECG, electrocardiogram, ERN, extended release niacin, HDL, high density lipoprotein HMG-CoA hydroxymethyl glutaryl coenzyme A, HPLC, high performance liquid chromatography, ICAM-1 , intercellular adhesion molecule 1 , IDL intermediate density lipoprotein IL interleukin (e g IL-6, IL-8) ITT, intent to treat, LDL, low density lipoprotein, LPA lysophosphatidic acid, MCP- 1 , monocyte
  • a "subject in need thereof refers to a subject diagnosed with CVD or exhibiting one or more conditions associated with CVD, a subject who has been diagnosed with or exhibited one or more conditions associated with CVD in the past, or a subject who has been deemed at risk of developing CVD or one or more conditions associated with CVD in the future due to hereditary or environmental factors
  • Cardiovascular disease” or “CVD” as used herein includes, for example atherosclerosis, including coronary artery atherosclerosis and carotid artery atherosclerosis, coronary artery disease (CAD), coronary heart disease (CHD), conditions associated with CAD and CHD, cerebrovascular disease and conditions associated with cerebrovascular disease, peripheral vasculai disease and conditions associated with peripheral vascular disease, aneurysm, vasculitis, venous thrombosis, diabetes melhtus, and metabolic syndrome
  • Conditions associated with CAD and CHD include, for example, angina and myocardi
  • cholesterol level refers to blood cholesterol level, serum cholesterol level, plasma cholesterol level, or cholesterol level from another biological fluid
  • a decrease in cholesterol levels as used herein may refer to a decrease in total cholesterol levels or a decrease in one or more of total cholesterol, non-HDL cholesterol, LDL, VLDL, and/or IDL levels
  • a decrease in LDL as used herein may refer to a decrease in total LDL a decrease in LDL particles, a decrease in small LDL particles, a decrease in oxidized LDL levels, and/or a decrease in ApoB levels
  • a decrease in VLDL as used herein may refer to a decrease in total VLDL or to a decrease in the level of one or more of VLDL subparticles V1 to V6
  • An improvement in HDL/LDL ratio as used herein refers to any increase in the ratio of HDL to LDL, and may be accomplished by decreasing LDL levels increasing HDL levels, or some combination thereof
  • An increase in LDL particle size as used herein refers to an increase in
  • sPLA 2 inhibitor refers to any compound or prodrug thereof that inhibits the activity of SPLA 2
  • a "therapeutically effective amount' of a composition as used herein is an amount of a composition that produces a desired therapeutic effect in a subject, such as treating a target condition
  • the precise therapeutically effective amount is an amount of the composition that will yield the most effective results in terms of therapeutic efficacy in a given subject This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic composition (including, e g activity, pharmacokinetics, pharmacodynamics, and bioavailability) the physiological condition of the subject (including, e g age, body weight, sex, disease type and stage, medical history, general physical condition, responsiveness to a given dosage, and other present medications), the nature of the pharmaceutically acceptable carrier or carriers in the composition, and the route of administration
  • the characteristics of the therapeutic composition including, e g activity, pharmacokinetics, pharmacodynamics, and bioavailability
  • the physiological condition of the subject including, e g age, body weight, sex, disease type and stage, medical history,
  • a "pharmaceutically acceptable carrier” as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue organ, or portion of the body to another tissue, organ, or portion of the body
  • a carrier may comprise, for example, a liquid, solid, or semi-solid filler, solvent, surfactant, diluent, excipient, adjuvant, binder, buffer, dissolution aid solvent, encapsulating material, sequestering agent, dispersing agent, preservative, lubricant disintegrant, thickener, emulsifier, antimicrobial agent antioxidant, stabilizing agent coloring agent, or some combination thereof
  • Each component of the carrier must be “pharmaceutically acceptable” in that it must be compatible with the other ingredients of the composition and must be suitable for contact with any tissue, organ, or portion of the body that it may encounter, meaning that it must not carry a risk of toxicity, irritation allergic response, immunogenicity or any other complication that excessively outweighs
  • Metabolic syndrome is a disorder characterized by a group of metabolic risk factors These factors include, for example dyslipidemia abdominal obesity, elevated blood pressure (hypertension) insulin resistance or glucose intolerance, prothrombotic state, and proinflammatory state Subjects are generally classified as having metabolic syndrome if they meet three of the five following criteria 1 ) abdominal obesity (waist circumference >35 inches in women, >40 inches in men), 2) low HDL levels ( ⁇ 50 mg/dL in women, ⁇ 40 mg/dL in men), 3) high blood pressure (>130/85 mm Hg) or current treatment with antihypertensive medication 4) hypertriglyceridemia (TG levels >150 mg/dL), and 5) impaired fasting glucose (blood glucose levels of >110 mg/dL) Metabolic syndrome is associated with elevated levels of various inflammatory markers, such as CRP or IL-6 Subjects with metabolic syndrome are at increased risk of developing CAD, CHD, conditions associated with CAD and CHD 1 and type 2 diabetes
  • hypercholesterolemia and hypertriglyceridemia can lead to the development of atheromatous plaques on the inner arterial linings via the process of atherogenesis, which in turn results in atherosclerosis
  • Atherosclerosis leads to significantly reduced blood flow through the arteries, which in turn leads to the development of CAD, CHD, and conditions associated with CAD and CHD
  • Compounds used in the treatment of CVD include compounds for lowering cholesterol levels and/or increasing HDL levels, such as for example statins, bile acid sequestrants such as cholestyramine resin (Questran® Prevalite®), colestipol hydrochloride (Colestid®), or colesevelam hydrochloride (WelChol® Cholestagel®), fibrates such as bezafibrate (Bezalip®) ciprofibrate (Modalim®), clofibrate, gemfibrozil (Lopid®), or fenofibrate (Antara®, TriCor®, ABT
  • statins are compounds that inhibit HMG- CoA reductase from catalyzing the conversion of HMG-CoA to mevalonate a rate-limiting step in the cholesterol biosynthetic pathway
  • statins function as potent lipid lowering agent Statin administration significantly decreases blood LDL levels and moderately decreases blood TG levels
  • statins may prevent CVD by improving endothelial function, modulating inflammatory responses, maintaining plaque stability, and preventing thrombus formation
  • examples of statins that may be used in conjunction with the compositions and methods disclosed herein include but are not limited to, atorvastatin or atorvastatin calcium (marketed as Lipitor® or Torvast ®, see, e g , O S Patent Nos 4,681 ,893 or 5,273,995) and atorvastatin combinations (e g atorvastatin plus amlodipine (
  • statins are administered in their active form
  • Phospholipases A 2 are a family of enzymes that catalyze hydrolysis of the sn-2 fatty acyl ester bond of phospholipids to produce free fatty acids and lysophospholipids such as arachidonic acid (AA) and lysophosphatidylcholine AA can then be converted into eicosanoids such as prostaglandins, leukot ⁇ enes, thromboxanes, and lipoxins, while lysophosphatidylcholine can be metabolized to lysophosphatidic acid (LPA) or platelet-activating factor (PAF) PLA 2 S have been classified into several groups based on factors such as cellular localization amino acid sequence molecular mass and calcium requirement for enzymatic activity (Ramoner 2005)
  • Secretory phospholipase A 2 is an extracellular or secreted subgroup of PLA 2 that plays a role in inducing inflammation
  • Elevated levels of SPLA 2 types HA, HD, HE HF III, V, and X have been observed in all stages of atherosclerosis development and have been implicated in atherogenesis based on their ability to degrade phospholipid (Kimura-Matsumoto 2007)
  • SPLA 2 type HA has been found to be expressed at vascular smooth muscle cells and foam cells in human arteriosclerosis lesions and this expression has been recognized to have a correlation with the development of arteriosclerosis (Menschikowski 1995 Elinder 1997)
  • Transgenic mice that express high levels of human type HA SPLA 2 have increased LDL levels, decreased HDL levels, and arteriosclerotic lesions (Ivandic 1999, Tietge 2000), and develop arteriosclerosis at a higher rate compared to normal mice when given a high fat diet (Ivandic 1999) Treatment with SPLA 2 modifies
  • sPLA 2 expression has also been correlated with an increased risk of development of CAD
  • Higher circulating levels of SPLA 2 and of SPLA 2 type ilA specifically, have been observed in patients with documented CAD than in control patients (Kugiyama 1999 Uu 2003, Boekholdt 2005, Chait 2005 Hartford 2006)
  • higher circulating levels of SPLA 2 were found to provide an accurate prognostic indicator for development of CAD in healthy individuals (Mallat 2007)
  • Measurement of SPLA 2 activity has been shown to be an independent predictor of death and new or recurrent myocardial infarction in subjects with acute coronary syndrome, and provides greater prognostic accuracy than measuring type MA concentration only (Mallat 2005)
  • SPLA 2 may have detrimental effects in the setting of ischemic events This is based largely on the finding of SPLA 2 depositions in the necrotic center of infarcted human myocardium (Nijmeijer 2002)
  • administration of the SPLA 2 inhibitor A-002 As disclosed herein, administration of the SPLA 2
  • compositions comprising one or more SPLA 2 inhibitors for use in the methods disclosed herein may be administered to a subject on a one-time basis or in multiple administrations
  • the compositions may be administered at set intervals over a particular time period determined in advance, or they may be administered indefinitely or until a particular therapeutic benchmark is reached, such as for example until a subject exhibits cholesterol levels below a specified threshold
  • the one or more SPLA 2 inhibitors may be administered from one or more times per day to once every week, once every month, or once every several months
  • the one or more SPLA 2 inhibitors may be administered twice a day, and in other embodiments the one or more sPLA ⁇ inhibitors may be administered once a day As disclosed herein, both twice a day and once a day administration of A-002 resulted in significant decreases in serum lipid levels
  • kits are provided that comprise one or more SPLA 2 inhibitors
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug salt, polymorph co-crystal, or solvate of A-001 , and in certain of these embodiments, the pharmaceutically acceptable prodrug is A-002
  • the kit provides instructions for usage, such as dosage or administration instructions
  • A-002 As disclosed herein, twice daily administration of A-002 was shown to further decrease total cholesterol levels in mice and LDL, LDL particle, and small LDL particle levels in humans that were receiving statin treatment Likewise, A-002 was shown to further decrease serum LDL levels in humans that were receiving ezetimibe treatment Similar results were obtained when A-002 was administered once a day in combination with statins These results indicate that administration of an sPLA ?
  • statin an additional decrease in cholesterol levels in subjects that are already being treated with another compound used in the treatment of CVD, such as a statin
  • administration of A-002 in conjunction with statins resulted in an unexpected synergistic decrease in total cholesterol levels and aortic lesion formation in mice and in LDL and small LDL particle levels in humans
  • the synergistic decrease in LDL following coadministration of A-002 and statins was observed in the statin subpopulation as a whole
  • synergism appeared to occur between A-002 and each of the individual statins within the general statin subpopulation, although statistical analysis of this effect was complicated by the limited number of test and placebo subjects for each statin
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 , and in certain of these embodiments the pharmaceutically acceptable prodrug is A-002
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins or statin combination drugs
  • the one or more SPLA 2 inhibitors comprise A-001 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001 , and in certain of these embodiments, the pharmaceutically acceptable prodrug is A-002
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs
  • the one or more statins are selected from the group consisting of atorvastatin, simvastatin rosuvastatin, lovastatin, pravastatin, cerivastatin fluvastatin, mevastatin, and pravastatin
  • the statin combination drugs are selected from the group consisting of atorva
  • the one or more SPLA 2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 and in certain of these embodiments, the pharmaceutically acceptable prodrug is A-002
  • the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs
  • the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin and pravastatin
  • the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine, atorvastatin plus
  • a therapeutically effective amount of an SPLA 2 inhibitor or a compound used in the treatment of CVD for use in the methods or compositions disclosed herein may be determined for each compound individually
  • statins or statin combination drugs may be administered or included in a pharmaceutical composition at a dosage that is well known in the art to decrease cholesterol levels
  • the amount of the compound used in the treatment of CVD that constitutes a therapeutically effective amount may be different than the amount of the compound that constitutes a therapeutically effective amount of the compound when administered alone due to, for example, interactions between the compound and the one or more SPLA 2 inhibitors
  • the effective dosage of a statin for use in combination therapy may be lower than the standard dosage for the statin when administered alone In this situation, one of skill in the art will be able to readily determine a therapeutically effective amount for the combination composition using methods well known in the art In certain embodiment
  • indole-based sPLA ⁇ inhibitors A variety of indole-based sPLA ⁇ inhibitors are known in the art
  • indole-based sPLA 2 inhibitors that may be used in conjunction with the present invention include but are not limited to those set forth in U S Patent Nos 5,654,326 (Bach) 5,733,923 (Bach), 5,919,810 (Bach), 5,919,943 (Bach), 6, 175 021 (Bach), 6,177 440 (Bach), 6,274,578 (Denney), and 6,433 001 (Bach), the entire disclosures of which are incorporated by reference herein
  • Methods of making indole-based SPLA 2 inhibitors are set forth in, for example, U S Patent Nos 5,986,106 (Khau), 6,265,591 (Anderson), and 6,380 397 (Anderson), the entire disclosures of which are incorporated by reference herein SPLA 2 inhibitors for use in the present invention may be generated using these synthesis methods or using any other
  • SPLA 2 inhibitors for use in the current invention are 1 H- ⁇ ndole-3-glyoxylamide compounds having the structure wherein each X is independently oxygen or sulfur,
  • R 1 is selected from the group consisting of (a), (b), and (c), wherein
  • (a) is C7-C20 alkyl, C 7 -C 2 O alkenyl, C 7 -C 2 O alkynyl, carbocyclic radicals, or heterocyclic radicals,
  • (b) is a member of (a) substituted with one or more independently selected non-interfering substituents and
  • (c) is the group -(L) -Rso, where, -(L)- is a divalent linking group of 1 to 12 atoms selected from carbon hydrogen, oxygen, nitrogen and sulfur, wherein the combination of atoms in -(L)- are selected from the group consisting of (i) carbon and hydrogen only, (n) sulfur only, (IN) oxygen only, ( ⁇ v) nitrogen and hydrogen only (v) carbon, hydrogen, and sulfur only, and (v ⁇ ) carbon, hydrogen, and oxygen only, and where Rgo is a group selected from (a) or (b),
  • R 2 is hydrogen, halo, C 1 -C 3 alkyl, C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, -O- (Ci-C 2 alkyl), -S-(Ci-C 2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen,
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -(L a )-(ac ⁇ d ⁇ c group), wherein -(L 9 )- is an acid linker having an acid linker length of 1 to 4, provided that at least one of R 4 and R 5 must be -(L a )-(ac ⁇ d ⁇ c group),
  • R 6 and R 7 are each independently selected from hydrogen, non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non- interfe ⁇ ng substituents, heterocyclic radicals and heterocyclic radicals substituted with non-interfering substituents, provided that for any of the groups Ri, Re, and R 7 , the carbocyclic radical is selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenly acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb),
  • n is a number from 1 to 8, provided, that for any of the groups Ri RQ and R 7 , the heterocyclic radical is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazoiyl, phenylimidazolyl, triazolyl isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, ⁇ m ⁇ dazo(1 2-A)pyr ⁇ d ⁇ nyl, benzot ⁇ azolyl, anthranilyl, 1 2- benzisoxazolyl, benzoxazolyl, benzotnazolyl, purinyl pryidinyl, dipyridylyl phenylpy ⁇
  • Rgi and Rg 2 are each independently selected from the group consisting of hydrogen, C 1 -C 1 O alkyl, carboxy carbalkoxy, and halo p is a number from 1 to 5, and Z is selected from the group consisting of a bond, - (CH 2 )- -O- -N(C 1 -C 10 alkyl)-, -NH-, and -S-
  • the acid linker -(L 3 )- has the formula wherein Q is selected from the group consisting Of -(CH 2 )-, -O- , -NH-, and -S-, and R 83 and R 84 are each independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, aryl, C 1 -C 10 alkaryl, Ci-C 10 aralkyl, hydroxy, and halo
  • a 1 H- ⁇ ndole-3-glyoxylam ⁇ de compound for use in the present invention is selected from the group consisting of ((3-(2- Am ⁇ no-1 ,2-d ⁇ oxoethyl)-2-ethyl-1 -(phenylmethyl)-i H- ⁇ ndol-4-yl)oxy)acet ⁇ c acid [[3-(2-Am ⁇ no-1 ,2-d ⁇ oxoethyl)-2-ethyl-1 -
  • SPLA 2 inhibitors for use in the current invention are 1 H- ⁇ ndole-3-glyoxylam ⁇ de compounds having the structure
  • R 1 is selected from the group consisting of
  • R 1O is a radical independently selected from halo, Ci-C 1O alkoxy, -S-
  • R 2 is selected from the group consisting of halo cyclopropyl, methyl, ethyl and propyl,
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -(L a )-(ac ⁇ d ⁇ c group), wherein -(L 3 )- is an acid linker provided that the acid linker -(L 3 )- for R 4 is selected from the group consisting of f
  • R 84 and R 85 are each independently selected from the group consisting of hydrogen, C 1 -Ci 0 alkyl, aryl, C1-C10 alkaryl, Ci-C 10 aralkyl, carboxy carbalkoxy, and halo, provided that at least one of R 4 and R 5 must be — (L a )-(ac ⁇ d ⁇ c group), and (acidic group) on -(L a )-(ac ⁇ d ⁇ c group) of R 4 or R 5 is selected from -CO 2 H, -SO 3 H, Or -P(O)(OH) 2 , R 6 and R 7 are each independently selected from the group consisting of hydrogen and non-interfering substituents with the non-interfering substituents being selected from the group consisting of C 1 -Ce alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 7 -Ci 2 aralkyl, C 7 -Ci 2 alka
  • 1 H- ⁇ ndole-3-glyoxylam ⁇ de compounds for use in the present invention are selected from the group consisting of ((3-(2- Am ⁇ no-1 ,2-d ⁇ oxoethyl)-2-methyl-1 -(phenylmethyl)-i H- ⁇ ndol-4-yl)oxy)acet ⁇ c acid, ((3-(2-Am ⁇ no-1 ,2-d ⁇ oxoethyl)-2-methyl-1-(phenylmethyl)-1 H-indol-4- yl)oxy)acet ⁇ c acid methyl ester, dl-2-((3-(2-Am ⁇ no-1 ,2-d ⁇ oxoethyl)-2-methyl-1- (phenylmethyl)-1 H- ⁇ ndol-4-yl) oxy)propano ⁇ c acid, dl-2-((3-(2-Am ⁇ no-1 ,2- d ⁇ oxoethyl)-2-methyl-1 -
  • SPLA 2 inhibitors for use in the current invention are 1 H- ⁇ ndole-3-glyoxylam ⁇ de compounds having the structure
  • each X is independently oxygen or sulfur
  • R 1 is selected from groups (a), (b), and (c) wherein
  • (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C?o alkynyl, carbocyclic radical, or heterocyclic radical
  • (b) is a member of (a) substituted with one or more independently selected non-interfering substituents and (c) is the group -(L)-ReO, wherein -(L)- is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur wherein the combination of atoms in -(L)- are selected from the group consisting of ( ⁇ ) carbon and hydrogen only, (n) sulfur only, (in) oxygen only, ( ⁇ v) nitrogen and hydrogen only, (v) carbon, hydrogen, and sulfur only, and (v ⁇ ) and carbon, hydrogen, and oxygen only, and where Rgo is a group selected from (a) or (b),
  • R 2 is selected from the group consisting of hydrogen, halo, C 1 -C 3 alkyl C 3 -C 4 cycloalkyl, C 3 -C 4 cycloalkenyl, -0-(C 1 -C 2 alkyl), -S-(C 1 -C 2 alkyl), and a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen
  • R 4 and R 5 are independently selected from the group consisting of hydrogen a non-interfering substituent, and the group -(L a )-(ac ⁇ d ⁇ c group) wherein - (L 3 )- is an acid linker having an acid linker length of 1 to 4, provided that at least one of R 4 and R 5 is -(L a )-(ac ⁇ d ⁇ c group),
  • Re and R7 are each independently selected from the group consisting of hydrogen, non-interfering substituents, carbocyclic radicals carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals and heterocyclic radicals substituted with non-interfering substituents and pharmaceutically acceptable salts solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof [0075]
  • SPLA 2 inhibitors for use in the current invention are methyl ester prodrug derivatives of 1 H- ⁇ ndole-3-glyoxylam ⁇ de compounds having the structure
  • R 1 is selected from the group consisting of
  • R 10 is a radical independently selected from halo, C 1 -C 10 alkyl, C 1 -
  • R 2 is selected from the group consisting of halo, cyclopropyl, methyl, ethyl, and propyl,
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -(L a )-(ac ⁇ d ⁇ c group), wherein -(L 3 )- is an acid linker, provided that the acid linker -(L 3 )- for R 4 is selected from the group consisting of -o- -CH-
  • the acid linker -(L 3 )- for R 5 is selected from the group consisting of
  • Rg 4 and Rgs are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, aryl, C 1 -C 10 alkaryl, Ci-C 10 aralkyl, carboxy, carbalkoxy, and halo, provided that at least one of R 4 and R 5 must be -(L a )-(ac ⁇ d ⁇ c group), and (acidic group) on -(L a )-(ac ⁇ d ⁇ c group) of R 4 or R 5 is selected from -CO 2 H -SO 3 H, or -P(O)(OH) 2
  • R 6 and R 7 are each independently selected from the group consisting of hydrogen and non-interfering substituents, with the non-interfe ⁇ ng substituents being selected from the group consisting of C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 7 -C 12 aralkyl, C 7 -Ci 2 al
  • R 1 is selected from the group consisting of
  • Ri 0 is a radical independently selected from halo, C 1 -C 10 alkyl, C 1 -
  • R 2 is selected from the group consisting of halo, cyclopropyl, methyl, ethyl and propyl
  • R 4 and R 5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -(L 3 )- (acidic group), wherein -(L 3 )- is an acid linker, provided that the acid linker -(L 3 )- for R 4 is selected from the group consisting of -o- -CH;
  • R 84 and R 85 are each independently selected from the group consisting of hydrogen, C 1 -C 10 alkyl, aryl. C 1 -C 10 alkaryl, C 1 -C 1 Q aralkyl, carboxy, carbalkoxy, and halo, provided that at least one of R 4 and R 5 must be -(La)-(acidic group), and (acidic group) on -(L a )-(ac ⁇ d ⁇ c group) of R 4 or R 5 is selected from -CO 2 H, -SO 3 H, or -P(O)(OH) 2 ,
  • Re and R 7 are each independently selected from the group consisting of hydrogen and non-interfering substituents with the non-interfering substituents being selected from the group consisting of C 1 -C 6 alkyl C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 7 -C 12 aralkyl C 7 -C 12 alkaryl, C 3 -Cg cycloalkyl C 3 -C 8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C 1 -C 6 alkoxy, C 2 -C 6 alkenyloxy, C 2 -C 6 alkynyloxy, C 2 -C 12 alkoxyalkyl, C 2 -C 12 alkoxyalkyloxy, C 2 - C 12 alkylcarbonyl, C 2 -C 12 alkylcarbonylamino C 2 -C 12 alkoxyamino, C 2 -C 12 al
  • R 1 is selected from the group consisting Of -NHNH 2 and -NH 2 ,
  • R 2 is selected from the group consisting of -OH and -0(CH 2 ) m R 5 , wherein R 5 is selected from the group consisting of H, -CO 2 H -CO 2 (C 1 -C 4 alkyl), -
  • R 6 and R 7 are each independently selected from the group consisting of -OH, -O(C 1 -C 4 )alkyl, R 15 is selected from the group consisting of -(C 1 - C 6 )alkyl and -CF 3 and m is 1-3,
  • R 3 is selected from the group consisting of H, -O(C 1 -C 4 )alkyl, halo, -(C 1 - C ⁇ Jalkyl, phenyl, -(C ⁇ C ⁇ alkylphenyl phenyl substituted with -(C 1 -Ce)SlKyI halo, or -CF 3 , -CH 2 OS ⁇ (C 1 -C 6 )alkyl, furyl, thiophenyl, -(C 1 - C ⁇ jhydroxyalkyl, and -(CH 2 ) n Rs, wherein R 8 is selected from the group consisting of H 1 -CONH 2 , -NR 9 R 10 , -CN, and phenyl, wherein R 9 and Ri 0 are each independently -(C 1 -C 4 )alkyl or -phenyl(Ci-C 4 )alkyl, and n is 1 to 8, R 4 is selected from the group consisting of H,
  • Ci 4 cycloalkyi, pyridyl, phenyl, and phenyl substituted with -(Ci-C 6 )alkyl, halo,
  • A is selected from the group consisting of phenyl and pyridyl wherein the nitrogen is at the 5-, 6-, 7-, or 8-pos ⁇ t ⁇ on,
  • Z is selected from the group consisting of cyclohexenyl, phenyl, pyridyl wherein the nitrogen is at the 1- 2-, or 3-pos ⁇ t ⁇ on, and a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur and oxygen at the 1-, 2-, or 3-pos ⁇ t ⁇ on and nitrogen at the 1-, 2-, 3-, or
  • SPLA 2 inhibitors for use in the current invention are substituted tricyclics having the structure
  • Z is selected from the group consisting of cyclohexenyl and phenyl
  • R 21 is a non-interfering substituent
  • R 1 IS -NHNH 2 Or -NH 2
  • R 2 is selected from the group consisting of -OH and -0(CH 2 ) m Rs
  • R 5 is selected from the group consisting of H, -CO 2 H, -CONH 2 , -CO 2 (C 1 -C 4 alkyl), -SO 3 H 1 -SO 3 (C 1 -C 4 alkyl), tetrazolyl, -CN, -NH 2 , -NHSO 2 R 15 , - CONHSO 2 R 15 , phenyl phenyl substituted with -CO 2 H or -CO 2 (C 1 -C 4 )BlKyI, and o
  • R 6 R 7 P( R 6 R 7 ) , wherein Re and R 7 are each independently selected from the group consisting of -OH, -O(d-C 4 )alkyl, R 15 is selected from the group consisting Of -(C 1 - Ce)alkyl and -CF 3 and m is 1-3,
  • R 3 selected from the group consisting of H, -O(C 1 -C 4 )alkyl, halo, -(Ci- Ce)alkyl phenyl, -(C!-C 4 )alkylphenyl, phenyl substituted with -(C 1 -Ce)alkyl, halo, Or -CF 3 , -CH 2 OS ⁇ (C 1 -C 6 )alkyl, furyl, thiophenyl -(C 1 -C 6 )hydroxyalkyl, and -(CH 2 ) n Rs, wherein Rg is selected from the group consisting of H, - CONH 2 , -NRgR-io, -CN and phenyl Rg and R 1 O are each independently selected from the group consisting of H -CF 3 phenyl, -(d-C ⁇ alkyl, -(C 1 - C 4 )alkylphenyl, and -phenyl(C 1
  • A-001 competitively inhibits SPLA 2
  • an SPLA 2 inhibitor for use in the present invention is [[3-(2-Am ⁇ no-1 2-d ⁇ oxoethyl)-2-ethyl-1-(phenylmethyl)- 1 H- ⁇ ndol-4-yl]oxy]acet ⁇ c acid methyl ester, also referred to herein as compound A-002
  • Compound A-002 has the structure
  • Compound A-002 which is sometimes referred to in the art as S-3013 or LY333013, is a prodrug form of A-O01 that is rapidly absorbed and hydrolyzed to A-O01 following administration to a subject
  • an SPLA 2 inhibitor for use in the present invention is ⁇ 9-[(phenyl)methyl]-5-carbamoylcarbazol-4- yl ⁇ oxyacet ⁇ c acid also referred to herein as compound A-003 or LY433771
  • Compound A-003 has the structure
  • an SPLA 2 inhibitor for use in the present invention is ((3-(2-am ⁇ no-1 ,2-d ⁇ oxoethyl)-2-methyl-1 -(phenylmethyl)- 1 H- ⁇ ndol-4-yl)oxy)acet ⁇ c acid N-morpholino ethyl ester, also referred to herein as compound 421079
  • Compound 421079 has the structure
  • mice Male ApoE ' " mice were fed a high fat diet (21 % fat, 0 15% cholesterol 19 5% casein) ad libitum for two weeks in order to acclimate to the diet Plasma cholesterol levels and body weight were measured in order to obtain baseline levels, and mice were randomized into thtee groups of 20 mice based on these measurements After the acclimation period, mice remained on the high fat diet and were administered A-002 (30 mg/kg or 90 mg/kg) or vehicle only (5% acacia) twice a day for 16 weeks by oral gavage [0086] Plasma cholesterol levels and body weight were measured at 4, 8, 12 and 16 weeks after the start of A-002 administration Comparisons of measurements between test and control mice at each time period were performed using a two-way analysis of variance test (ANOVA) for repeated measures followed by post-hoc Bonferroni test for significance [0087] At the end of the 16th week, mice were sacrificed and plasma samples, heart tissue, and aortas from the heart to approximately 3 mm
  • mice All three groups of mice (control, 30 mg/kg A-002, and 90 mg/kg A-
  • Control mice exhibited approximately 13% plaque coverage in aortic tissue at 16 weeks ( Figure 3) 30 mg/kg A-002 and 90 mg/kg A-002 mice exhibited 6 3% and 6 8% plaque coverage respectively ( Figure 3)
  • A-002 treatment resulted in a significant decrease in plaque content
  • Example 2 Effect of A-002 administration on angiotensin ll-mediated atherosclerotic plaque formation and aneurysm
  • a mouse model of accelerated atherosclerosis was utilized to determine the effect of A-002 administration on atherosclerosis and aneurysm formation
  • ApoE ' mice acclimated to the same high fat diet utilized in Example 1 were administered angiotensin Il with water, angiotensin with 5% acacia, or saline infusion and water twice daily for four weeks
  • Angiotensin Il has been shown to promote atherosclerosis and aneurysm formation in apoE deficient mice (Daugherty 2000)
  • plaque coverage was assessed by three independent reviewers, and their assessments were averaged to determine plaque coverage
  • Angiotensin Il with water or with 5% acacia resulted in similar rates of plaque coverage ( Figure 4) and aneurysm (Table 1 )
  • mice were sacrificed and plasma heart tissue and aortic tissue were collected En face lesion size was determined via digital imaging analysis Percent lesion coverage for each dosage group is summarized in Table 2 and Figure 5 Plaque content (as measured as en face lesion) was reduced in mice administered A-002 alone, statin alone, or A- 002 in combination with statin The reduction in plaque content in mice administered A-002 plus statin was substantially greater than the reduction in mice administered either compound alone (Table 2, compare Group D vs Groups A and C, Group E vs Groups B and C) Further, the reduction in plaque content in mice administered A-002 plus statin was substantially greater than the sum of the reduction in plaque content in mice administered A-002 alone and mice administered statin alone. (Table 2, compare the change in mean % en face lesion vs. control for Group D (i.e., -4.210%) with the sum of the change in mean % en face lesion vs. control for Group A and
  • Group C i.e., the sum of -2.241 % and -0.813%, or -3.054%.
  • Plasma total cholesterol and HDL levels were measured. Mean levels of total cholesterol were decreased in mice administered A-002 alone or in combination with statin (Table 3, Figure 6). Administration of high dosage A- 002 plus statin resulted in a greater decrease in total cholesterol than administration of high dosage A-002 or statin alone (Table 3. compare Group E vs. Groups B and C; Figure 6). Mean levels of HDL were increased in mice administered A-002 at either dosage (Table 4). This increase was greater in mice administered high dose A-002 plus statin than in mice administered high dose A-002 or statin alone (Table 4 compare Group E vs Groups B and C, Figure 7)
  • Example 4 Effect of A-002 or A-002 plus statin administration on serum lipid levels in humans [0096] 204 human subjects from the United States with CVD, specifically stable coronary artery disease, were randomized to receive placebo or A- 002 via oral administration twice a day over an eight week administration period at dosages of 50 mg 100 mg, 250 mg, or 500 mg Levels of various lipids and inflammatory markers were measured at the outset of the trial and at the end of weeks four and/or eight For data sets with a normal distribution mean levels of lipids or inflammatory markers were analyzed For data sets with non-normal distribution, median levels were analyzed Administration of A-002 at all dosages tested resulted in a decrease in mean levels of serum LDL (Table 5), LDL particles (Table 6), small LDL particles (Table 7) total cholesterol (Table 8), and TG (Table 9), and median levels of SPLA 2 (Table 10) In addition, administration of A-002 decreased median levels of CRP (Table 11 ) The magnitude of the observed decreases in LDL particle,
  • the median baseline LDL concentration in the 204 subject United States ITT population was 72.0 mg/dl.
  • A-002 administration resulted in a significant decrease in mean LDL levels in a 97 subject subpopulation with baseline LDL levels equal to or higher than the median concentration (Table 12).
  • administration of A-002 decreased mean serum LDL levels in a 53 subject subpopulation with diabetes (Table 13).
  • Table 12 Changes in serum LDL concentration in subpopulation with baseline serum LDL concentration greater than or equal to 72 mg/dl following A-002 administration
  • Table 15 Changes in serum LDL concentration in statin subpopulation with baseline serum LDL concentration greater than or equal to 72 mg/dl following A-002 administration
  • AEGR-733/ezetim ⁇ be colesevelam hydrochloride (WelChol®), MK-0524A (Cordaptive®), lisinopril/MC-1 antibody (MC-4232), and Angiotensin Receptor Blocker (ARB)/MC-1 (MC-4262).
  • Table 16 Changes in serum LDL concentration in statin subpopulation following A-002 administration
  • Table 18 Changes in serum LDL levels in non-statin subpopulation following A-002 administration
  • Table 19 Changes in serum LDL concentration in non-statin subpopulation with baseline serum LDL levels greater than or equal to 72 mg/dl following A- 002 administration
  • Serum LDL data for subjects in the statin subpopulation were subdivided based on the specific statin each subject was receiving.
  • Statins with significant representation included atorvastatin, rosuvastatin. simvastatin, lovastatin, pravastatin, and fluvastat ⁇ n, as well as the statin combination drugs simvastatin/ezetimibe (Vytorin®), atorvastatin/ezetimibe, atorvastatin/amlodipine (Caduet®), lovastatin/extended release niacin (Advicor®), rosuvastatin/TriCor®, rosuvastatin/ABT-335, simvastatin/extended release niacin (Simcor®), simvastatin/MK-0524A (MK-0524B), pravastatin/fenofibrate, atorvastatin/APA-01.
  • statin and statin combination dosages varied within each individual statin subgroup.
  • the number of test and placebo subjects in each individual statin subgroup from the larger statin subpopulation was too low to allow for detailed statistical analysis.
  • there appeared to be a trend towards the same synergistic decrease in LDL levels that was observed in the statin subpopulation as a whole in several of the statin subgroups such as for example with certain dosages of atorvastatin, rosuvastatin, and simvastatin.
  • A-002 and compounds used in the treatment of CVD on LDL levels was not limited to statins.
  • 30 subjects from the ITT population were receiving ezetimibe at a dosage of 10 mg during the course of the A-002 trial.
  • Administration of A-002 resulted in a decrease in mean serum LDL levels in the ezetimibe subpopulation after eight weeks (Table 21 ), indicating that administration of A-002 plus ezetimibe results in a greater decrease in LDL levels than administration of ezetimibe alone (Table 21).
  • Table 22 Summary of the synergistic effects of combined A-002 and ezetimibe administration versus administration of A-002 or ezetimibe alone
  • Serum TG. CRP, and IL-6 levels were measured at eight weeks in 86 subjects from the ITT population diagnosed with metabolic syndrome. Administration of A-002 resulted in a decrease in serum levels of each of these markers (Tables 23-25). Subjects administered placebo exhibited an increase in CRP and IL-6 levels (Tables 24-25). Table 23: Changes in serum TG concentration in metabolic syndrome subpopulation following A-002 administration
  • Fixed dose tablets containing A-002 and one or more statins may be generated using methods known in the art
  • a fixed dose tablet containing a therapeutically effective amount of A-002 (e g , 250 or 500 mg) and a therapeutically effective amount of a statin (e g , 10, 20, 40 or 80 mg) may be generated using a formula such as that set forth in Table 26
  • a compound such as calcium carbonate may be added to the formulation to enhance dissolution and solubility.
  • a flow chart detailing one method of preparing the tablet above is set forth in Figure 8 BHA polysorbate 80 and purified water were mixed to create granulation fluid which was stored overnight Lactose anhydrous lactose fast flo and the first portion of croscarmellose sodium were weighed and screened through a coarse mesh then combined with A-002 and simvastatin (which can also be sieved if necessary) and dry blended for 1 -2 minutes using a mixer at slow speed
  • microcrystalline cellulose may be included in the dry mix Hydroxypropyl cellulose was combined with the granulation fluid, resulting in greatly increased viscosity
  • the resultant solution was added slowly to the mixer containing the A-002/s ⁇ mvastat ⁇ n mix During addition, mixing speed was gradually increased Granulation end-point was reached when fine granules formed without the mass becoming wet or sticky
  • a film coating may be applied to combination A-002/statin tablets using methods well known in the art.
  • the coating suspension is prepared by adding a film coat mixture such as Opadry YS-1- 18027-A to purified water in a mixing vessel. The mixing speed is reduced to avoid foaming and the suspension is mixed for 60 or more minutes, until uniform. After mixing, the suspension is allowed to stand for 60 or more minutes to deaerate.
  • a coater such as the Accela Coater is set up and the theoretical amount of coating suspension to be sprayed is calculated based on the number and size of tablets being coated. Tablets are loaded onto the coating pan.
  • the fan is turned on, and gun-to-bed distance (around 6-10 inches), supply air temperature (around 58°C), exhaust air temperature (around 45°C). air volume inlet (around 1500 cfm), and negative pan pressure differential are verified.
  • the tablets are pre-heated, and a sample number of tablets are weighed to determine the average core tablet weight. The coating solution is sprayed onto the tablets while being gently mixed.
  • the average tablet weight is recalculated.
  • target tablet weight is reached, the supply air temperature is reduced to around 45 C 'C and the pan is jogged at intervals for around five minutes to allow the tablets to dry.
  • the supply air temperature is reduced to around 3O 0 C and tablets are jogged manually for around ten more minutes
  • the coated tablets are then discharged from the coating pan
  • Example 6 Once a day dosing of A-002 or A-002 plus statin [00111] 135 human subjects over the age of 18 with CVD, specifically stable CAD, were randomized to receive either placebo or one of two dosages (250 mg or 500 mg) of A-002 via once a day oral administration over an eight week time period 89 of the subjects received A-002, while 46 of the subjects received placebo Subjects that were receiving statins or other compounds used in the treatment of CVD at the outset of the trial continued to receive those therapeutics throughout the trial 121 of the 135 subjects were on statins during the trial There was little variation between dosage groups with
  • Table 49 Changes in serum non-HDL cholesterol concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
  • Table 50 Changes in serum total cholesterol concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
  • Table 51 Changes in serum small LDL particle concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
  • Table 52 Changes in serum oxidized LDL concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
  • Table 53 Changes in serum ApoB concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration.
  • Table 54 Changes in LDL particle size in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration.
  • Table 55 Changes in serum CRP concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:

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Abstract

Administration of SPLA2 inhibitors has been found to decrease cholesterol levels, atherosclerotic plaque formation and aortic aneurysm in mice, and to decrease cholesterol and triglyceride levels in humans. Interestingly, administration of SPLA2 inhibitors was found to decrease cholesterol levels even when the inhibitors were administered only once per day. Therefore, provided herein are methods of treating dyslipidemia, CVD, and conditions associated with CVD such as atherosclerosis and metabolic syndrome, by administering one or more sPLA2 inhibitors. Significantly, administration of SPLA2 inhibitors and various compounds used in the treatment of CVD, such as for example statins, resulted in greater decreases in LDL and LDL particle levels in a synergistic manner. In addition, administration of sPLA2 inhibitors and statins resulted in a synergistic decrease in plaque content. Therefore, also provided herein are compositions comprising one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD, such as for example statins, and methods of using these compositions to treat dyslipidemia, CVD, and conditions associated with CVD such as atherosclerosis and metabolic syndrome.

Description

TREATMENT OF CARDIOVASCULAR DISEASE AND DYSL1PIDEMIA
USING SECRETORY PHOSPHOLIPASE A2 (SPLA2) INHIBITORS AND
SPLA2 INHIBITOR COMBINATION THERAPIES
CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The subject application claims the benefit of U S Application No 1 1/874,869, filed October 18, 2007 U S Provisional Patent Application No 60/969,591 , filed August 31 , 2007, and U S Provisional Patent Application No 60/915,910, filed May 3 2007 The disclosures of each of these applications are incorporated herein by reference in their entirety including drawings
BACKGROUND
[0002] In 2004, it was estimated that over 75 million Americans had one or more forms of cardiovascular disease (CVD) Coronary heart disease (CHD) and coronary artery disease (CAD) are the most common types of CVD CHD and CAD occur when coronary arteries that supply blood to the heart become hardened and narrowed due to atherosclerosis A variety of therapeutic options are currently employed in the treatment of CVD and conditions associated with CVD Many of these therapeutic options function by lowering cholesterol levels, particularly LDL levels Among the most popular and effective of these therapeutic options are statins a class of compounds that inhibit cholesterol biosynthesis and prevent the build-up of arterial plaque Statin administration has been shown to lower LDL and triglyceride levels and to substantially reduce coronary events and death from CVD However, statin therapy alone is insufficient to completely treat CVD Therefore, there is a need in the art for more effective methods of treating CVD and conditions associated with CVD SUMMARY
[0003] In certain embodiments, methods are provided for treating dyshpidemia in a subject in need thereof by administering a therapeutically effective amount of one or more sPLA2 inhibitors In certain embodiments, the one or more sPLA2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers In certain embodiments the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-002 a prodrug of A-O01 In certain embodiments, administration of one or more SPLA2 inhibitors results in a decrease in cholesterol and/or triglyceride levels In certain of these embodiments, administration of one or more SPLA2 inhibitors results in a decrease in total cholesterol, non-HDL cholesterol LDL, LDL particle, small LDL particle, oxidized LDL, and/or ApoB levels In certain embodiments administration of one or more SPLA2 inhibitors results in an increase in HDL levels and/or LDL particle size In certain embodiments, administration of one or more SPLA2 inhibitors results in a decrease in levels of one or more inflammatory markers In certain of these embodiments the inflammatory markers may include, but are not limited to, SPLA2, CRP, and/or IL-6 In certain embodiments, administration of one or more sPLA2 inhibitors results in an improvement in HDL/LDL ratio In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments the one or more sPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg [0004] In certain embodiments, methods are provided for decreasing cholesterol levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors In certain embodiments the one or more SPLA2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers In certain embodiments the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystai or solvate of A-O01 In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain embodiments, administration of one or more SPLA2 inhibitors results in a decrease in total cholesterol, non-HDL cholesterol, LDL LDL particle, small LDL particle oxidized LDL, and/or ApoB levels In certain embodiments, administration of one or more SPLA2 inhibitors results in an improvement in HDL/LDL ratio In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more sPLA? inhibitors are administered twice per day In other embodiments the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg
[0005] In certain embodiments, methods are provided for decreasing triglyceride levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors In certain embodiments the one or more SPtA2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug salt, polymorph co-crystal, or solvate of A-O01 In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain embodiments the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more sPLA2 inhibitors are administered twice per day In other embodiments, the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg [0006] In certain embodiments methods are provided for increasing HDL levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors In certain embodiments, the one or more SPLA2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers In certain embodiments the one or more sPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-001 In certain of these embodiments, the one or more sPLA2 inhibitors comprise A-002, a prodrug of A-001 In certain embodiments, administration of one or more SPLA2 inhibitors results in an improvement in HDL/LDL ratio In certain embodiments, improvement in HDL/LDL ratio is further accomplished by a reduction in LDL levels In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments, the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg
[0007] In certain embodiments, methods are provided for treating CVD or a condition associated with CVD in a subject in need thereof by administering a therapeutically effective amount of one or more sPLA2 inhibitors In certain embodiments, the one or more SPLA2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug salt polymorph, co-crystal or solvate of A-O01 In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments, the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg In certain embodiments, administration of one or more SPLA2 inhibitors results in a decrease in levels of one or more inflammatory markers In certain of these embodiments the inflammatory markers may include but are not limited to, SPLA2, CRP, and/or IL-6 In certain embodiments, CVD or a condition associated with CVD includes, but is not limited to atherosclerosis, metabolic syndrome, coronary artery disease, coronary heart disease, cerebrovascular disease peripheral vascular disease, and/or conditions associated with coronary artery disease, coronary heart disease cerebrovascular disease, or peripheral vascular disease
[0008] In certain embodiments, methods are provided for treating metabolic syndrome in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors In certain embodiments, the one or more SPLA2 inhibitors are administered in a composition that further comprises one or more pharmaceutically acceptable carriers In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 In certain of these embodiments the one or more SPLA2 inhibitors comprise A-002 a prodrug of A-O01 In certain embodiments the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg In certain embodiments administration of one or more sPLA2 inhibitors results in a decrease in levels of one or more inflammatory markers In certain of these embodiments the inflammatory markers may include, but are not limited to, sPLA2, CRP, and/or IL-6
[0009] In certain embodiments, compositions are provided comprising one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD In certain embodiments, the composition further comprises one or more pharmaceutically acceptable carriers In certain embodiments, the one or more SPLA2 inhibitors comprise A-001 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-001 In certain of these embodiments, the one or more sPLA2 inhibitors comprise A-002, a prodrug of A-001 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin lovastatin pravastatin, cerivastatin, fluvastatin mevastatin, pravastatin and various salts, solvates, stereoisomers, and prodrug derivatives thereof In certain of these embodiments the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine, atorvastatin plus CP-529414 atorvastatin plus APA-01 simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK- 0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta- adrenergic blockers, calcium channel blockers, and antithrombotics [0010] In certain embodiments, methods are provided for treating dyslipidemia in a subject in need thereof by administering a therapeutically effective amount of one or more sPLA2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-001 or a pharmaceutically acceptable prodrug, salt polymorph, co-crystal, or solvate of A-001 In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-002 a prodrug of A-001 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin simvastatin rosuvastatin lovastatin pravastatin ceπvastatin, fluvastatin, mevastatin, pravastatin and various salts, solvates, stereoisomers, and prodrug derivatives thereof In certain of these embodiments the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine atorvastatin plus CP-529414 atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin simvastatin plus MK-0524A lovastatin plus extended release niacin rosuvastatin plus fenofibrate, pravastatin plus fenofibrate and statin plus TAK-457 In certain embodiments the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics In certain embodiments, administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in cholesterol levels and/or triglyceride levels In certain of these embodiments administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in total cholesterol non-HDL cholesterol LDL, LDL particle, small LDL particle oxidized LDL and/or ApoB levels In certain embodiments administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an increase in HDL levels and/or LDL particle size In certain embodiments, administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an improvement in HDL/LDL ratio In certain embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered simultaneously In certain of these embodiments the one or more sPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered in a single formulation, while in other embodiments the compounds may be administered simultaneously in two or more formulations In each of these embodiments, the formulatιon(s) may further comprise one or more pharmaceutically acceptable carriers In other embodiments the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered sequentially In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments, the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more sPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg In certain embodiments, administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in levels of one or more inflammatory markers In certain of these embodiments, the inflammatory markers may include but are not limited to, SPLA2, CRP, and/or IL-6
[0011] In certain embodiments, methods are provided for decreasing cholesterol levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD In certain embodiments the one or more sPLA2 inhibitors comprise A-001 or a pharmaceutically acceptable prodrug, salt, polymorph co-crystal, or solvate of A-001 In certain of these embodiments the one or more sPLA2 inhibitors comprise A-002 a prodrug of A-001 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin lovastatin pravastatin cerivastatin, fluvastatin mevastatin, pravastatin, and various salts, solvates, stereoisomers, and prodrug derivatives thereof In certain of these embodiments, the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK- 0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors angiotensin Il receptor antagonists, beta- adrenergic blockers, calcium channel blockers, and antithrombotics In certain embodiments, administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in total cholesterol, non-HDL cholesterol, LDL, LDL particle small LDL particle levels, oxidized LDL and/or ApoB levels In certain embodiments administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an increase in LDL particle size In certain embodiments, administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an improvement in HDL/LDL ratio In certain embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered simultaneously In certain of these embodiments the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered in a single formulation, while in other embodiments the compounds may be administered simultaneously in two or more formulations In each of these embodiments, the formulatιon(s) may further comprise one or more pharmaceutically acceptable carriers In other embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered sequentially In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments, the one or more sPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more sPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg
[0012] In certain embodiments, methods are provided for decreasing triglyceride levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 In certain of these embodiments, the one or more sPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin fluvastatin, mevastatin, pravastatin, and various salts, solvates, stereoisomers, and prodrug derivatives thereof In certain of these embodiments the statin combination drugs are selected ftom the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus AP A-01 , simvastatin plus ezetimibe simvastatin plus extended release niacin, simvastatin plus MK- 0524A lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta- adrenergic blockers, calcium channel blockers and antithrombotics In certain embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered simultaneously In certain of these embodiments the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered in a single formulation, while in other embodiments the compounds may be administered simultaneously in two or more formulations In each of these embodiments, the formulatιon(s) may further comprise one or more pharmaceutically acceptable carriers In other embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered sequentially In certain embodiments, the one or more sPLA^ inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments, the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg
[0013] In certain embodiments methods are provided for increasing HDL levels in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt polymorph, co-crystal or solvate of A-O01. In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain of these embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin. pravastatin and various salts, solvates, stereoisomers and prodrug derivatives thereof In certain of these embodiments, the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine atorvastatin plus CP-529414, atorvastatin plus AP A-01 , simvastatin plus ezetimibe simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fen ofib rate and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics In certain embodiments, administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an improvement in HDL/LDL ratio In certain embodiments, improvement in HDL/LDL ratio is further accomplished by a reduction in LDL levels In certain embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered simultaneously In certain of these embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered in a single formulation, while in other embodiments the compounds may be administered simultaneously in two or more formulations in each of these embodiments the formulatιon(s) may further comprise one or more pharmaceutically acceptable carriers In other embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered sequentially In certain embodiments the one or more sPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg [0014] In certain embodiments, methods are provided for treating CVD or a condition associated with CVD in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug salt polymorph, co-crystal, or solvate of A-001 In certain of these embodiments, the one or more SPLA2 inhibitors comprise A- 002, a prodrug of A-001 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin lovastatin pravastatin, cerivastatin, fluvastatin, mevastatin, pravastatin, and various salts, solvates, stereoisomers, and prodrug derivatives thereof In certain of these embodiments, the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics In certain embodiments, administration of one or more SPLA2 inhibitors results in a decrease in levels of one or more inflammatory markers In certain of these embodiments, the inflammatory markers may include, but are not limited to, SPLA2, CRP, and/or IL-6 In certain embodiments, CVD or a condition associated with CVD includes, but is not limited to, atherosclerosis, metabolic syndrome coronary artery disease, coronary heart disease, cerebrovascular disease, peripheral vascular disease, and/or conditions associated with coronary artery disease, coronary heart disease cerebrovascular disease, or peripheral vascular disease In certain embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered simultaneously In certain of these embodiments the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered in a single formulation, while in other embodiments the compounds may be administered simultaneously in two or more formulations In each of these embodiments, the formulatιon(s) may further comprise one or more pharmaceutically acceptable carriers In other embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered sequentially In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day in other embodiments, the one or more sPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg
[0015] in certain embodiments, methods are provided for treating metabolic syndrome in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 In certain of these embodiments, the one or more sPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, ceπvastatin, fluvastatin, mevastatin, pravastatin, and various salts solvates, stereoisomers, and prodrug derivatives thereof In certain of these embodiments, the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK- 0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates niacin or niacin derivatives cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta- adrenergic blockers calcium channel blockers, and antithrombotics In certain embodiments, administration of one or more SPLA2 inhibitors results in a decrease in levels of one or more inflammatory markers In certain of these embodiments, the inflammatory markers may include, but are not limited to, SPLA2 CRP and/or IL-6 In certain embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered simultaneously In certain of these embodiments the one or more sPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered in a single formulation, while in other embodiments the compounds may be administered simultaneously in two or more formulations In each of these embodiments the formulatιon(s) may further comprise one or more pharmaceutically acceptable carriers In other embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered sequentially In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments, the one or more sPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg
[0016] In certain embodiments, methods are provided for increasing the effectiveness of a compound used in the treatment of CVD in a subject by administering one or more SPLA2 inhibitors to said subject In certain embodiments the one or more sPLA? inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain embodiments, the compound used in the treatment of CVD may be a statin or statin combination drug In certain of these embodiments, the statin may be selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin ceπvastatin, fluvastatin, mevastatin, pravastatin, and various salts, solvates, stereoisomers and prodrug derivatives thereof In certain of these embodiments, the statin combination drug may be selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodtpine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK- 0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments the compound used in the treatment of CVD may be a non- statin compound selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers calcium channel blockers, and antithrombotics In certain embodiments, the one or more sPLA^ inhibitors may be administered simultaneously with the compound used in the treatment of CVD In certain of these embodiments, the one or more sPLA2 inhibitors and the compound used in the treatment of CVD may be administered in a single formulation, while in other embodiments the compounds may be administered simultaneously in two or more formulations In each of these embodiments, the formulatιon(s) may further comprise one or more pharmaceutically acceptable carriers In other embodiments, the one or more sPLA2 inhibitors and the compound used in the treatment of CVD may be administered sequentially In certain embodiments, the one or more SPLA2 inhibitors may be administered to the subject twice or more per day, and in certain of these embodiments the one or more SPLA2 inhibitors are administered twice per day In other embodiments the one or more SPLA2 inhibitors may be administered to the subject on a once a day basis In certain embodiments, the one or more SPLA2 inhibitors may be administered at a dosage of about 50 to about 500 mg
[0017] In certain embodiments, the use of one or more SPLA2 inhibitors for preparation of a medicament for treating dyslipidemia, treating CVD and conditions associated with CVD, lowering cholesterol levels lowering triglyceride levels, increasing HDL levels, and improving HDL/LDL ratios in a subject is provided In certain embodiments the one or more sPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 In certain of these embodiments, the one or more sPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain embodiments, the medicament further comprises one or more pharmaceutically acceptable carriers
[0018] In certain embodiments, the use of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD for preparation of a medicament for treating dyslipidemia, treating CVD and conditions associated with CVD lowering cholesterol levels lowering triglyceride levels, increasing HDL levels and/or improving HDL/LDL ratios in a subject is provided In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt polymorph, co-crystal, or solvate of A-O01 In certain of these embodiments, the one or more SPLA2 inhibitors comprise A-002, a prodrug of A-O01 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments the one or more statins are selected from the group consisting of atorvastatin simvastatin rosuvastatin lovastatin, pravastatin cerivastatin, fluvastatin, mevastatin pravastatin and various salts solvates, stereoisomers, and prodrug derivatives thereof In certain of these embodiments, the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine atorvastatin plus CP-529414 atorvastatin plus APA-01 simvastatin plus ezetimibe, simvastatin plus extended release niacin simvastatin plus MK-0524A, lovastatin plus extended release niacin rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics In certain embodiments, the medicament further comprises one or more pharmaceutically acceptable carriers
[0019] In addition to the exemplary embodiments described above, further embodiments and aspects will become apparent by reference to the drawings and by study of the following descriptions
BRIEF DESCRIPTION OF DRAWINGS
[0020] Figure 1 Effect of A-002 administration on body weight in mice ApoE ; mice were administered vehicle only 30 mg/kg A-002 or 90 mg/kg A- 002 twice daily over 16 weeks Body weight was measured once a week [0021] Figure 2 Effect of A-002 administration on plasma total cholesterol levels in mice ApoE ' mice were administered vehicle only, 30 mg/kg A-002 or 90 mg/kg A-002 twice daily over 16 weeks Total plasma cholesterol levels were measured at 0 4 8 12 and 16 weeks
[0022] Figure 3 Effect of A-002 administration on atherosclerotic plaque coverage in mice ApoE 7 mice were administered vehicle only, 30 mg/kg A- 002 or 90 mg/kg A-002 twice daily over 16 weeks At 16 weeks aortic plaque coverage was measured
[0023] Figure 4 Effect of A-002 administration on angiotensin ll-mediated atherosclerotic plaque formation and aortic aneurysm ApoE ' mice were administered saline plus water angiotensin Il in water vehicle, angiotensin Il in acacia vehicle or angiotensin Il in acacia vehicle plus 30 mg/kg A-002 At 4 weeks, aortic plaque coverage was measured [0024] Figure 5 En face lesions in A-002 and/or statin dosage groups ApoE ' mice on a high fat diet were administered various dosages of A-002 statin, or A-002 plus statin over twelve weeks and en face lesion content was measured using digital imaging methods Lesion size is expressed as percent coverage over entire tissue sample A low dose A-002, B high dose A-002, C statin, D low dose A-002 plus statin, E high dose A-002 plus statin, and F vehicle only
[0025] Figure 6 Total plasma cholesterol levels in A-002 and/or statin dosage groups ApoE ' mice on a high fat diet were administered various dosages of A-002, statin, or A-002 plus statin over twelve weeks, and total cholesterol levels were measured A low dose A-002 B high dose A-002, C statin, D low dose A-002 plus statin, E high dose A-002 plus statin and F vehicle only
[0026] Figure 7 HDL levels in A-002 and/or statin dosage groups ApoE ' mice on a high fat diet were administered various dosages of A-002, statin or A-002 plus statin over twelve weeks, and HDL levels were measured A low dose A-002, B high dose A-002, C statin, D low dose A-002 plus statin E high dose A-002 plus statin, and F vehicle only
[0027] Figure 8 A-002/sιmvastatιn combination tablet preparation protocol [0028] Figure 9 HPLC profiles A Simvastatin B A-002 C A- 002/sιmvastatιn combination tablet #19 D A-002/sιmvastatιn combination tablet #27
DETAILED DESCRIPTION
[0029] The following description of the invention is merely intended to illustrate various embodiments of the invention As such, the specific modifications discussed are not to be construed as limitations on the scope of the invention It will be apparent to one skilled in the art that various equivalents, changes and modifications may be made without departing from the scope of the invention, and it is understood that such equivalent embodiments are to be included herein
Abbreviations
[0030] AA, arachidonic acid, ACE, angiotensin converting enzyme, Ang, angiotensin, ApoB, apolipoprotein B, ARB, Angiotensin Receptor Blocker, BID, twice daily, BMI, body mass index, CAD, coronary artery disease, CETP, cholesteryl ester transfer protein, cfm, cubic feet per minute, CHD, coronary heart disease, CRP, C-reactive protein, CVD cardiovascular disease, ECG, electrocardiogram, ERN, extended release niacin, HDL, high density lipoprotein HMG-CoA hydroxymethyl glutaryl coenzyme A, HPLC, high performance liquid chromatography, ICAM-1 , intercellular adhesion molecule 1 , IDL intermediate density lipoprotein IL interleukin (e g IL-6, IL-8) ITT, intent to treat, LDL, low density lipoprotein, LPA lysophosphatidic acid, MCP- 1 , monocyte chemotactic proteιn-1 , Ml, myocardial infarction, MIP-1α, macrophage inflammatory protein 1 alpha MTP microsomal triglyceride transfer protein PAD peripheral artery disease, PAF, platelet activating factor, PLA2, phosphohpase A2, QD, once daily, SPLA2, secretory phosphohpase A2, TEAE, treatment-emergent adverse event, TG, triglyceride TIA, transient ischemic attack, TNFα, tumor necrosis factor alpha, VCAM-1 , vascular cell adhesion molecule 1 , VLDL, very low density lipoprotein [0031] The terms "treat," "treating," or "treatment" as used herein with regards to a condition refers to preventing the condition, slowing the onset or rate of development of the condition reducing the risk of developing the condition, preventing or delaying the development of symptoms associated with the condition, reducing or ending symptoms associated with the condition, generating a complete or partial regression of the condition, or some combination thereof For example, with regard to atherosclerosis, "treatment" may refer to a decrease in the likelihood of developing atherosclerotic plaque deposits, a decrease in the rate of development of deposits, a decrease in the number or size of existing deposits, or improved plaque stability Likewise, "treatment" with regard to dyslipidemia may refer to a decrease in lipid levels, cholesterol levels, and/or triglyceride (TG) levels [0032] The term "subject" as used herein refers to any mammal preferably a human
[0033] In certain embodiments, a "subject in need thereof refers to a subject diagnosed with CVD or exhibiting one or more conditions associated with CVD, a subject who has been diagnosed with or exhibited one or more conditions associated with CVD in the past, or a subject who has been deemed at risk of developing CVD or one or more conditions associated with CVD in the future due to hereditary or environmental factors "Cardiovascular disease" or "CVD" as used herein includes, for example atherosclerosis, including coronary artery atherosclerosis and carotid artery atherosclerosis, coronary artery disease (CAD), coronary heart disease (CHD), conditions associated with CAD and CHD, cerebrovascular disease and conditions associated with cerebrovascular disease, peripheral vasculai disease and conditions associated with peripheral vascular disease, aneurysm, vasculitis, venous thrombosis, diabetes melhtus, and metabolic syndrome "Conditions associated with CAD and CHD" as used herein include, for example, angina and myocardial infarction (Ml, heart attack) "Conditions associated with cerebrovascular disease" as used herein include for example, transient ischemic attack (TlA) and stroke "Conditions associated with peripheral vascular disease" as used herein include, for example, claudication "Conditions associated with CVD" as used herein include, for example, dyshpidemia such as for example hyperiipidemia (elevated lipid levels), hypercholesterolemia (elevated cholesterol levels), and hypertriglyceridemia (elevated TG levels), elevated glucose levels, low HDL/LDL ratio, and hypertension Therefore, in certain embodiments, a subject in need thereof may be a subject exhibiting dyslipidemia or a subject that has exhibited dyslipidemia in the past or has been deemed at risk for developing dyslipidemia in the future In certain of these embodiments, the subject may exhibit elevated cholesterol levels or may have exhibited elevated cholesterol levels in the past or been deemed at risk for developing elevated cholesterol levels in the future Likewise, in certain of these embodiments, the subject may exhibit elevated triglyceride levels, or may have exhibited elevated triglyceride levels in the past or been deemed at risk for developing elevated triglyceride levels in the future In certain embodiments, a subject in need thereof may have a condition associated with inflammation, may have been diagnosed with such a condition in the past, or may have been deemed at risk for developing such a condition in the future In addition to atherosclerosis and certain other forms of CVD, conditions associated with inflammation include, for example, multiple sclerosis (Cunningham 2006), Alzheimer's disease (Moses 2006), sickle cell (Styles 1996), rheumatoid arthritis, and osteoarthritis (Jamal 1998) In these embodiments, a subject in need thereof may exhibit elevated sPLA2 levels, may have exhibited elevated SPLA2 levels in the past, or may have been deemed at risk for developing elevated SPLA2 levels In other embodiments, a subject in need thereof may exhibit SPLA2 levels falling within a normal range In certain embodiments, a subject in need thereof may exhibit elevated levels of one or more additional markers associated with inflammation, including but not limited to CRP, IL-6, MCP-1 , TNFα, IL-8, ICAM-I 1 VCAM-I , and MIP-1 α
[0034] The term "cholesterol level" as used herein refers to blood cholesterol level, serum cholesterol level, plasma cholesterol level, or cholesterol level from another biological fluid A decrease in cholesterol levels as used herein may refer to a decrease in total cholesterol levels or a decrease in one or more of total cholesterol, non-HDL cholesterol, LDL, VLDL, and/or IDL levels A decrease in LDL as used herein may refer to a decrease in total LDL a decrease in LDL particles, a decrease in small LDL particles, a decrease in oxidized LDL levels, and/or a decrease in ApoB levels A decrease in VLDL as used herein may refer to a decrease in total VLDL or to a decrease in the level of one or more of VLDL subparticles V1 to V6 An improvement in HDL/LDL ratio as used herein refers to any increase in the ratio of HDL to LDL, and may be accomplished by decreasing LDL levels increasing HDL levels, or some combination thereof An increase in LDL particle size as used herein refers to an increase in mean particle size [0035] The term "elevated cholesterol level" as used herein refers to a cholesterol level that is above an accepted normal threshold level, such as those promulgated by the National Heart Lung and Blood Institute (NHLBI) National Cholesterol Education Program (NCEP) The accepted normal threshold cholesterol level may vary from subject to subject based on various risk factors, such as for example a prior history of CVD In certain embodiments, a subject exhibiting elevated cholesterol levels may have a blood LDL level greater than or equal to 70 mg/dl In certain of these embodiments, a subject exhibiting elevated cholesterol levels may have a blood LDL greater than or equal to 100 mg/dl, in other embodiments greater than or equal to 130 mg/dl, in other embodiments greater than or equal to 160 mg/dl, and in still other embodiments greater than or equal to 190 mg/dl In certain embodiments, a subject exhibiting elevated cholesterol levels may have a blood total cholesterol level greater than or equal to 200 mg/dl In certain of these embodiments, a subject exhibiting elevated cholesterol levels may have a blood total cholesterol greater than or equal to 240 mg/dl [0036] The term "triglyceride level" as used herein refers to blood triglyceride level, serum triglyceride level plasma triglyceride level, or triglyceride level from another biological fluid The term "elevated triglyceride level" as used herein refers to a triglyceride level that is above an accepted normal threshold level The accepted normal threshold triglyceride level may vary from subject to subject based on various risk factors such as for example a prior history of CVD In certain embodiments, a subject exhibiting elevated triglyceride levels may have a blood triglyceride level greater than or equal to 150 mg/dl In certain of these embodiments, a subject exhibiting elevated triglyceride levels may have a blood triglyceride level greater than or equal to 200 mg/dl, in other embodiments greater than or equal to 300 mg/dl, in other embodiments greater than or equal to 400 mg/dl, and in still other embodiments greater than or equal to 500 mg/dl [0037] The term "statin" as used herein refers to any compound that inhibits HMG-CoA reductase, an enzyme that catalyzes the conversion of HMG-CoA to mevalonate
[0038] The term "sPLA2 inhibitor" as used herein refers to any compound or prodrug thereof that inhibits the activity of SPLA2
[0039] A "therapeutically effective amount' of a composition as used herein is an amount of a composition that produces a desired therapeutic effect in a subject, such as treating a target condition The precise therapeutically effective amount is an amount of the composition that will yield the most effective results in terms of therapeutic efficacy in a given subject This amount will vary depending upon a variety of factors, including but not limited to the characteristics of the therapeutic composition (including, e g activity, pharmacokinetics, pharmacodynamics, and bioavailability) the physiological condition of the subject (including, e g age, body weight, sex, disease type and stage, medical history, general physical condition, responsiveness to a given dosage, and other present medications), the nature of the pharmaceutically acceptable carrier or carriers in the composition, and the route of administration One skilled in the clinical and pharmacological arts will be able to determine a therapeutically effective amount through routine experimentation, namely by monitoring a subject's response to administration of a composition and adjusting the dosage accordingly For additional guidance, see, e g , Remington The Science and Practice of Pharmacy, 21 st Edition, Univ of Sciences in Philadelphia (USIP), Lippincott Williams & Wilkins, Philadelphia, PA, 2005 and Goodman & Gilman's The Pharmacological Basis of Therapeutics, 1 1th Edition, McGraw-Hill, New York, NY, 2006, the entire disclosures of which are incorporated by reference herein
[0040] A "pharmaceutically acceptable carrier" as used herein refers to a pharmaceutically acceptable material, composition, or vehicle that is involved in carrying or transporting a compound of interest from one tissue organ, or portion of the body to another tissue, organ, or portion of the body Such a carrier may comprise, for example, a liquid, solid, or semi-solid filler, solvent, surfactant, diluent, excipient, adjuvant, binder, buffer, dissolution aid solvent, encapsulating material, sequestering agent, dispersing agent, preservative, lubricant disintegrant, thickener, emulsifier, antimicrobial agent antioxidant, stabilizing agent coloring agent, or some combination thereof Each component of the carrier must be "pharmaceutically acceptable" in that it must be compatible with the other ingredients of the composition and must be suitable for contact with any tissue, organ, or portion of the body that it may encounter, meaning that it must not carry a risk of toxicity, irritation allergic response, immunogenicity or any other complication that excessively outweighs its therapeutic benefits Examples of pharmaceutically acceptable carriers for use in the presently disclosed pharmaceutical compositions include, but are not limited to, diluents such as microcrystalline cellulose or lactose (e g , anhydrous lactose, lactose fast flo), binders such as gelatin, polyethylene glycol, wax, microcrystalline cellulose, synthetic gums such as polyvinylpyrrolidone, or cellulosic polymers such as hydroxypropyl cellulose (e g , hydroxypropyl methylcellulose (HPMC)), lubricants such as magnesium stearate, calcium stearate, stearic acid, or microcrystalline cellulose, disintegrants such as starches, cross-linked polymers, or celluloses (e g , croscarmellose sodium (CCNa), fillers such as silicon dioxide, titanium dioxide, microcrystaliine cellulose, or powdered cellulose, surfactants or emulsifiers such as polysorbates (e g , Polysorbate 20, 40 60, or 80, Span 20, 40, 60, 65, or 80) antioxidant agents such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, or ascorbic acid (either free acid or salt forms thereof), buffers such as phosphate or citrate buffers, sequestering agents such as ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), or edetate disodium, dispersing agents such as sodium carboxymethylcelluose, hydroxypropyl methylcellulose, povidone, or polyvinylpyrrolidone, dissolution aids such as calcium carbonate, and excipients such as water, saline, dextrose, glycerol, or ethanol, citric acid, calcium metabisulfite, lactic acid, malic acid, succinic acid or tartaric acid
[0041] Metabolic syndrome is a disorder characterized by a group of metabolic risk factors These factors include, for example dyslipidemia abdominal obesity, elevated blood pressure (hypertension) insulin resistance or glucose intolerance, prothrombotic state, and proinflammatory state Subjects are generally classified as having metabolic syndrome if they meet three of the five following criteria 1 ) abdominal obesity (waist circumference >35 inches in women, >40 inches in men), 2) low HDL levels (<50 mg/dL in women, <40 mg/dL in men), 3) high blood pressure (>130/85 mm Hg) or current treatment with antihypertensive medication 4) hypertriglyceridemia (TG levels >150 mg/dL), and 5) impaired fasting glucose (blood glucose levels of >110 mg/dL) Metabolic syndrome is associated with elevated levels of various inflammatory markers, such as CRP or IL-6 Subjects with metabolic syndrome are at increased risk of developing CAD, CHD, conditions associated with CAD and CHD1 and type 2 diabetes
[0042] Over time, hypercholesterolemia and hypertriglyceridemia can lead to the development of atheromatous plaques on the inner arterial linings via the process of atherogenesis, which in turn results in atherosclerosis Atherosclerosis leads to significantly reduced blood flow through the arteries, which in turn leads to the development of CAD, CHD, and conditions associated with CAD and CHD
[0043] Reduction of cholesterol levels, particularly LDL levels, and/or reduction of TG levels have been shown to delay the onset and decrease the progression of atherosclerosis thereby reducing the risk of developing CAD and CHD In certain cases, adequate cholesterol and/or TG reduction may be accomplished through diet adjustment In other cases however, adequate reduction requires the administration of one or more compounds used in the treatment of CVD Compounds used in the treatment of CVD include compounds for lowering cholesterol levels and/or increasing HDL levels, such as for example statins, bile acid sequestrants such as cholestyramine resin (Questran® Prevalite®), colestipol hydrochloride (Colestid®), or colesevelam hydrochloride (WelChol® Cholestagel®), fibrates such as bezafibrate (Bezalip®) ciprofibrate (Modalim®), clofibrate, gemfibrozil (Lopid®), or fenofibrate (Antara®, TriCor®, ABT-335) niacin or niacin derivatives such as xanthinol niacinate, niacin immediate-release (Niacor®), extended release forms of niacin (ERN) (Niaspan®, Niaspan MF or Niaspan CF), or extended release niacin combinations (e g , extended release niacin plus the DP-1 antagonist laropiprant (MK-0524), combination known as MK-0524A and marketed as Cordaptive®), cholesterol absorption inhibitors such as ezetimibe (Zetia®), AVE 5530, or MD-0727 cholesteryl ester transfer protein (CETP) inhibitors such as JTT-705/RO4607381 (R1658), CP-529414 (Torcetrapib®), or MK-0859, microsomal triglyceride transfer protein (MTP) inhibitors such as AEGR-733 and AEGR-733 combinations (e g AEGR-733 plus ezetimibe), squalene synthase inhibitors such as lapaquistat acetate (TAK-475) and lapaquistat acetate combinations (e g , TAK-475 plus one or more statins), and other miscellaneous compounds such as dextrothyroxine, ISIS 301012 cardioprotectants such as MC-1 antibody, glycoprotein llb/liia inhibitors such as tirofiban hydrochloride (Aggrastat®), TG100-1 15, AEGR 773, AEGR 427, stanols, or sterols In addition to compounds that lower cholesterol levels or increase HDL levels, compounds used in the treatment of CVD include for example, ACE inhibitors such as lisinopril captopπl, enalapπl nitrosated ACE inhibitors, or ACE inhibitor combinations (e g , lisinopril plus MC-1 antibody, combination referred to as MC-4232) angiotensin Il receptor antagonists, nitrosated angiotensin Il receptor antagonists, or angiotensin Il receptor antagonist combinations (e g , Angiotensin Receptor Blocker (ARB) plus MC- 1 , combination referred to as MC-4262), beta-adrenergic blockers or nitrosated beta-adrenergic blockers, calcium channel blockers, or antithrombotics such as aspirin or nitrosated aspirin
[0044] Among the most well-known and commonly used compounds used tn the treatment of CVD are statins Statins are compounds that inhibit HMG- CoA reductase from catalyzing the conversion of HMG-CoA to mevalonate a rate-limiting step in the cholesterol biosynthetic pathway As such, statins function as potent lipid lowering agent Statin administration significantly decreases blood LDL levels and moderately decreases blood TG levels In addition it has been proposed that statins may prevent CVD by improving endothelial function, modulating inflammatory responses, maintaining plaque stability, and preventing thrombus formation Examples of statins that may be used in conjunction with the compositions and methods disclosed herein include but are not limited to, atorvastatin or atorvastatin calcium (marketed as Lipitor® or Torvast ®, see, e g , O S Patent Nos 4,681 ,893 or 5,273,995) and atorvastatin combinations (e g atorvastatin plus amlodipine (marketed as Norvasc®), combination marketed as Caduet®, see, e g , U S Patent No 6,455,574 atorvastatin plus CP-529414 (marketed as Torcetrapib®), atorvastatin plus APA-01 , atorvastatin plus ezetimibe), cerivastatin (marketed as Lipobay® or Baycol®), fluvastatin (marketed as Lescol® U S Patent No 4,739,073) lovastatin (marketed as Mevacor® or Altocor® see, e g , U S Patent No 4,231 ,938) lovastatin combinations (e g , lovastatin plus Niaspan®, combination marketed as Advicor®), mevastatin, pravastatin (marketed as Livalo® or Pitava®), pravastatin (marketed as Pravachol®, Mevalotin® Selektine®, or Lipostat®, see, e g , U S Patent No 4,346,227), pravastatin combinations (e g pravastatin plus fenofibrate), rosuvastatin (marketed as Crestor®) rosuvastatin combinations (e g , rosuvastatin plus TriCor®), simvastatin (marketed as Zocor® or Lipex®, see, e g , U S Patent Nos 4,444,784, 4,916,239, and 4,820,850), and simvastatin combinations (e g , simvastatin plus ezetimibe, combination marketed as Vytoπn®, see, e g . U S Patent No 7,229,982, simvastatin plus Niaspan®, combination marketed as Simcor®, simvastatin plus MK-0524A, combination referred to as MK-0524B), as well as various pharmaceutically acceptable salts, solvates, salts, stereoisomers, prodrugs derivatives, or nitroderivatives of the compounds listed above In some cases, such as for example with simvastatin, the active form of the statin is a metabolite formed in the body of a subject following administration In other cases, statins are administered in their active form
[0045] Phospholipases A2 (PLA2S) are a family of enzymes that catalyze hydrolysis of the sn-2 fatty acyl ester bond of phospholipids to produce free fatty acids and lysophospholipids such as arachidonic acid (AA) and lysophosphatidylcholine AA can then be converted into eicosanoids such as prostaglandins, leukotπenes, thromboxanes, and lipoxins, while lysophosphatidylcholine can be metabolized to lysophosphatidic acid (LPA) or platelet-activating factor (PAF) PLA2S have been classified into several groups based on factors such as cellular localization amino acid sequence molecular mass and calcium requirement for enzymatic activity (Ramoner 2005)
[0046] Secretory phospholipase A2 (sPLA2) is an extracellular or secreted subgroup of PLA2 that plays a role in inducing inflammation Elevated levels of SPLA2 types HA, HD, HE HF III, V, and X have been observed in all stages of atherosclerosis development and have been implicated in atherogenesis based on their ability to degrade phospholipid (Kimura-Matsumoto 2007) SPLA2 type HA has been found to be expressed at vascular smooth muscle cells and foam cells in human arteriosclerosis lesions and this expression has been recognized to have a correlation with the development of arteriosclerosis (Menschikowski 1995 Elinder 1997) Transgenic mice that express high levels of human type HA SPLA2 have increased LDL levels, decreased HDL levels, and arteriosclerotic lesions (Ivandic 1999, Tietge 2000), and develop arteriosclerosis at a higher rate compared to normal mice when given a high fat diet (Ivandic 1999) Treatment with SPLA2 modifies LDL lipoproteins such that they have higher affinity for extracellular matrix proteins (Camejo 1998, Sartipy 1999, Hakala 2001), resulting in an increased retention of LDL particles in the arterial wall In addition, there is some evidence that SPLA2 remodels HDL, resulting in HDL catabolism (Pruzanski 1998) Increased expression of sPLA2 type V has been shown to increase arteriosclerosis in mice, while a deficiency of SPLA2 type V has been shown to reduce arteriosclerosis (Rosengren 2006, Bostrom 2007)
[0047] sPLA2 expression has also been correlated with an increased risk of development of CAD Higher circulating levels of SPLA2 and of SPLA2 type ilA specifically, have been observed in patients with documented CAD than in control patients (Kugiyama 1999 Uu 2003, Boekholdt 2005, Chait 2005 Hartford 2006) In addition, higher circulating levels of SPLA2 were found to provide an accurate prognostic indicator for development of CAD in healthy individuals (Mallat 2007) Measurement of SPLA2 activity has been shown to be an independent predictor of death and new or recurrent myocardial infarction in subjects with acute coronary syndrome, and provides greater prognostic accuracy than measuring type MA concentration only (Mallat 2005) It has also been proposed that SPLA2 may have detrimental effects in the setting of ischemic events This is based largely on the finding of SPLA2 depositions in the necrotic center of infarcted human myocardium (Nijmeijer 2002) [0048] As disclosed herein, administration of the SPLA2 inhibitor A-002, which is a prodrug form of A-O01 , decreased plasma total cholesterol levels increased plasma HDL levels, and decreased atherosclerotic plaque formation and aortic aneurysm in mice In humans with CVD twice daily administration of A-002 decreased serum LDL, LDL particle, small LDL particle, total cholesterol and TG levels Decreases in LDL were observed in a diabetic subpopulation as well as in a subpopulation exhibiting elevated baseline LDL levels, while decreases in TG levels were observed in a metabolic syndrome subpopulation Additionally, administration of A-002 was found to decrease serum levels of the inflammatory markers SPLA2, CRP and IL-6 Surprisingly, similar results were obtained with once a day administration of A-002 which caused a decrease in LDL non-HDL cholesterol, total cholesterol, small LDL particle, oxidized LDL, triglyceride, and ApoB levels and an increase in LDL particle size In addition, once a day dosing with A-002 prevented the large increase in CRP levels observed in the placebo group Based on the experimental results disclosed herein showing that administration of SPLA2 inhibitors decreases total cholesterol levels atherosclerotic plaque formation, and aortic aneurysm in mice decreases total cholesterol, non-HDL cholesterol, LDL, LDL particle small LDL particle, oxidized LDL particle, TG, and ApoB levels in humans, and increases LDL particle size in humans administration of a therapeutically effective amount of one or more SPLA2 inhibitors may be used to treat CVD and conditions associated with CVD, such as for example dyshpidemia, atherosclerosis metabolic syndrome, CAD, CHD and conditions associated with CAD and CHD [0049] Provided herein in certain embodiments are methods of treating CVD and conditions associated with CVD in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors In certain of these embodiments, administration of one or more SPLA2 inhibitors may result in, among other effects, a decrease in cholesterol levels, a decrease in TG levels, an increase in LDL particle size, and/or an improvement in HDL/LDL ratio Therefore, also provided herein are methods of treating dyslipidemia in a subject in need thereof In certain embodiments, one or more SPLA2 inhibitors for use in these methods comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 In certain of these embodiments, the pharmaceutically acceptable prodrug is A-002 In certain embodiments, administration of one or more SPLA2 inhibitors may result in a decrease in one or more markers associated with inflammation Such markers include but are not limited to, SPLA2, CRP, and IL-6 Also provided herein are compositions comprising one or more SPLA2 inhibitors for use in the methods disclosed herein, such as for example in the treatment of CVD, conditions associated with CVD, and/or dyslipidemia or to lower total cholesterol, LDL non-HDL cholesterol, LDL particle, small LDL particle, oxidized LDL, ApoB, and/or triglyceride levels or to raise HDL levels In certain embodiments, these compositions further comprise one or more pharmaceutically acceptable carriers
[0050] Compositions comprising one or more SPLA2 inhibitors for use in the methods disclosed herein may be administered to a subject on a one-time basis or in multiple administrations In those embodiments wherein these compositions are given in multiple administrations, the compositions may be administered at set intervals over a particular time period determined in advance, or they may be administered indefinitely or until a particular therapeutic benchmark is reached, such as for example until a subject exhibits cholesterol levels below a specified threshold In certain embodiments, the one or more SPLA2 inhibitors may be administered from one or more times per day to once every week, once every month, or once every several months In certain embodiments, the one or more SPLA2 inhibitors may be administered twice a day, and in other embodiments the one or more sPLA^ inhibitors may be administered once a day As disclosed herein, both twice a day and once a day administration of A-002 resulted in significant decreases in serum lipid levels
[0051] In certain embodiments kits are provided that comprise one or more SPLA2 inhibitors In certain embodiments the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug salt, polymorph co-crystal, or solvate of A-001 , and in certain of these embodiments, the pharmaceutically acceptable prodrug is A-002 In certain embodiments, the kit provides instructions for usage, such as dosage or administration instructions
[0052] As disclosed herein, twice daily administration of A-002 was shown to further decrease total cholesterol levels in mice and LDL, LDL particle, and small LDL particle levels in humans that were receiving statin treatment Likewise, A-002 was shown to further decrease serum LDL levels in humans that were receiving ezetimibe treatment Similar results were obtained when A-002 was administered once a day in combination with statins These results indicate that administration of an sPLA? inhibitor unexpectedly causes an additional decrease in cholesterol levels in subjects that are already being treated with another compound used in the treatment of CVD, such as a statin As further disclosed herein, administration of A-002 in conjunction with statins resulted in an unexpected synergistic decrease in total cholesterol levels and aortic lesion formation in mice and in LDL and small LDL particle levels in humans The synergistic decrease in LDL following coadministration of A-002 and statins was observed in the statin subpopulation as a whole In addition synergism appeared to occur between A-002 and each of the individual statins within the general statin subpopulation, although statistical analysis of this effect was complicated by the limited number of test and placebo subjects for each statin These results indicate that the synergistic decrease in LDL levels generated by co-admmistration of A-002 and statins is not limited to one particular statin but rather occurs across the entire range of statins Administration of A-002 in conjunction with ezetimibe led to a similar synergistic decrease in LDL levels, indicating that the synergism between A-002 and compounds used in the treatment of CVD is not limited to statins Therefore, methods are provided herein for treating CVD and conditions associated with CVD including dyslipidemia and atherosclerosis, in a subject in need thereof by administering a therapeutically effective amount of one or more sPLA? inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD, such as for example statins Also provided herein are methods of increasing the effectiveness of a compound used in the treatment of CVD, such as for example a statin by administering one or more SPLA2 inhibitors in conjunction with the compound used in the treatment of CVD [0053] Provided herein in certain embodiments are methods of treating dyslipidemia in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 , and in certain of these embodiments the pharmaceutically acceptable prodrug is A-002 In certain embodiments the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, ceπvastatin, fluvastatin mevastatin, and pravastatin and the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non- statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin M receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics In certain of these embodiments, the one or more compounds used in the treatment of CVD comprise ezetimibe In certain embodiments, administration of one or more SPLA2 inhibitors and one or more statins results in a decrease in cholesterol levels, and in certain of these embodiments the decrease in cholesterol levels is greater than that observed following administration of one or more SPLA2 inhibitors or one or more statins alone In certain of these embodiments the decrease in cholesterol levels is synergistic meaning that the decrease is greater than the expected additive effect of one or more SPLA2 inhibitors and one or more statins In certain of these embodiments administration of one or more SPLA2 inhibitors and one or more statins results in an improved HDL/LDL ratio, either by decreasing LDL levels, increasing HDL levels or both
[0054] Provided herein in certain embodiments are methods of treating CVD or conditions associated with CVD in a subject in need thereof by administering a therapeutically effective amount of one or more SPLA2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD In certain embodiments the one or more SPLA2 inhibitors comprise A-001 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001 , and in certain of these embodiments, the pharmaceutically acceptable prodrug is A-002 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin rosuvastatin, lovastatin, pravastatin, cerivastatin fluvastatin, mevastatin, and pravastatin, and the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics In certain of these embodiments, the one or more compounds used in the treatment of CVD comprise ezetimibe In certain embodiments treatment of CVD or a condition associated with CVD may be associated with a decrease in cholesterol levels In other embodiments, however treatment of certain forms of CVD may not be associated with a concomitant decrease in cholesterol levels For example, sPLA2 inhibitor and statin administration may result in a decrease in atherosclerotic plaque formation without a measurable decrease in cholesterol levels via a mechanism such as inhibition of inflammation In these embodiments, treatment of CVD may be associated with a decrease in levels of one or more inflammatory markers such as for example SPLA2, CRP, and/or IL-6 In certain embodiments, administration of a combination of one or more SPLA2 inhibitors and one or more statins results in a greater degree of treatment than that observed following administration of one or more SPLA2 inhibitors or statins alone In certain of these embodiments, the degree of treatment is synergistic, meaning that the degree of treatment is greater than the expected additive effect of one or more SPLA2 inhibitors and one or more statins [0055] Provided herein in certain embodiments are methods for increasing the effectiveness of a compound used in the treatment of CVD by administering one or more SPLA2 inhibitors in conjunction with the compound used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt polymorph, co-crystal or solvate of A-001 , and in certain of these embodiments, the pharmaceutically acceptable prodrug is A-002 In certain embodiments the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin rosuvastatin lovastatin pravastatin, cerivastatin, fluvastatin mevastatin, and pravastatin and the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics In certain of these embodiments, the one or more compounds used in the treatment of CVD comprise ezetimibe An increase in effectiveness of a compound used in the treatment of CVD as used herein refers to an increase the therapeutic effect of the compound, a decrease in the dosage of the compound required to obtain a particular level of therapeutic effect, or some combination thereof For example an increase in effectiveness of a statin as used herein may refer to a greater decrease in LDL levels following administration of a particular dosage of a statin, a decrease in the dosage of statin required to bring about a particular decrease in LDL levels, or some combination thereof
[0056] Likewise, in certain embodiments methods are provided for increasing the effectiveness of an sPLA2 inhibitor by administering one or more compounds used in the treatment of CVD In certain embodiments the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 and in certain of these embodiments, the pharmaceutically acceptable prodrug is A-002 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin and pravastatin, and the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics In certain of these embodiments the one or more compounds used in the treatment of CVD comprise ezetimibe [0057] In certain embodiments one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD, such as for example one or more statins, may be administered to a subject separately, ; e , as separate compositions In these embodiments, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered simultaneously or sequentially Further, the one or more SPLA2 inhibitors and the one or more compounds used in the treatment of CVD may be administered at different times, and one compound may be administered more frequently than another In certain embodiments wherein the one or more compounds used in the treatment of CVD are statins and wherein the SPLA2 inhibitors and/or statins are given in multiple administrations, one or both may be administered anywhere from once or more times per day to once every week, once every month, or once every several months In certain preferred embodiments, the one or more SPLA2 inhibitors and/or statins may be administered twice a day, and in other preferred embodiments the one or more SPLA2 inhibitors and/or statins may be administered once a day [0058] In certain embodiments, kits are provided that comprise one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-O01 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-O01 , and in certain of these embodiments, the pharmaceutically acceptable prodrug is A-002 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, ceπvastatin fluvastatin, mevastatin, and pravastatin, and the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin simvastatin plus MK-0524A, lovastatin plus extended release niacin rosuvastatin plus fenofibrate pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non- statin compounds selected from the group consisting of bile acid sequestrants, fibrates niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics Within the kit the one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD may be divided into separate compartments For example, the kit may comprise multiple bottles or packets, wherein each bottle or packet contains either one or more SPLA2 inhibitors or one or more compounds used in the treatment of CVD In other embodiments, the one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD may be found in a single, undivided container In certain embodiments, the kit provides instructions for usage such as dosage or administration instructions [0059] Provided herein in certain embodiments are pharmaceutical compositions comprising a therapeutically effective amount of one or more SPLA2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD In certain embodiments, the one or more SPLA2 inhibitors comprise A-001 or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal, or solvate of A-001 , and in certain of these embodiments the pharmaceutically acceptable prodrug is A-002 In certain embodiments the one or more compounds used in the treatment of CVD comprise one or more statins or statin combination drugs In certain of these embodiments, the one or more statins are selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, ceπvastatin, fluvastatin mevastatin, and pravastatin, and the statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus AP A-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 In certain embodiments, the one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers calcium channel blockers, and antithrombotics In certain of these embodiments the one or more compounds used in the treatment of CVD comprise ezetimibe [0060] Pharmaceutical compositions comprising one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD, such as for example one or more statins, may be administered to a subject on a onetime basis or in multiple administrations In those embodiments wherein the compositions are given in multiple administrations they may be administered at set intervals over a particular time period determined in advance, or they may be administered indefinitely or until a particular therapeutic benchmark is reached such as for example until a subject exhibits cholesterol levels, triglyceride levels, or inflammatory marker levels that are below a specified threshold In certain embodiments the compositions may be administered from once or more times per day to once every month or once every several months In certain of these embodiments the compositions are administered once or twice per day [0061] Pharmaceutical compositions comprising one or more SPLA2 inhibitors, one or more compounds used in the treatment of CVD, or one or more SPLA2 inhibitors plus one or more compounds used in the treatment of CVD as disclosed herein may be delivered to a subject by any administration pathway known in the art, including but not limited to oral, aerosol, enteral, nasal, ophthalmic, parenteral, or transdermal (e g , topical cream or ointment patch) "Parenteral" refers to a route of administration that is generally associated with injection, including infraorbital, infusion intraarterial, intracapsular, intracardiac, intradermal, intramuscular intraperitoneal intrapulmonary intraspinal, intrasternal, intrathecal, intrauterine, intravenous subarachnoid, subcapsular, subcutaneous transmucosal, or transtracheal SPLA2 inhibitor, statin, or combined SPLA2 inhibitor and statin pharmaceutical compositions as described herein may be administered in any pharmaceutically acceptable form including for example in the form of a solid liquid solution, suspension, emulsion dispersion, micelle, or liposome Preparations for injection may include sterile solutions ready for injection, sterile dry soluble products, such as lyophilized powders, ready to be combined with a solvent just prior to use, including hypodermic tablets, sterile suspensions ready for injection, sterile dry insoluble products ready to be combined with a vehicle just prior to use and sterile emulsions The solutions may be either aqueous or nonaqueous In certain embodiments the compositions may comprise one or more pharmaceutically acceptable carriers or may be administered in conjunction with one or more pharmaceutically acceptable carriers [0062] In certain embodiments, pharmaceutical compositions comprising one or more sPLA2 inhibitors, one or more compounds used in the treatment of CVD or one or more SPLA2 inhibitors plus one or more compounds used in the treatment of CVD as described herein may be formed into oral dosage units, such as for example tablets, pills, or capsules Such an oral dosage unit may comprise the active ingredients (e g , A-002 and one or more statins) and one or more pharmaceutically acceptable carriers As disclosed herein, the feasibility of such an oral dosage unit was demonstrated by producing a batch of tablets comprising A-002 and simvastatin as the active ingredients Each tablet was formulated with 250 mg of A-002 and 40 mg of simvastatin Pharmaceutically acceptable carriers utilized in formulating the tablets included anhydrous lactose, lactose fast flo, and microcrystalline cellulose as diluents hydroxypropyl cellulose as a binder, croscarmellose sodium as a disintegrants butylated hydroxyanisole as an antioxidant, magnesium stearate as a lubricant and polysorbate 80 as a surfactant Water was used as a solvent when formulating the tablet The final tablets contained high concentrations of both active ingredients as determined by HPLC analysis, indicating that an SPLA2 inhibitor and one or more compounds used in the treatment of CVD, such as for example one or more statins, may be formulated into a single oral dosage unit The specific tablet formulation disclosed herein is provided as an example only One of ordinary skill in the art will recognize that the therapeutically acceptable carriers utilized in the formulation may be varied, and that such variations are routine in the art Likewise, the active ingredients may vary As disclosed herein, administration of A-002 in combination with a variety of statins causes a synergistic decrease in serum lipid levels Therefore, in certain embodiments, A-002 may be combined with any statin known in the art, including but not limited to atorvastatin or atorvastatin calcium, cerivastatin fluvastatin, lovastatin mevastatin, pravastatin, pravastatin, rosuvastatin, and/or simvastatin In certain embodiments, an oral dosage unit may comprise a coating that surrounds the active ingredients and pharmaceutically acceptable camer(s) [0063] In certain embodiments, pharmaceutical compositions comprising one or more SPLA2 inhibitors, one or more compounds used in the treatment of CVD, or one or more SPLA2 inhibitors plus one or more compounds used in the treatment of CVD as disclosed herein may be administered via a time release delivery vehicle, such as for example a time release oral dosage unit A "time release vehicle" as used herein refers to any delivery vehicle that releases active agent (e g , A-002 and one or more statins) at some time after administration or over a period of time following administration rather than immediately upon administration Time release may be obtained by a coating on the vehicle that dissolves over a set timeframe following administration In certain embodiments, the time release vehicle may comprise multiple layers of coating alternated with multiple layers of active ingredients, such that each layer of coating releases a certain volume of active ingredients as it dissolves In other embodiments, SPLA2 inhibitor, statin, or combined SPLA2 inhibitor and statin pharmaceutical compositions may be administered via an immediate release delivery vehicle
[0064] A therapeutically effective amount of an SPLA2 inhibitor or a compound used in the treatment of CVD for use in the methods or compositions disclosed herein may be determined for each compound individually For example, statins or statin combination drugs may be administered or included in a pharmaceutical composition at a dosage that is well known in the art to decrease cholesterol levels One of skill in the art will recognize that in those embodiments wherein one or more compounds used in the treatment of CVD are combined with one or more SPLA2 inhibitors in a single composition, the amount of the compound used in the treatment of CVD that constitutes a therapeutically effective amount may be different than the amount of the compound that constitutes a therapeutically effective amount of the compound when administered alone due to, for example, interactions between the compound and the one or more SPLA2 inhibitors For example, the effective dosage of a statin for use in combination therapy may be lower than the standard dosage for the statin when administered alone In this situation, one of skill in the art will be able to readily determine a therapeutically effective amount for the combination composition using methods well known in the art In certain embodiments, a therapeutically effective amount of an SPLA2 inhibitor for use alone or in combination with one or more compounds used in the treatment of CVD may be from about 5 to about 10,000 mg/dose In certain of these embodiments, a therapeutically effective amount of an SPLA2 inhibitor may be from about 25 to about 5,000 mg/dose and in certain of these embodiments a therapeutically effective amount may be from about 50 to about 500 mg/dose [0065] In certain embodiments, an SPLA2 inhibitor for use in the compositions and methods disclosed herein may be an indole-based SPLA2 inhibitor, meaning that the compound contains an indole nucleus having the structure
Figure imgf000056_0001
[0066] A variety of indole-based sPLA^ inhibitors are known in the art For example, indole-based sPLA2 inhibitors that may be used in conjunction with the present invention include but are not limited to those set forth in U S Patent Nos 5,654,326 (Bach) 5,733,923 (Bach), 5,919,810 (Bach), 5,919,943 (Bach), 6, 175 021 (Bach), 6,177 440 (Bach), 6,274,578 (Denney), and 6,433 001 (Bach), the entire disclosures of which are incorporated by reference herein Methods of making indole-based SPLA2 inhibitors are set forth in, for example, U S Patent Nos 5,986,106 (Khau), 6,265,591 (Anderson), and 6,380 397 (Anderson), the entire disclosures of which are incorporated by reference herein SPLA2 inhibitors for use in the present invention may be generated using these synthesis methods or using any other synthesis method known in the art In certain embodiments SPLA2 inhibitors for use in the present invention may be sPLA2 type HA, type V, and/or type X inhibitors Various examples of indole-based sPLA2 inhibitors are set forth below These examples are merely provided as illustrations of the types of inhibitors that may be used in conjunction with the present invention, and as such are not meant to be limiting One of ordinary skill in the art will recognize that a variety of other indole-based SPLA2 inhibitors may be used
[0067] In certain embodiments, SPLA2 inhibitors for use in the current invention are 1 H-ιndole-3-glyoxylamide compounds having the structure
Figure imgf000057_0001
wherein each X is independently oxygen or sulfur,
R1 is selected from the group consisting of (a), (b), and (c), wherein
(a) is C7-C20 alkyl, C7-C2O alkenyl, C7-C2O alkynyl, carbocyclic radicals, or heterocyclic radicals,
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents and
(c) is the group -(L) -Rso, where, -(L)- is a divalent linking group of 1 to 12 atoms selected from carbon hydrogen, oxygen, nitrogen and sulfur, wherein the combination of atoms in -(L)- are selected from the group consisting of (i) carbon and hydrogen only, (n) sulfur only, (IN) oxygen only, (ιv) nitrogen and hydrogen only (v) carbon, hydrogen, and sulfur only, and (vι) carbon, hydrogen, and oxygen only, and where Rgo is a group selected from (a) or (b),
R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -O- (Ci-C2 alkyl), -S-(Ci-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen,
R4 and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -(La)-(acιdιc group), wherein -(L9)- is an acid linker having an acid linker length of 1 to 4, provided that at least one of R4 and R5 must be -(La)-(acιdιc group),
R6 and R7 are each independently selected from hydrogen, non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non- interfeπng substituents, heterocyclic radicals and heterocyclic radicals substituted with non-interfering substituents, provided that for any of the groups Ri, Re, and R7, the carbocyclic radical is selected from the group consisting of cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, tolulyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenly acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb),
Figure imgf000058_0001
where n is a number from 1 to 8, provided, that for any of the groups Ri RQ and R7, the heterocyclic radical is selected from the group consisting of pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazoiyl, phenylimidazolyl, triazolyl isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, ιmιdazo(1 2-A)pyrιdιnyl, benzotπazolyl, anthranilyl, 1 2- benzisoxazolyl, benzoxazolyl, benzotnazolyl, purinyl pryidinyl, dipyridylyl phenylpyπdinyl, benzylpyπdinyl, pyπmidinyl, phenylpyπmidinyl, pyrazinyl, 1 3 5-trιazιnyl, quinolinyl, phthalazinyi, quinazolinyl, and quinoxalinyl, and provided that for the groups R1, R2, R4, Rs, Re, and R7 the non-interfering substituent is selected from the group consisting of Ci-Ce alkyl, C2-Ce alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl Cj-Cg cycloalkyl, C3-C8 cycloalkenyl, phenyl tolulyl, xylenyl, biphenyl, Ci-Cc alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2- C12 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-Ci2 alkylamino, Ci-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy, Ci-C6 haloalkylsulfonyl, C2-C6 haloalkyl C1-C6 hydroxyalkyl -C(O)O(C1-C6 alkyl), -(CH2)n-O-(Ci-C6 alkyl) benzyloxy, phenoxy phenylthio, - (CONHSO2R), -CHO, amino, amidino, bromo carbamyl, carboxyl, carbalkoxy, -(CHa)n -CO2H chloro cyano cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro phosphono, -SO3H, thioacetal thiocarbonyl, and C1-C6 carbonyl, where n is from 1 to 8, and pharmaceutically acceptable salts solvates, prodrug derivatives racemates tautomers, or optical isomers thereof [0068] In certain of these embodiments, -(L)- has the formula
Figure imgf000059_0001
wherein Rgi and Rg2 are each independently selected from the group consisting of hydrogen, C1-C1 O alkyl, carboxy carbalkoxy, and halo p is a number from 1 to 5, and Z is selected from the group consisting of a bond, - (CH2)- -O- -N(C1-C10 alkyl)-, -NH-, and -S-
[0069] In certain of these embodiments wherein R4 is -(La)-(acιdιc group), the acid linker -(L3)- has the formula
Figure imgf000060_0001
wherein Q is selected from the group consisting Of -(CH2)-, -O- , -NH-, and -S-, and R83 and R84 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, Ci-C10 aralkyl, hydroxy, and halo
[0070] In certain of these embodiments wherein R5 is -(La)-(acιdιc group), the acid linker -(L3)- has the formula
phenylene/
Figure imgf000060_0002
wherein r is a number from 2 to 7, s is 0 or 1 , Q is selected from the group consisting Of -(CH2) O-, -NH-, and -S-, and R85 and R86 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, aryl, Ci-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo [0071] In certain embodiments, a 1 H-ιndole-3-glyoxylamιde compound for use in the present invention is selected from the group consisting of ((3-(2- Amιno-1 ,2-dιoxoethyl)-2-ethyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid [[3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1 -(phenylmethyl)-i H-ιndol-4-yl]oxy]acetιc acid methyl ester, ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-methyl-1-(phenylmethyl)-1 H- ιndol-4-yl)oxy)acetιc acid, dl-2-((3-(2-Amιno-1 ,2-dιoxoethyl)-2-methyl-1 - (phenylmethyl)-1 H-ιndol-4-yl) oxy)propanoιc acid, ((3-(2-Amιno-1 ,2- dioxoethyl)-1-((1 , 1'-biphenyl)-2-ylmethyl)-2-methyl-1 H-indol-4-yl)oxy)acetic acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1-((1 , 1'-bιphenyl)-3-ylmethyl)-2-methyl-1 H- ιndol-4-yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1-((1 ,1'-bιphenyl)-4- ylmethyl)-2-methyl-1 H-ιndol-4-yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)- 1-((2,6-dιchlorophenyl)methyl)-2-methyl-1 H-ιndol-4-yi)oxy)acetιc acid, ((3-(2- Amιno-1 ,2-dιoxoethyl)-1-(4(-fluorophenyl)methyl)-2-methyl-1 H-ιndol- 4- yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-methyl-1-((1- naphthaienyl)methyl)-1 H-ιndol- 4-yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2- dιoxoethyt)-1-((3-chlorophenyl)methyi)-2-ethyl-1 H-ιndol-4-yl)oxy)acetιc acid, ((3-(2-Amιno-1 2-dιoxoethyl)-1 -((1 , 1'-bιphenyl)-2-ylmethyl)-2-ethyl-1 H-ιndoi-4- yl)oxy)acetιc acid, ((3-(2-amιno-1 ,2-dιoxoethyl)-1-((1 ,1 '-bιpheπyl)-2-ylmethyl)- 2-propyl-1 H-ιndol-4-yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-2- cyclopropyI-1-(phenylmethyl)-1 H-ιndol-4-yl) oxy)acetιc acid, ((3-(2-Amιno-1 ,2- dιoxoethyl)-1-((1 ,1'-bιphenyl)-2-ylmethyl)-2-cyclopropyl-1 H-ιndol-4- yl)oxy)acetιc acid, and 4-((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-5-yl)oxy) butanoic acid or pharmaceutically acceptable salts solvates prodrug derivatives, racemates tautomers, or optical isomers thereof
[0072] In certain embodiments, SPLA2 inhibitors for use in the current invention are 1 H-ιndole-3-glyoxylamιde compounds having the structure
Figure imgf000061_0001
wherein both X are oxygen
R1 is selected from the group consisting of
Figure imgf000062_0001
and
Figure imgf000062_0002
wherein R1O is a radical independently selected from halo, Ci-C1O alkoxy, -S-
( C1-C10 alkyl), and C1-C1O haloalkyl, and t is a number from 0 to 5,
R2 is selected from the group consisting of halo cyclopropyl, methyl, ethyl and propyl,
R4 and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -(La)-(acιdιc group), wherein -(L3)- is an acid linker provided that the acid linker -(L3)- for R4 is selected from the group consisting of f
-O CH;
"S CH2
-N CH 2
Figure imgf000062_0003
Figure imgf000063_0001
provided that the acid linker -(L3)- for R5 is selected from the group consisting of:
Figure imgf000063_0002
Figure imgf000064_0001
wherein R84 and R85 are each independently selected from the group consisting of hydrogen, C1-Ci0 alkyl, aryl, C1-C10 alkaryl, Ci-C10 aralkyl, carboxy carbalkoxy, and halo, provided that at least one of R4 and R5 must be — (La)-(acιdιc group), and (acidic group) on -(La)-(acιdιc group) of R4 or R5 is selected from -CO2H, -SO3H, Or -P(O)(OH)2, R6 and R7 are each independently selected from the group consisting of hydrogen and non-interfering substituents with the non-interfering substituents being selected from the group consisting of C1-Ce alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-Ci2 aralkyl, C7-Ci2 alkaryl C3-Cs cycloalkyl C3-C8 cycloalkenyl, phenyl, tolulyl xylenyl, biphenyl, Ci-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-Ci2 alkoxyalkyloxy C2- Ci2 alkylcarbonyl, C2-C12 alkylcarbonylamino, C2-Ci2 alkoxyamino, C2-Ci2 alkoxyaminocarbonyl, C2-Ci2 alkylamino, C1-C6 alkylthio, C2-Ci2 alkylthiocarbonyl, C1-C6 alkylsulfinyl, Ci-C6 alkylsulfonyl C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl C1-C6 hydroxyalkyl, -C(O)O(C1-C6 alkyl), -(CH2)O-O-(C1-C6 alkyl), benzyloxy, phenoxy, phenylthio - (CONHSO2R), -CHO, amino, amidino, bromo, carbamyl carboxyl carbalkoxy, -(CH2) n-CO2H, chloro, cyano, cyanoguanidinyl fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro phosphono -SO3H, thioacetal, thiocarbonyl and C1-C6 carbonyl wherein n is from 1 to 8 and pharmaceutically acceptable salts, solvates, prodrug derivatives racemates, tautomers or optical isomers thereof
[0073] In certain embodiments, 1 H-ιndole-3-glyoxylamιde compounds for use in the present invention are selected from the group consisting of ((3-(2- Amιno-1 ,2-dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-methyl-1-(phenylmethyl)-1 H-indol-4- yl)oxy)acetιc acid methyl ester, dl-2-((3-(2-Amιno-1 ,2-dιoxoethyl)-2-methyl-1- (phenylmethyl)-1 H-ιndol-4-yl) oxy)propanoιc acid, dl-2-((3-(2-Amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl) oxy)propanoιc acid methyl ester, ((3-(2-Ammo-1 2-dιoxoethyl)-1 -((1 ,1 '-bιphenyl)-2-ylmethyl)-2- methyl-1 H-in dol-4-yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1-((1 , 1'- bιphenyl)-2-ylmethyl)-2-methyl-1 H-ιn dol-4-yl)oxy)acetιc acid methyl ester, ((3- (2-Amιno-1 ,2-dιoxoethyl)-1 -((1 , 1 '-bιphenyl)-3-ylmethyl)-2 -methyl-1 H-in dol-4- yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1-((1 ,1'-bιphenyl)-3-ylmethyl)- 2-methyl-1 H-ιn dol-4-yl)oxy)acetιc acid methyl ester, ((3-(2-Amιno-1 ,2- dιoxoethyl)-1-((1 ,1'-bιphenyl)-4-ylmethyl)-2-methyl-1 H-ιn doi-4-yl)oxy)acetιc acid, ((3-(2-Amtno-1 ,2-dιoxoethyl)-1-((1 ,1'-bιphenyl)-4-ylmethyl)-2-methyl-1 H- in dol-4-yl)oxy)acetιc acid methyl ester, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1-((2,6- dιchlorophenyl)methyl)-2-methyl-1 H-ιn dol-4-yl)oxy)acetιc acid, ((3-(2-Amιno- 1 ,2-dιoxoethyl)-1-((2,6-dιchlorophenyl)methyl)-2-methyl-1 H-in dol-4- yl)oxy)acetιc acid methyl ester, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1-(4(- fluorophenyl)methyl)-2-methyl-1 H-ιndol- 4-yl)oxy)acetιc acid, ((3-(2-Amιno- 1 ,2-dιoxoethyl)-1-(4(-fluorophenyl)methyl)-2-methyl-1 H-ιndol- 4-yl)oxy)acetιc acid methyl ester, ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-methyl-1-((1- naphthalenyl)methyl)-1 H-ιndol- 4-yI)oxy)acetιc acid, ((3-(2-Amιno-1 2- dιoxoethyl)-2-methyl-1-((1-naphthalenyl)methyl)-1 H-ιndol- 4-yl)oxy)acetιc acid methyl ester ((3-(2-Amιno-1 ,2-dιoxoethyl)-1 -((3-chlorophenyl)methyl)-2-ethyl- 1 H-ιndol-4 -yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1-((3- chlorophenyl)methyl)-2-ethyl-1 H-ιndol-4 -yl)oxy)acetιc acid methyl ester, ((3- (2-Amιno-1 ,2-dιoxoethyl)-1 -((1 ,1 '-bιphenyl)-2-ylmethyl)-2-ethyl-1 H-ind ol-4- yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1-((1 ,1'-biphenyl)-2-ylmethyl)- 2-ethyl-1 H-ιnd ol-4-yl)oxy)acetιc acid methyl ester ((3-(2-amιno-1 ,2- dιoxoethyl)-1-((1 , 1'-bιphenyl)-2-ylmethyl)-2-propyl-1 H-ιn dol-4-yl)oxy)acetιc acid, ({3-(2-amιno-1 ,2-dιoxoethyl)-1-((1 1 '-bιphenyl)-2-ylmethyl)-2-propyl-1 H-!n dol-4-yl)oxy)acetιc acid methyl ester, ((3-(2-Amιno-1 ,2-dιoxoethyl)-2- cyclopropyl-1 -(phenylmethyl)-i H-ιndol-4-yl) oxy)acetιc acid, ((3-(2-Amιno-1 ,2- dιoxoethyl)-2-cyclopropyl-1 -(phenylmethyl)-i H-ιndol-4-yl) oxy)acetιc acid methyl ester, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1 -((1 ,1 '-bιphenyl)-2-ylmethyl)-2- cyclopropyl- 1 H-ιndol-4-yl)oxy)acetιc acid, ((3-(2-Amιno-1 ,2-dιoxoethyl)-1- ((1 , 1 '-bιphenyl)-2-ylmethyl)-2-cyclopropyl- 1 H-ιndol-4-yl)oxy)acetιc acid methyl ester, 4-((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1 -(phenylmethyl)-i H-ιndol-5- yl)oxy) butanoic acid, 4-((3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1 -(phenylmethyl)- 1 H-ιndol-5-yl)oxy) butanoic acid tert-butyl ester, or pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof
[0074] In certain embodiments, SPLA2 inhibitors for use in the current invention are 1 H-ιndole-3-glyoxylamιde compounds having the structure
Figure imgf000067_0001
wherein each X is independently oxygen or sulfur,
R1 is selected from groups (a), (b), and (c) wherein
(a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C?o alkynyl, carbocyclic radical, or heterocyclic radical
(b) is a member of (a) substituted with one or more independently selected non-interfering substituents and (c) is the group -(L)-ReO, wherein -(L)- is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen, and sulfur wherein the combination of atoms in -(L)- are selected from the group consisting of (ι) carbon and hydrogen only, (n) sulfur only, (in) oxygen only, (ιv) nitrogen and hydrogen only, (v) carbon, hydrogen, and sulfur only, and (vι) and carbon, hydrogen, and oxygen only, and where Rgo is a group selected from (a) or (b),
R2 is selected from the group consisting of hydrogen, halo, C1-C3 alkyl C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0-(C1-C2 alkyl), -S-(C1-C2 alkyl), and a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen R4 and R5 are independently selected from the group consisting of hydrogen a non-interfering substituent, and the group -(La)-(acιdιc group) wherein - (L3)- is an acid linker having an acid linker length of 1 to 4, provided that at least one of R4 and R5 is -(La)-(acιdιc group),
Re and R7 are each independently selected from the group consisting of hydrogen, non-interfering substituents, carbocyclic radicals carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals and heterocyclic radicals substituted with non-interfering substituents and pharmaceutically acceptable salts solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof [0075] In certain embodiments, SPLA2 inhibitors for use in the current invention are methyl ester prodrug derivatives of 1 H-ιndole-3-glyoxylamιde compounds having the structure
Figure imgf000069_0001
wherein both X are oxygen,
R1 is selected from the group consisting of
Figure imgf000069_0002
and
Figure imgf000069_0003
wherein R10 is a radical independently selected from halo, C1-C10 alkyl, C1-
C1O alkoxy,-S-( C1-C10 alkyl), and C1-C10 haloalkyl, and t is a number from 0 to 5,
R2 is selected from the group consisting of halo, cyclopropyl, methyl, ethyl, and propyl,
R4 and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -(La)-(acιdιc group), wherein -(L3)- is an acid linker, provided that the acid linker -(L3)- for R4 is selected from the group consisting of -o- -CH-
-s- -CH,
-N- -CH,
-H9C- -CH,
Figure imgf000070_0001
provided that the acid linker -(L3)- for R5 is selected from the group consisting of
Figure imgf000070_0002
Figure imgf000071_0001
wherein Rg4 and Rgs are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, Ci-C10 aralkyl, carboxy, carbalkoxy, and halo, provided that at least one of R4 and R5 must be -(La)-(acιdιc group), and (acidic group) on -(La)-(acιdιc group) of R4 or R5 is selected from -CO2H -SO3H, or -P(O)(OH)2, R6 and R7 are each independently selected from the group consisting of hydrogen and non-interfering substituents, with the non-interfeπng substituents being selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-Ci2 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy C2-C12 alkoxyalkyi, C2-C12 alkoxyalkyloxy, C2- Ci2 alkylcarbonyl, C2-Ci2 alkylcarbonylamino, C2-Ci2 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkylamino C1-C6 alkylthio, C2-C12 alkylthiocarbonyl. C1-C0 alkylsulfinyl, Ci-C6 alkylsulfonyl C2-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl C1-C6 hydroxyalkyl -C(O)O(Ci-C6 alkyl), -(CH2)H-O-(C1-C6 alkyl), benzyloxy phenoxy, phenylthio, - (CONHSO2R), -CHO, amino, amidino, bromo, carbamyl carboxyl carbalkoxy, -(CH2) n-CO2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino hydrazido, hydroxy, hydroxyamino iodo, nitro phosphono, -SO3H thioacetal, thiocarbonyl, and C1-C6 carbonyl, wherein n is from 1 to 8, and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof [0076] In certain embodiments, SPLA2 inhibitors for use in the current invention are (acyloxy) alkyl ester prodrug derivatives of 1 H-ιndole-3- glyoxylamide compounds having the structure
Figure imgf000073_0001
wherein both X are oxygen,
R1 is selected from the group consisting of
Figure imgf000073_0002
and
Figure imgf000073_0003
wherein Ri0 is a radical independently selected from halo, C1-C10 alkyl, C1-
C10 alkoxy,-S-( C1-C10 alkyl), and C1-C10 haloalkyl and t is a number from 0 to 5,
R2 is selected from the group consisting of halo, cyclopropyl, methyl, ethyl and propyl
R4 and R5 are independently selected from the group consisting of hydrogen, a non-interfering substituent, and -(L3)- (acidic group), wherein -(L3)- is an acid linker, provided that the acid linker -(L3)- for R4 is selected from the group consisting of -o- -CH;
-CH,
Figure imgf000074_0001
-H,C- -CH,
Figure imgf000074_0002
provided that the acid linker -(L3)- for R5 is selected from the group consisting of
Figure imgf000074_0003
Figure imgf000075_0001
wherein R84 and R85 are each independently selected from the group consisting of hydrogen, C1-C10 alkyl, aryl. C1-C10 alkaryl, C1-C1Q aralkyl, carboxy, carbalkoxy, and halo, provided that at least one of R4 and R5 must be -(La)-(acidic group), and (acidic group) on -(La)-(acιdιc group) of R4 or R5 is selected from -CO2H, -SO3H, or -P(O)(OH)2,
Re and R7 are each independently selected from the group consisting of hydrogen and non-interfering substituents with the non-interfering substituents being selected from the group consisting of C1-C6 alkyl C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl C7-C12 alkaryl, C3-Cg cycloalkyl C3-C8 cycloalkenyl, phenyl, tolulyl, xylenyl, biphenyl, C1-C6 alkoxy, C2-C6 alkenyloxy, C2-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2- C12 alkylcarbonyl, C2-C12 alkylcarbonylamino C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C2-C12 alkylamino C1-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C2-C6 haloalkoxy C1-C6 haloalkylsulfonyl, C2-C6 haloalkyl, C1-C6 hydroxyalkyl, -C(O)O(C1-C6 alkyl), -(CH2)n-O-(C1-C6 alkyl) benzyloxy, phenoxy, phenylthio, - (CONHSO2R), -CHO, amino, amidino bromo, carbamyl, carboxyl carbalkoxy, -(CH2) n-CO2H, chloro cyano cyanoguanidinyl, fluoro, guanidino, hydrazide hydrazino hydrazido, hydroxy hydroxyamino iodo, nitro phosphono -SO3H, thioacetal, thiocarbonyl, and C1-C6 carbonyl, wherein n is from 1 to 8, and pharmaceutically acceptable salts solvates, prodrug derivatives, racemates tautomers, or optical isomers thereof [0077] In certain embodiments, sPLA2 inhibitors for use in the current invention are substituted tricyclics having the structure
Figure imgf000077_0001
wherein
R1 is selected from the group consisting Of -NHNH2 and -NH2,
R2 is selected from the group consisting of -OH and -0(CH2) mR5, wherein R5 is selected from the group consisting of H, -CO2H -CO2(C1-C4 alkyl), -
SO3H, -SO3(C1-C4 alkyl), tetrazolyl -CN, -NH2, -NHSO2R15, -
CONHSO2Ri5, phenyl, phenyl substituted with -CO2H or -CO2(C1-C4)alkyl, and
Figure imgf000077_0002
wherein R6 and R7 are each independently selected from the group consisting of -OH, -O(C1-C4)alkyl, R15 is selected from the group consisting of -(C1- C6)alkyl and -CF3 and m is 1-3,
R3 is selected from the group consisting of H, -O(C1-C4)alkyl, halo, -(C1- CεJalkyl, phenyl, -(C^C^alkylphenyl phenyl substituted with -(C1-Ce)SlKyI halo, or -CF3, -CH2OSι(C1-C6)alkyl, furyl, thiophenyl, -(C1- Cβjhydroxyalkyl, and -(CH2)nRs, wherein R8 is selected from the group consisting of H1 -CONH2, -NR9R10, -CN, and phenyl, wherein R9 and Ri0 are each independently -(C1-C4)alkyl or -phenyl(Ci-C4)alkyl, and n is 1 to 8, R4 is selected from the group consisting of H, -(Cs-Cujalkyl, -(C3-
Ci4)cycloalkyi, pyridyl, phenyl, and phenyl substituted with -(Ci-C6)alkyl, halo,
-CF3, -OCF3, -(Ci-C4)alkoxy -CN, -(C1-C4)alkylthιo, phenyl(C1-C4)alkyl, -
(C1-C4)alkylphenyl, phenyl, phenoxy, or naphthyl,
A is selected from the group consisting of phenyl and pyridyl wherein the nitrogen is at the 5-, 6-, 7-, or 8-posιtιon,
Z is selected from the group consisting of cyclohexenyl, phenyl, pyridyl wherein the nitrogen is at the 1- 2-, or 3-posιtιon, and a 6-membered heterocyclic ring having one heteroatom selected from the group consisting of sulfur and oxygen at the 1-, 2-, or 3-posιtιon and nitrogen at the 1-, 2-, 3-, or
4- position, or wherein one carbon on the heterocyclic ring is optionally substituted with =0 and wherein one of A or Z is a heterocyclic ring, and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates tautomers or optical isomers thereof
[0078] In certain embodiments, SPLA2 inhibitors for use in the current invention are substituted tricyclics having the structure
Figure imgf000078_0001
wherein
Z is selected from the group consisting of cyclohexenyl and phenyl,
R21 is a non-interfering substituent,
R1 IS -NHNH2 Or -NH2, R2 is selected from the group consisting of -OH and -0(CH2) mRs, wherein R5 is selected from the group consisting of H, -CO2H, -CONH2, -CO2(C1 -C4 alkyl), -SO3H1-SO3(C1-C4 alkyl), tetrazolyl, -CN, -NH2, -NHSO2R15, - CONHSO2R15, phenyl phenyl substituted with -CO2H or -CO2(C1-C4)BlKyI, and o
— P( R6R7) , wherein Re and R7 are each independently selected from the group consisting of -OH, -O(d-C4)alkyl, R15 is selected from the group consisting Of -(C1- Ce)alkyl and -CF3 and m is 1-3,
R3 selected from the group consisting of H, -O(C1-C4)alkyl, halo, -(Ci- Ce)alkyl phenyl, -(C!-C4)alkylphenyl, phenyl substituted with -(C1-Ce)alkyl, halo, Or -CF3, -CH2OSι(C1-C6)alkyl, furyl, thiophenyl -(C1-C6)hydroxyalkyl, and -(CH2) nRs, wherein Rg is selected from the group consisting of H, - CONH2, -NRgR-io, -CN and phenyl Rg and R1O are each independently selected from the group consisting of H -CF3 phenyl, -(d-C^alkyl, -(C1- C4)alkylphenyl, and -phenyl(C1-C4)alkyl, and n is 1 to 8, R4 is selected from the group consisting of H, -(C5-Ci4)alkyl, -(C3- Ci4)cycloalkyl pyridyl, phenyl, phenyl substituted with — (Ci— CβJalkyl, halo, - CF3, -OCF3, -(C1-C4)BIkOXy, -CN, -(C^C^alkylthio, -phenyl(C1-C4)alkyl - (C-i-C4)alkylphenyl, phenyl, phenoxy and naphthyl, and pharmaceutically acceptable salts solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof [0079] In certain embodiments, sPLA2 inhibitors for use in the current invention are selected from the group consisting of {9-[(phenyl)methyl]-5- carbamoylcarbazol-4-yl}oxyacetιc acid, 9-benzyl-5,7-dιmethoxy-1 ,2,3,4- tetrahydrocarbazole-4-carboxylιc acid hydrazide, 9-benzyl-5,7-dιmethoxy- 1 2,3,4-tetrahydrocarbazole-4-carboxamιde, [9-benzyl-4-carbamoyI-7~ methoxy-1 2 3,4-tetrahydrocarbazol-5-yl]oxyacetιc acid, [9-benzyl-4- carbamoyl-7-methoxycarbazol-5-yl]oxyacetιc acid, methyl [9-benzyl-4- carbamoyl-7-methoxycarbazol-5-yl]oxyacetιc acid, 9-benzyl-7-methoxy-5- cyanomethyloxy-1 2,3,4-tetrahydrocarbazole-4-carboxamιde 9-benzyl-7- methoxy-5-(1 H-tetrazol-5-yl-methyl)oxy)-1 ,2,3,4-tetrahydrocarbazole-4- carboxamide {9-[(phenyl)methyl]-5-carbamoyl-2-methyl-carbazol-4- yl}oxyacetιc acid {9-[(3-fluorophenyl)methyl]-5-carbamoyl-2-methylcarbazol- 4-yl}oxyacetιc acid {9-[(3-methylphenyl)methyl]-5-carbamoyl-2- methylcarbazol-4-yl}oxyacetιc acid {9-[(phenyl)methyl]-5-carbamoyl-2-(4- trιfluoromethylphenyl)-carbazol-4-yl}oxyacetιc acid, 9-benzyl-5-(2- methanesulfonamιdo)ethyloxy-7-methoxy-1 ,2,3,4-tetrahydrocarbazole-4- carboxamide 9-benzyl-4-(2-methanesulfonamιdo)ethyloxy-2- methoxycarbazoIe-5-carboxamιde 9-benzyl-4-(2- trifluoromethanesuifonamido)ethyloxy-2-methoxycarbazole-5-carboxamide, 9- benzyl-5-methanesulfonamιdoylmethyloxy-7-methoxy-1 , 2,3,4- tetrahydrocarbazole-4-carboxamιde, 9-benzyl-4- methanesulfonamιdoylmethyloxy-carbazole-5-carboxamιde, [5-carbamoyl-2- pentyl-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid, [5-carbamoyl-2-(1- methylethyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid, [5-carbamoyl-9- (phenylmethyl)-2-[(tπ(-1 -methylethyl)sιlyl)oxymethyl]carbazol-4-yl]oxyacetιc acid [5-carbamoyl-2-phenyl-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid, [5- carbamoyl-2-(4-chlorophenyl)-9-(phenylmethyl)carbazol-4-yI]oxyacetιc acid [5-carbamoyl-2-(2-furyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid, [5- carbamoyl-9-(phenylmethyl)-2-[(tπ(-1-methylethyl)sιlyl)oxymethyl]carbazol-4- yljoxyacetic acid, {9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4- y!}oxyacetιc acid, {9-[(2-tπfluotomethy]phenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid, {9-[(2-benzylphenyI)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid, {9-[(1 -naphthyi)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2-cyanophenyl)methyl]-5-carbamoylcarbazo!-4-yl}oxyacetιc acid, {9- [(3-cyanophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(3,5- dιmethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid (9-[(3- ιodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, (9-[(2- Chlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2 3- dιfluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2,6- dιfluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2,6- dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2- biphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid {9-[(2- Bιphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid methyl ester, [9- Benzyl-4-carbamoyl-1 2,3,4-tetrahydrocarbazol-5-yl]oxyacetιc acid, {9-[(2- Pyπdyl)methyI]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(3- Pyπdyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, [9-benzyl-4- carbamoyl-8-methyl-1 2 3 4-tetrahydrocarbazol-5-yl]oxyacetιc acid, [9-benzyl- 5-carbamoyl-1 -methylcarbazol-4-yl]oxyacetιc acid, [9-benzyl-4-carbamoyl-8- fluoro-1 2,3,4-tetrahydrocarbazol-5-yl]oxyacetιc acid, [9-benzyl-4-carbamoyl- 8-chloro-1 2,3 4-tetrahydrocarbazol-5-yl]oxyacetιc acid [5-carbamoyl-9- (phenylmethyl)-2-[[(propen-3-yl)oxy]methyl]carbazol-4-yl]oxyacetιc acid, [5- carbamoyt-9-(phenylmethyl)-2-[(propyloxy)methyl]catbazol-4-yl]oxyacetιc acid, 9-benzyl-7-methoxy-5-((carboxamιdomethyl)oxy)-1 ,2,3,4- tetrahydrocarbazole-4-carboxamιde, 9-benzyl-7-methoxy-5-cyanomethyloxy- carbazole-4-carboxamιde, 9-benzyl-7-methoxy-5-((1 H-tetrazol-5-yl- methyl)oxy)-carbazole-4-carboxamιde, 9-benzyl-7-methoxy-5- ((carboxamιdomethyl)oxy)-carbazoIe-4-carboxamιde [9-Benzyl-4-carbamoyl- 1 ,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid {9-[(phenyi)methyl]-5- carbamoyl-2-methyl-carbazol-4-yl}oxyacetιc acid, {9-[(3-fluorophenyl)methyl]- 5-carbamoyl-2-methylcarbazol-4-yl}oxyacetιc acid {9-[(3- methylphenyl)methyl]-5-carbamoyl-2-methylcarbazol-4-yl}oxyacetιc acid, {9- [(phenyl)methyl]-5-carbamoyl-2-(4-tπfluoromethylphenyl)-carbazol-4- yl}oxyacetιc acid, 9-benzyl-5-(2-methanesulfonamιdo)ethyloxy-7-methoxy- 1 ,2,3 4-tetrahydrocarbazole-4-carboxamιde 9-benzyl-4-(2- methanesulfonamιdo)ethyloxy-2-methoxycarbazole-5-carboxamιde, 9-benzyl- 4-{2-tπfluoromethanesulfonamιdo)ethyloxy-2-methoxycarbazole-5- carboxamide, 9-benzyl-5-methanesulfonamιdoylmethyloxy-7-methoxy-1 ,2,3 A- tetrahydrocarbazole-4-carboxamιde, 9-benzyl-4- methanesulfonamιdoylmethyloxy-carbazole-5-carboxamιde, [5-carbamoyl-2- pentyl-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid, [5-carbamoyl-2-(1- methylethyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid [5-carbamoyi-9- {phenylmethyl)-2-[(tπ(-1-methyIethyl)sιlyl)oxymethyl]carbazol-4-yl]oxyacetιc acid, [5-carbamoyi-2-phenyl-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid, [5- carbamoyl-2-(4-chlorophenyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid, [5-carbamoyl-2-(2-furyl)-9-(phenylmethyl)carbazol-4-yl]oxyacetιc acid, [5- carbamoyl-9-(phenylmethyl)-2-[(tπ(-1-methylethyl)sιlyl)oxymethyl]carbazol-4- yl]oxyacetιc acid, {9-[(3-fluorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid , {9-[(3-chlorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid, {9-[(3-phenoxyphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid, {9-[(2-Fluorophenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid, {9-[(2-trιfluoromethylphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid, {9-[(2-benzylphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid, {9-[(3-tπfIuoromethylphenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid {9-[(1-naphthyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, {9-[(2-cyanophenyi)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid {9- [(3-cyanophenyl)methyI]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2- methylphenyl)methyl]-5-carbamoylcarbazol-4-y!}oxyacetιc acid, {9-[(3- methylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(3,5- dιmethylphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid {9-[(3- ιodophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2- Chlorophenyl)methyi]-5-carbamoyicarbazol-4-yl}oxyacetιc acid, {9-[(2,3- dιfluorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2 6- dιfluoropheny!)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2,6- dιchlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(3- trιfluoromethoxyphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid {9- [(2-bιphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(2- Bιphenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid methyl ester, [9- Benzyl-4-carbamoyl-1 ,2,3,4-tetrahydrocarbazole-5-yl]oxyacetic acid, {9-[(2- Pyrιdyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, {9-[(3- Pyπdyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetιc acid, [9-benzyl-4- carbamoyl-8-methyl-1 ,2,3,4-tetrahydrocarbazol-5-yl]oxyacetιc acid, [9-benzyl- 5-carbamoyl-1-methylcarbazol-4-yl]oxyacetιc acid, [9-benzyl-4-carbamoyl-8- fluoro-1 ,2,3,4-tetrahydrocarbazol-5-yl]oxyacetιc acid, [9-benzyl-5-carbamoyl- 1-fluorocarbazol-4-yl]oxyacetιc acid, [θ-benzyM-carbamoyl-δ-chloro-i 2 3,4- tetrahydrocarbazol-5-yI]oxyacetιc acid [9-benzyl-5-carbamoyl-1 - chlorocarbazol-4-yl]oxyacetιc acid [9-[(Cyclohexyl)methyl]-5- carbamoylcarbazol-4-yl]oxyacetιc acid [9-[(Cyclopentyl)methyl]-5- carbamoylcarbazol-4-yl]oxyacetιc acid [5-carbamoyl-9-(phenylmethyl)-2-(2- thιenyl)carbazol-4-yl]oxyacetιc acid, [5-carbamoyl-9-(phenylmethyl)-2- [[(propen-3-yl)oxy]methyl]carbazol-4-yl]oxyacetιc acid [5-carbamoyl-9- (phenyimethyl)-2-[(propyloxy)methyl]carbazol-4-yl]oxyacetιc acid 9-benzyl-7- methoxy-5-((carboxamιdomethyl)oxy)-1 2 3 4-tetrahydrocarbazoie-4- carboxamide, θ-benzyl-y-methoxy-δ-cyanomethyloxy-carbazole^- carboxamide, 9-benzyl-7-methoxy-5-((1 H-tetrazol-5-yl-methyl)oxy)-carbazole- 4-carboxamιde, 9-benzyl-7-methoxy-5-((carboxamιdomethyl)oxy)-carbazole- 4-carboxamιde, [9-Benzyl-4-carbamoyl-1 2,3,4-tetrahydrocarbazole-5- yljoxyacetic acid, (R S)-(9-benzyl-4-carbamoyl-1-oxo-3-thιa-1 2 3 4- tetrahydrocarbazol-5-yl)oxyacetιc acid (R S)-(9-benzyl-4-carbamoyl-3-thιa- 1 2 3,4-tetrahydrocarbazol-5-yl)oxyacetιc acid, 2-(4-oxo-5-carboxamιdo-9- benzyl-9/-/-pyrιdo[3,4-6]ιndolyl)acetιc acid chloride, [N-benzyl-1-carbamoyl-l- aza-1 ,2 3,4-tetrahydrocarbazol-8-yl]oxyacetιc acid, 4-methoxy-6- methoxycarbonyl-10-phenylmethyl-6,7,8 9-tetrahydropyπdo[1 2-a]ιndole (4- carboxamιdo-9-phenylmethyl-4,5-dιhydrothιopyrano[3 4-b]ιndol-5-yl)oxyacetιc acid 3 4-dιhydro-4-carboxamιdol-5-methoxy-9-phenylmethylpyrano[3 A- όjindole, 2-[(2,9 bιs-benzyl-4-carbamoyl-1 2 3 4-tetrahydro-betacarbolιn-5- yl)oxy]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(2-methylbenzyl)-9/-/-pyrιdo[3,4- jb]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(3-methylbenzyl)-9H- pyrιdo[3,4-ib]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(4-methylbenzyl)- 9H-pyπdo[3,4-ιb]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(4-tert- butylbenzyl)-9H-pyπdo[3,4-ό]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9- pentafluorobenzyl-9H-pyrιdo[3,4-ό]ιndoiyl]acetιc acid, 2-[4-oxo-5- carboxamιdo-9-(2-fluorobenzyl)-9H-pyπdo[3,4-/b]ιndolyl]acetιc acid 2-[4-oxo- 5-carboxamιdo-9-(3-fluorobenzyl)-9/-/-pyrιdo[3 4-ό]ιndolyl]acetιc acid, 2-[4- oxo-5-carboxamιdo-9-(4-fluorobenzyl)-9H-pyrιdo[3 4-b]ιndotyl]acetιc acid, 2- [4-oxo-5-carboxamιdo-9-(2,6-dιfiuorobenzyl)-9/-/-pyrιdo[3,4-b]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(3,4-dιfIuorobenzyl)-9H-pyπdo[3,4- 6]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(2,5-dιfiuorobenzyl)-9/-/- pyπdo[3,4-ιb]ιndolyi]acetιc acid 2-[4-oxo-5-carboxamιdo-9-(3,5- dιfIuorobenzyl)-9H-pyrιdo[3 4-b]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9- (2,4-dιfluorobenzyl)-9H-pyrιdo[3,4-jb]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamιdo-9-(2,3-dιfluorobenzyl)-9/-/-pyπdo[3,4-b]ιndolyl]acetιc acid, 2-[4- oxo-5-carboxamιdo-9-[2-(trιfluoromethyl)benzyl]-9/-/-pyrιdo[3,4-ύ]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[2-(trιfluoromethyl)benzyl]-9/-/-pyrιdo[3,4- ib]mdolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[3-(trιfluoromethyl)benzyl]-9/-/- pyπdo[3,4-b]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[4- (trιfluoromethyl)benzyl]-9/-/-pyπdo[3,4-jb]ιndolyl]acetιc acid 2-[4-oxo-5- carboxamιdo-9-[3,5-bιs(trιfluoromethyl)benzyl]-9/-/-pyrιdo[3,4-j!3]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[2,4-bιs(trιfluoromethyl)benzyl]-9/-/-pyrιdo[3 A- ib]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(a-methyInaphthyl)-9/-/- pyrιdo[3,4-ιb]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(b-methylnaphthyl)- 9/-/-pyrιdo[3 4-6]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(3,5- dιmethylbenzyl)-9H-pyrιdo[3,4-ib]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo- 9-(2,4-dιmethylbenzyl)-9H-pyπdo[3,4-jb]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamιdo-9-(2-phenylbenzyl)-9/-/-pyrιdo[3,4-ύ]ιndolyl]acetιc acid, 2-[4-oxo- 5-carboxamιdo-9-(3-phenyibenzyl)-9H-pyπdo[3,4-jb]ιndoIyl]acetιc acid 2-[4- oxo-5-carboxamιdo-9-(4-phenylbenzyl)-9/-/-pyπdo[3,4-5]ιndolyl]acetιc acid, 2- [4-oxo-5-carboxamιdo-9-(1 -fluorenylmethy)-9H-pyπdo[3,4-5]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(2-fluoro-3-methylbenzyl)-9H-pyπdo[3,4- ό]ιndolyl]acetιc acid 2-[4-oxo-5-carboxamιdo-9-(3-benzoylbenzyl)-9/-/- pyrιdo[3,4-ύ]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(2-phenoxybenzyl)- 9H-pyrιdo[3,4-ιb]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(3- phenoxybenzyl)-9H-pyπdo[3 4-6]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo- 9-(4-phenoxybenzyl)-9/-/-pyπdo[3,4-ό]ιndolyl]acetic acid, 2-[4-oxo-5- carboxamido-9-[3-[2-(fluorophenoxy)benzyl]]-9H-pyrιdo[3,4-b]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[3-[4-(fluorophenoxy)benzyl]]-9H-pyrιdo[3,4- Λ]ιndolyl]acetιc acid 2-[4-oxo-5-carboxamιdo-9-[2-fluoro-3- {trifluoromethyl)benzyl]-9/-/-pyπdo[3,4-ύ]ιndolyl]acetιc acid 2-[4-oxo-5- carboxamιdo-9-[2-fluoro-4-(trifluoromethyl)benzyl]-9/-/-pyπdo[3,4- /j]ιndoiyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[2-fluoro-5- (trιfluoromethyl)benzyl]-9H-pyrιdo[3,4-Jb]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamιdo-9-[3-fluoro-5-(tπfluoromethyl)benzyl]-9H-pyπdo[3,4- /)]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[4-fluoro-2- (tπfluoromethyl)benzyl]-9/-/-pyrιdo[3,4-ό]ιndolyl]acetιc acid 2-[4-oxo-5- carboxamιdo-9-[4-fluoro-3-(tπfluoromethyl)benzyl]-9H-pyπdo[3,4- ib]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[2-fluoro-6- (tπfluoromethyl)benzyl]-9/-/-pyrιdo[3,4-ύ]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamιdo-9-(2,3,6-tπfluorobenzyl)-9/-/-pyπdo[3,4-ύ]ιndolyI]acetιc acid 2-[4- oxo-5-carboxamιdo-9-(2,3,5-trιfluoroben2yl)-9H-pyrιdo[3,4-j!3]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(2,4,5-tπfluorobenzyl)-9H-pyrιdo[3,4- jb]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(2,4,6-trιfluorobenzyl)-9H- pyπdo[3,4-ιb]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(2,3,4- trιfluorobenzyl)-9/-/-pyrιdo[3,4-ό]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9- (3,4,5-tπfluorobenzyl)-9/-/-pyrιdo[3,4-ό]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamιdo-9-[3-(trιfluoromethoxyl)benzyl]-9/-/-pyπdo[3,4-ύ]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[4-(trιfluoromethoxyl)benzyl]-9H-pyrιdo[3,4- Jb]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[4- methoxy(tetrafluoro)benzyl]-9H-pyrιdo[3 4-ό]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamido-9-(2-methoxybenzyl)-9H-pyrido[3 4-ό]ιndolyl]acetιc acid, 2-[4- oxo-5-carboxamιdo-9-(3-methoxybenzyl)-9H-pyrιdo[3,4-jb]ιndolyi]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(4-methoxybenzyl)-9H-pyπdo[3,4-t»]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(4-ethyIbenzyl)-9/-/-pyrιdo[3,4-ό]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(4-ιsopropylbenzyl)-9H-pyrιdo[3,4- /b]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(3,4 5-tπmethoxybenzyl)-9H- pyrιdo[3,4-ύ]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(3,4- methylenedιoxybenzyl)-9/-/-pyπdo[3,4-ό]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamιdo-9-(4-methoxy-3-methylbenzyi)-9H-pyrιdo[3,4-£)]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(3,5-dιmethoxybenzyl)-9H-pyπdo[3,4- Jb]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(2,5-dιmethoxybenzyi)-9H- pyπdo[3,4-ib]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(4-ethoxybenzyl)- 9H-pyrιdo[3,4-ό]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9- (cyclohexyImethyl)-9H-pyπdo[3 4-ό]ιndolyl]acetιc acid 2-[4-oxo-5- carboxamιdo-9-(cyclopenty!methyl)-9H-pyπdo[3,4-sb]ιndolyl]acetιc acid, 2-[4- oxo-5-carboxamιdo-9-ethyl-9/-/-pyrιdo[3,4-b]ιndolyl]acetic acid, 2-[4-oxo-5- carboxamιdo-9-(1 -propyl)-9H-pyπdo[3,4-jb]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamido-9-(2-propyl)-9H-pyndo[3,4-o]indolyl]acetic acid, 2-[4-oxo-5- carboxamιdo-9-(1-butyl)-9/-/-pyrιdo[3,4-jb]ιndolyl]acetιc acid, 2-[4-oxo-5- carboxamido-9-(2-butyl)-9H-pyrido[3,4-,f})indolyl]acetic acid, 2-[4-oxo-5- carboxamιdo-9-ιsobutyl-9/-/-pyπdo[3,4-/b]ιndolyl]acetιc acιd, 2-[4-oxo-5- carboxamιdo-9-[2-(1-phenylethyl)]-9/-/-pyrιdo[3,4-ό]ιndolyl]acetιc acid, 2-[4- oxo-5-carboxamιdo-9-[3-(1-phenyIpropyl)]-9H-pyπdo[3 4-t»]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-[4-(1-phenylbutyl)]-9/-/-pyrιdo[3,4-6]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamιdo-9-(1-pentyt)-9H-pyπdo[3,4-6]ιndolyl]acetιc acid, 2-[4-oxo-5-carboxamido-9-(1-hexyl)-9H-pyrido[3,4-ib]indolyl]acetic acid 4-[(9- benzyi-4-carbamoyI-1 ,2,3,4-tetrahydrocarbazol-6-yl)oxy]butyπc acid, 3-[(9- benzyl-4-carbamoyl-1 2,3 4-tetrahydrocarbazol-6-yl)oxy]propylphosphonιc acid, 2-[(9-benzyl-4-carbamoyI-1 ,2,3,4-tetrahydrocarbazoi-6- yl)oxy]methylbenzoιc acid, 3-[(9-benzyl-4-carbamoyl-7-n-octyl-1 ,2,3,4- tetrahydrocarbazol-6-yl)oxy]propylphosphonιc acid, 4-[(9-benzyl-4-carbamoyl- 7-ethyl-1 2,3,4-tetrahydrocarbazol-6-yl)oxy]butyrιc acid, 3-[(9-benzyl-4- carbamoyl-7-ethyl-1 2,3,4-tetrahydrocarbazol-6-yl)oxy]propylphosphonιc acid, 3-[(9-benzyl-4-carbamoyl-7-ethyl-1 ,2,3,4-tetrahydrocarbazol-6- yl)oxy]propylphosphonιc acid, (S)-(+)-4-[(9-benzyl-4-carbamoy!-7-ethyl- 1 2,3,4-tetrahydrocarbazol-6-yl)oxy]butyπc acid 4-[9-benzyl-4-carbamoyl-6- (2-cyanoethyl)-1 2 3 4-tetrahydrocarbazol-6-yl]oxybutyrιc acid, 4-[9-benzyl-4- carboxamιdo-7-(2-phenylethyl)-1 ,2,3,4-tetrahydrocarbazol-6-yl]oxybutyrιc acid, 4-[9-benzyl-4-carboxamιdocarbazol-6-yl]oxybutyπc acid, methyl 2-[(9- benzyl-4-carbamoyl-1 ,2 3,4-tetrahydrocarbazol-6-yl)oxy]methylbenzoate 4-[9- benzyl-4-carbamoyl-7-(2-cyanoethyl)-1 ,2,3,4-tetrahydrocarbazol-6- yl]oxybutyrιc acid, θ-benzyl-y-methoxy-δ-cyanomethyloxy-i ,2,3,4- tetrahydrocarbazole-4-carboxamιde, [9-benzyl-4-carbamoyl-8-methyl- carbazole-5-yl]oxyacetιc acid, and [θ-benzyM-carbamoyl-carbazole-δ- yljoxyacetic acid, or pharmaceutically acceptable salts, solvates prodrug derivatives, racemates, tautomers, or optical isomers thereof [0080] In certain preferred embodiments, an SPLA2 inhibitor for use in the present invention is ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1 -(phenylmethyl)-i H- ιndol-4-yl)oxy)acetιc acid, also referred to herein as compound A-001 Compound A-001 which is also referred to in the art as S-5920 or LY315920, has the structure
Figure imgf000089_0001
A-001 competitively inhibits SPLA2
[0081] In certain other preferred embodiments, an SPLA2 inhibitor for use in the present invention is [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1-(phenylmethyl)- 1 H-ιndol-4-yl]oxy]acetιc acid methyl ester, also referred to herein as compound A-002 Compound A-002 has the structure
Figure imgf000090_0001
Compound A-002, which is sometimes referred to in the art as S-3013 or LY333013, is a prodrug form of A-O01 that is rapidly absorbed and hydrolyzed to A-O01 following administration to a subject
[0082] In certain other preferred embodiments, an SPLA2 inhibitor for use in the present invention is {9-[(phenyl)methyl]-5-carbamoylcarbazol-4- yl}oxyacetιc acid also referred to herein as compound A-003 or LY433771 Compound A-003 has the structure
Figure imgf000090_0002
[0083] In still other preferred embodiments, an SPLA2 inhibitor for use in the present invention is ((3-(2-amιno-1 ,2-dιoxoethyl)-2-methyl-1 -(phenylmethyl)- 1 H-ιndol-4-yl)oxy)acetιc acid N-morpholino ethyl ester, also referred to herein as compound 421079 Compound 421079 has the structure
Figure imgf000091_0001
Like A-002, compound 421079 is a prodrug of A-001 [0084] The following examples are provided to better illustrate the claimed invention and are not to be interpreted as limiting the scope of the invention To the extent that specific materials are mentioned, it is merely for purposes of illustration and is not intended to limit the invention One skilled in the art may develop equivalent means or reactants without the exercise of inventive capacity and without departing from the scope of the invention It will be understood that many variations can be made in the procedures herein described while still remaining within the bounds of the present invention It is the intention of the inventors that such variations are included within the scope of the invention Examples
Example 1 Effect of A-002 administration on plasma cholesterol levels and atherosclerotic plaque formation in mice
[0085] Male ApoE '" mice were fed a high fat diet (21 % fat, 0 15% cholesterol 19 5% casein) ad libitum for two weeks in order to acclimate to the diet Plasma cholesterol levels and body weight were measured in order to obtain baseline levels, and mice were randomized into thtee groups of 20 mice based on these measurements After the acclimation period, mice remained on the high fat diet and were administered A-002 (30 mg/kg or 90 mg/kg) or vehicle only (5% acacia) twice a day for 16 weeks by oral gavage [0086] Plasma cholesterol levels and body weight were measured at 4, 8, 12 and 16 weeks after the start of A-002 administration Comparisons of measurements between test and control mice at each time period were performed using a two-way analysis of variance test (ANOVA) for repeated measures followed by post-hoc Bonferroni test for significance [0087] At the end of the 16th week, mice were sacrificed and plasma samples, heart tissue, and aortas from the heart to approximately 3 mm distal to the iliac bifurcation were collected Aortas were placed on microscope slides and stained with Oil Red O for scanning and image analysis of atherosclerotic lesion size Vessel images were captured using a Microtek Scanmaker 9600XL scanner (Microtek, Carson, CA) and Photoshop 6 0 software (Adobe Systems lnc , San Jose, CA) Atherosclerotic plaque coverage was quantified for the entire length of the vessel including the arch using Image-Pro Plus software Vessels were also analyzed for plaque coverage in the descending abdominal aorta, starting in the region of the first intercostal branches to the iliac bifurcation (not including the arch) Plaque content was expressed as a percent of the aortic surface For assessment of significance in atherosclerotic plaque content between test and control mice, a one-way analysis of variance test followed by Bonferroni post-hoc test was used
[0088] All three groups of mice (control, 30 mg/kg A-002, and 90 mg/kg A-
002) had similar baseline body weights (Figure 1 ) Body weight increased over the 16 week test period by approximately 155%, 150%, and 141 % for control, 30 mg/kg A-002, and 90 mg/kg A-002 mice respectively (Figure 1 )
There was no statistically significant difference in body weight between the three groups
[0089] Baseline total plasma cholesterol levels were not significantly different between the three groups (Figure 2) At four weeks, mice receiving A-002 at either dosage exhibited a significant decrease in total cholesterol This effect remained consistent throughout the remainder of the 16 week test period At
16 weeks, the change from baseline in total cholesterol was +15%, -10%, and
-12% in control, 30 mg/kg A-002, and 90 mg/kg A-002 mice, respectively
(Figure 2) There was no apparent dose-response effect
[0090] Control mice exhibited approximately 13% plaque coverage in aortic tissue at 16 weeks (Figure 3) 30 mg/kg A-002 and 90 mg/kg A-002 mice exhibited 6 3% and 6 8% plaque coverage respectively (Figure 3)
Therefore, A-002 treatment resulted in a significant decrease in plaque content
Example 2 Effect of A-002 administration on angiotensin ll-mediated atherosclerotic plaque formation and aneurysm [0091] A mouse model of accelerated atherosclerosis was utilized to determine the effect of A-002 administration on atherosclerosis and aneurysm formation ApoE ' mice acclimated to the same high fat diet utilized in Example 1 were administered angiotensin Il with water, angiotensin with 5% acacia, or saline infusion and water twice daily for four weeks Angiotensin Il has been shown to promote atherosclerosis and aneurysm formation in apoE deficient mice (Daugherty 2000) At the end of the test period, plaque coverage was assessed by three independent reviewers, and their assessments were averaged to determine plaque coverage [0092] Angiotensin Il with water or with 5% acacia resulted in similar rates of plaque coverage (Figure 4) and aneurysm (Table 1 ) Administration of A-002 at 30 mg/kg twice daily significantly decreased plaque content and aortic level aneurysms in angiotensin ll/acacia mice (Figure 4) Table 1 Effect of A-002 administration on aneurysm rate
Figure imgf000094_0001
Example 3 Effect of A-002 or A-002 plus statin on lesion formation and composition in mice
[0093] Body weight plasma total cholesterol, and plasma HDL levels were measured for six groups of twelve ApoE ' mice The mice were then placed on a high fat diet for twelve weeks to allow for formation of significant fatty atherosclerotic plaques The high fat diet was a modified version of the Western diet (TD 88137 Harlan Teklad Madison Wl) consisting of casein (195 g/kg), DL-methionine (3 g/kg) sucrose (341 44 g/kg) corn starch (150 g/kg), anhydrous milkfat (210 g/kg) cholesterol (1 5 g/kg), cellulose (50 g/kg), mineral mix AIN-76 (Teklad 35 g/kg), calcium carbonate (4 g/kg), vitamin mix (Teklad #40060, 10 g/kg) ethyoxyquin (antioxidant, 0 04 g/kg), and either 0 0156 g/kg ("low dose") A-002 (Group A), 1 56 g/kg ("high dose") A-002 (Group B) 0 02 g/kg pravastatin (Group C), low dose A-002 plus 0 02 g/kg pravastatin (Group D), high dose A-002 plus 0 02 g/kg pravastatin (Group E), or vehicle only (Group F) Mice were administered diets A-F in a blinded manner and food was provided ad libitum The diet was initially prepared based on the assumption that each mouse weighed 22 5 g and ate 4 5 g/day Based on body weight and food consumption, the diet was modified over the 12 week course of treatment to adjust for a body weight of 26 g and a food intake of 2 5 g/day The dosages of A-002 were selected to cover a range of 100-fold based on pharmacokinetics in ApoE ' mice as well as toxicology and previously observed efficacy in this model
[0094] After twelve weeks, mice were sacrificed and plasma heart tissue and aortic tissue were collected En face lesion size was determined via digital imaging analysis Percent lesion coverage for each dosage group is summarized in Table 2 and Figure 5 Plaque content (as measured as en face lesion) was reduced in mice administered A-002 alone, statin alone, or A- 002 in combination with statin The reduction in plaque content in mice administered A-002 plus statin was substantially greater than the reduction in mice administered either compound alone (Table 2, compare Group D vs Groups A and C, Group E vs Groups B and C) Further, the reduction in plaque content in mice administered A-002 plus statin was substantially greater than the sum of the reduction in plaque content in mice administered A-002 alone and mice administered statin alone. (Table 2, compare the change in mean % en face lesion vs. control for Group D (i.e., -4.210%) with the sum of the change in mean % en face lesion vs. control for Group A and
Group C (i.e., the sum of -2.241 % and -0.813%, or -3.054%).) Thus, the administration of A-002 plus statin reduces plaque content in a synergistic manner.
Table 2: Effect of A-002 and/or statin administration on en face lesion size:
Figure imgf000096_0001
[0095] Plasma total cholesterol and HDL levels were measured. Mean levels of total cholesterol were decreased in mice administered A-002 alone or in combination with statin (Table 3, Figure 6). Administration of high dosage A- 002 plus statin resulted in a greater decrease in total cholesterol than administration of high dosage A-002 or statin alone (Table 3. compare Group E vs. Groups B and C; Figure 6). Mean levels of HDL were increased in mice administered A-002 at either dosage (Table 4). This increase was greater in mice administered high dose A-002 plus statin than in mice administered high dose A-002 or statin alone (Table 4 compare Group E vs Groups B and C, Figure 7)
Table 3 Effect of A-002 and/or statin administration on plasma total cholesterol levels
Figure imgf000097_0002
Table 4 Effect of A-002 and/or statin administration on plasma HDL levels
Figure imgf000097_0001
Figure imgf000097_0003
Example 4 Effect of A-002 or A-002 plus statin administration on serum lipid levels in humans [0096] 204 human subjects from the United States with CVD, specifically stable coronary artery disease, were randomized to receive placebo or A- 002 via oral administration twice a day over an eight week administration period at dosages of 50 mg 100 mg, 250 mg, or 500 mg Levels of various lipids and inflammatory markers were measured at the outset of the trial and at the end of weeks four and/or eight For data sets with a normal distribution mean levels of lipids or inflammatory markers were analyzed For data sets with non-normal distribution, median levels were analyzed Administration of A-002 at all dosages tested resulted in a decrease in mean levels of serum LDL (Table 5), LDL particles (Table 6), small LDL particles (Table 7) total cholesterol (Table 8), and TG (Table 9), and median levels of SPLA2 (Table 10) In addition, administration of A-002 decreased median levels of CRP (Table 11 ) The magnitude of the observed decreases in LDL particle, small LDL particle, and CRP levels are particularly noteworthy because subjects treated with placebo exhibited increases in these markers over the course of the trial (Tables 6, 7, and 11 )
Table 5 Changes in serum LDL concentration in ITT population following A- 002 administration
Figure imgf000098_0001
<0 0001
Figure imgf000099_0001
Figure imgf000099_0002
Table 6 Changes in serum LDL particle concentration in ITT population following A-002 administration
Figure imgf000099_0003
Table 7 Changes in serum small LDL particle concentration in ITT population following A-002 administration
Figure imgf000099_0004
Figure imgf000100_0001
line
Figure imgf000100_0002
Table 8 Changes in serum total cholesterol concentration in ITT population following A-002 administration
Figure imgf000100_0003
Table 9 Changes in serum TG concentration in ITT population following A- 002 administration Placebo
150 6 mg/dl_
37
-0 7 mg/dl
-0 46%
Figure imgf000100_0004
Table 10 Changes in serum SPLA2 concentration in ITT population following A-002 administration
Figure imgf000100_0005
Figure imgf000101_0001
Table 11 : Changes in serum CRP concentration in ITT population following A- 002 administration
Figure imgf000101_0002
[0097] The median baseline LDL concentration in the 204 subject United States ITT population was 72.0 mg/dl. A-002 administration resulted in a significant decrease in mean LDL levels in a 97 subject subpopulation with baseline LDL levels equal to or higher than the median concentration (Table 12). In addition, administration of A-002 decreased mean serum LDL levels in a 53 subject subpopulation with diabetes (Table 13).
Table 12: Changes in serum LDL concentration in subpopulation with baseline serum LDL concentration greater than or equal to 72 mg/dl following A-002 administration
Figure imgf000102_0001
Table 13: Changes in serum LDL concentration in diabetic subpopulation following A-002 administration
Figure imgf000102_0002
[0098] A decrease in mean small LDL particle levels was observed in the subset of the US population that was receiving statin treatment during the trial (Table 14), indicating that administration of A-002 plus statin results in a greater decrease in small LDL particles than administration of statin alone. Likewise, a decrease in mean serum LDL levels was observed in an 81 subject subpopulation of the statin treatment group exhibiting elevated baseline LDL levels (i.e., baseline LDL levels greater than or equal to 72 mg/dl) (Table 15).
Table 14: Changes in serum small LDL particle concentration in statin subpopulation following A-002 administration
Figure imgf000103_0001
Table 15: Changes in serum LDL concentration in statin subpopulation with baseline serum LDL concentration greater than or equal to 72 mg/dl following A-002 administration
Figure imgf000103_0002
Figure imgf000104_0001
[0099] The combined effect of A-002 and statin administration on LDL levels was tested in a population of 332 subjects. This population consisted of the original 204 United States subjects, plus an additional 128 subjects from the Ukraine with stable CAD that received placebo or A-002 based according to the same protocol as the United States subjects. A decrease in mean serum LDL levels was observed in the statin subpopulation at four and eight weeks (Table 16), indicating that administration of A-002 and statin results in a greater decrease in serum LDL levels than administration of statin alone. Similarly, A-002 decreased LDL levels in subjects receiving a variety of non-statin compounds used in the treatment of CVD, including ezetimibe. AEGR-733/ezetimϊbe, colesevelam hydrochloride (WelChol®), MK-0524A (Cordaptive®), lisinopril/MC-1 antibody (MC-4232), and Angiotensin Receptor Blocker (ARB)/MC-1 (MC-4262). Table 16' Changes in serum LDL concentration in statin subpopulation following A-002 administration
Figure imgf000104_0002
Figure imgf000105_0001
[00100] Comparison of the above statin subpopulation results with results for subjects that were not receiving statin treatment indicates that administration of A-002 plus statin results in a greater decrease in mean serum small LDL particle and LDL levels than the expected additive effect of A-002 and statin (compare Table 17 to Table 14 and Table 18 to Table 16). In the United States population, mean serum small LDL particle levels were reduced at eight weeks by 9.00% in subjects administered A-002 plus statin (Table 14). versus a decrease of 3.25% in subjects administered A-002 alone (Table 17) and an increase of 13.26% in subjects administered statin alone (Table 14). These results summarized in Table 20. In the combined United States and Ukraine populations, mean serum LDL levels were decreased by 14.04% at week four in subjects administered A-002 plus statin (Table 16), versus a decrease of 6.93% in subjects administered A-002 alone (Table 18) and a decrease of 3.36% in subjects administered statin alone (Table 16). At week eight, mean serum LDL levels were decreased by 12.48% in subjects administered A-002 plus statin (Table 16), versus a decrease of 4.22% in subjects administered A-002 alone (Table 18) and a decrease of 2.15% in subjects administered statin alone (Table 16). These results are also summarized in Table 20. Therefore, administration of A-002 plus statin decreases LDL and small LDL particle levels in a synergistic manner. [00101] This synergism was also observed in subjects from the United States population that had baseline LDL concentrations of 72 mg/dl or greater (compare Table 19 to Table 15). Mean serum LDL levels were decreased at eight weeks by 16.27% in subjects administered A-002 plus statin (Table 15), versus a decrease of 8.23% in subjects administered A- 002 alone (Table 19) and a decrease of 4.40% in subjects administered statin alone (Table 15). These results are summarized in Table 20. Table 17; Changes in serum small LDL particle concentration in non-statin subpopulation following A-002 administration
Figure imgf000106_0001
Table 18: Changes in serum LDL levels in non-statin subpopulation following A-002 administration
Figure imgf000106_0002
Figure imgf000107_0002
Table 19 Changes in serum LDL concentration in non-statin subpopulation with baseline serum LDL levels greater than or equal to 72 mg/dl following A- 002 administration
Figure imgf000107_0003
Table 20 Summary of the synergistic effects of combined A-002 and statin administration versus administration of A-002 or statin alone Q Observed f Observed l
Figure imgf000107_0001
} Observed ~]
Figure imgf000108_0001
[00102] Serum LDL data for subjects in the statin subpopulation were subdivided based on the specific statin each subject was receiving. Statins with significant representation included atorvastatin, rosuvastatin. simvastatin, lovastatin, pravastatin, and fluvastatϊn, as well as the statin combination drugs simvastatin/ezetimibe (Vytorin®), atorvastatin/ezetimibe, atorvastatin/amlodipine (Caduet®), lovastatin/extended release niacin (Advicor®), rosuvastatin/TriCor®, rosuvastatin/ABT-335, simvastatin/extended release niacin (Simcor®), simvastatin/MK-0524A (MK-0524B), pravastatin/fenofibrate, atorvastatin/APA-01. and TAK-457/statin. Statin and statin combination dosages varied within each individual statin subgroup. The number of test and placebo subjects in each individual statin subgroup from the larger statin subpopulation was too low to allow for detailed statistical analysis. However, there appeared to be a trend towards the same synergistic decrease in LDL levels that was observed in the statin subpopulation as a whole in several of the statin subgroups, such as for example with certain dosages of atorvastatin, rosuvastatin, and simvastatin. These results indicate that the observed synergy between A-002 and statins is not limited to a particular statin.
[00103] The synergistic effect of A-002 and compounds used in the treatment of CVD on LDL levels was not limited to statins. For example, 30 subjects from the ITT population were receiving ezetimibe at a dosage of 10 mg during the course of the A-002 trial. Administration of A-002 resulted in a decrease in mean serum LDL levels in the ezetimibe subpopulation after eight weeks (Table 21 ), indicating that administration of A-002 plus ezetimibe results in a greater decrease in LDL levels than administration of ezetimibe alone (Table 21). As with the statin subpopulation, administration of A-002 in conjunction with ezetimibe resulted in a synergistic decrease in mean LDL levels that was greater than the expected additive effect of A-002 and ezetimibe (Table 22). Table 21 : Changes in serum LDL concentration in ezetimibe subpopulation following A-002 administration
Figure imgf000109_0001
Table 22: Summary of the synergistic effects of combined A-002 and ezetimibe administration versus administration of A-002 or ezetimibe alone
Figure imgf000110_0001
[00104] Serum TG. CRP, and IL-6 levels were measured at eight weeks in 86 subjects from the ITT population diagnosed with metabolic syndrome. Administration of A-002 resulted in a decrease in serum levels of each of these markers (Tables 23-25). Subjects administered placebo exhibited an increase in CRP and IL-6 levels (Tables 24-25). Table 23: Changes in serum TG concentration in metabolic syndrome subpopulation following A-002 administration
Figure imgf000110_0002
Table 24. Changes in serum CRP concentration in metabolic syndrome subpopulation following A-002 administration
Figure imgf000111_0001
Table 25 Changes in serum IL-6 concentration in metabolic syndrome subpopulation following A-002 administration
Figure imgf000111_0002
Example 5 A-002 plus statin combination tablet
[00105] Fixed dose tablets containing A-002 and one or more statins may be generated using methods known in the art For example, a fixed dose tablet containing a therapeutically effective amount of A-002 (e g , 250 or 500 mg) and a therapeutically effective amount of a statin (e g , 10, 20, 40 or 80 mg), may be generated using a formula such as that set forth in Table 26 One of ordinary skill in the art will recognize that additional components may be added to this generic formulation. For example, a compound such as calcium carbonate may be added to the formulation to enhance dissolution and solubility. Likewise, one of skill in the art will recognize that this formulation is just one example of a generic A-002/statin formulation, and that the identity and weight of the recited components within the formulation may be varied without undue experimentation. Table 26: Generic A-002/statin formulation'
Figure imgf000112_0001
[00106] To verify the feasibility of including both A-002 and a statin in a single formulation, fixed dose tablets containing 250 mg A-002 and 40 mg simvastatin (marketed as Zocor®) were generated. Unit and batch formulas for these tablets are set forth in Tables 27 and 28, respectively. All inactive ingredients were purchased from Spectrum Chemicals. Butylated hydroxyanisole was included in the formulation for consistency with the marketed form of simvastatin (Zocor®). Table 27: Unit formula for A-002/simvastatin tablets:
Figure imgf000112_0002
Figure imgf000113_0001
Table 28 Batch formula for A-002/sιmvastatιn tablets
Figure imgf000113_0002
Figure imgf000113_0003
[00107] A flow chart detailing one method of preparing the tablet above is set forth in Figure 8 BHA polysorbate 80 and purified water were mixed to create granulation fluid which was stored overnight Lactose anhydrous lactose fast flo and the first portion of croscarmellose sodium were weighed and screened through a coarse mesh then combined with A-002 and simvastatin (which can also be sieved if necessary) and dry blended for 1 -2 minutes using a mixer at slow speed In certain embodiments of this protocol, microcrystalline cellulose may be included in the dry mix Hydroxypropyl cellulose was combined with the granulation fluid, resulting in greatly increased viscosity The resultant solution was added slowly to the mixer containing the A-002/sιmvastatιn mix During addition, mixing speed was gradually increased Granulation end-point was reached when fine granules formed without the mass becoming wet or sticky
[00108] The granulation was screened through coarse mesh onto foil lined trays and placed in an oven at 500C and ambient humidity for approximately three hours After drying (and optional milling and/or sieving) granules were placed in a low-density polyethylene (LDPE) bag Approximately one-fourth of the dried granules were pre-blended with microcrystalline cellulose and magnesium stearate in a small baggy, and then the remainder of the granules were combined with the pre-blend in a mixer The second portion of croscarmellose sodium was added in and the entire mixture was mixed for several minutes Tablets were prepared by weighing approximately 580 mg of the final blend into a tablet press and compressing at 200-2500 psi (Carver press) The resultant tablets were weighed individually and had an average weight of approximately 0 6 g Tablets appeared off-white to light tan in color [00109] Two representative tablets (numbers 19 and 27) were analyzed by reverse phase HPLC Tablets were placed in a stability chamber at 25°C/60%RH Representative HPLC results for two of the tablets are set forth in Figure 9 and summarized in Table 29 Tablets maintained high potency (/ e , high concentrations of A-002 and simvastatin) thereby validating the feasibility of generating A-002/statιn combination tablets for the treatment of various conditions Table 29: HPLC analysis of A-002/simvastatin combination tablets:
Figure imgf000115_0001
[00110] A film coating may be applied to combination A-002/statin tablets using methods well known in the art. In one such method, the coating suspension is prepared by adding a film coat mixture such as Opadry YS-1- 18027-A to purified water in a mixing vessel. The mixing speed is reduced to avoid foaming and the suspension is mixed for 60 or more minutes, until uniform. After mixing, the suspension is allowed to stand for 60 or more minutes to deaerate. A coater such as the Accela Coater is set up and the theoretical amount of coating suspension to be sprayed is calculated based on the number and size of tablets being coated. Tablets are loaded onto the coating pan. and the nozzle air pressure (around 80-100 psi), atomizing air pressure (around 25-45 psi), pattern air pressure (around 20-40 psi), delivery rate (around 300-400 g/minute), pan speed (around 4-10 rpm), and dew point setting (around 5-15°C) are verified. The fan is turned on, and gun-to-bed distance (around 6-10 inches), supply air temperature (around 58°C), exhaust air temperature (around 45°C). air volume inlet (around 1500 cfm), and negative pan pressure differential are verified. The tablets are pre-heated, and a sample number of tablets are weighed to determine the average core tablet weight. The coating solution is sprayed onto the tablets while being gently mixed. At various intervals of around 5-15 minutes, the average tablet weight is recalculated. Once target tablet weight is reached, the supply air temperature is reduced to around 45C'C and the pan is jogged at intervals for around five minutes to allow the tablets to dry. The supply air temperature is reduced to around 3O0C and tablets are jogged manually for around ten more minutes The coated tablets are then discharged from the coating pan Example 6 Once a day dosing of A-002 or A-002 plus statin [00111] 135 human subjects over the age of 18 with CVD, specifically stable CAD, were randomized to receive either placebo or one of two dosages (250 mg or 500 mg) of A-002 via once a day oral administration over an eight week time period 89 of the subjects received A-002, while 46 of the subjects received placebo Subjects that were receiving statins or other compounds used in the treatment of CVD at the outset of the trial continued to receive those therapeutics throughout the trial 121 of the 135 subjects were on statins during the trial There was little variation between dosage groups with respect to age height weight, or BMI
[00112] Levels of various lipids and inflammatory markers were measured at the outset of the trial and at weeks two, four and/or eight weeks after the start of A-002 administration In addition plasma A-002 levels were measured at various intervals Lipids that were measured included LDL small LDL particle, oxidized LDL non-HDL cholesterol, total cholesterol, ApoB, and triglycerides In addition levels of the inflammatory marker CRP were measured Lipid and inflammatory marker levels at each timepoint were compared to the baseline measurements to determine the effect of A-002 administration For data sets with a normal distribution mean levels of lipids or inflammatory markers were analyzed For data sets with non-normal distribution median levels were analyzed LDL particle size was also assessed [00113] Subjects in the ITT population receiving A-002 at either dosage exhibited substantial decreases at week eight in mean serum LDL, non-HDL cholesterol, and total cholesterol levels (Tables 30-32, respectively) and in median small LDL particle, oxidized LDL, TG, and ApoB levels (Tables 33- 36). Subjects receiving A-002 also exhibited an increase in mean LDL particle size (Table 37). In addition, subjects receiving A-002 did not show the same increase in median CRP levels that was observed in subjects receiving placebo (Table 38).
Table 30: Changes in serum LDL concentration in ITT population following A- 002 administration-
Figure imgf000117_0001
Table 31 : Changes in serum non-HDL cholesterol concentration in ITT population following A-002 administration:
Figure imgf000117_0002
Figure imgf000118_0001
Table 32 Changes in serum total cholesterol concentration in ITT population following A-002 administration
Figure imgf000118_0002
Table 33 Changes in serum small LDL particle concentration in ITT population following A-002 administration
Figure imgf000118_0003
Table 34: Changes in serum oxidized LDL concentration in ITT population following A-002 administration:
Figure imgf000119_0001
Table 35: Changes in serum TG concentration in ITT population following A- 002 administration:
Figure imgf000119_0002
Table 36' Changes in serum ApoB concentration in ITT population following A-002 administration:
Figure imgf000119_0003
Figure imgf000120_0001
Table 37 Changes in LDL particle size in ITT population following A-002 administration
Figure imgf000120_0002
Table 38 Changes in serum CRP concentiation in ITT population following A- 002 administration
Figure imgf000120_0003
Figure imgf000121_0001
[00114] The decrease in mean serum LDL, non-HDL cholesterol, and total cholesterol levels and median small LDL particle, oxidized LDL, TG, and ApoB levels, the increase in mean LDL particle size, and the lower than expected increase in median CRP levels observed in the ITT population were also observed at eight weeks in the 121 subject subpopulation that was receiving statins during the trial (Tables 39-47, respectively), indicating that administration of A-002 plus statin results in a greater therapeutic effect on these markers than administration of statin alone. Likewise, a decrease in LDL, non-HDL cholesterol, total cholesterol, small LDL particle, oxidized LDL. and ApoB levels, an increase in LDL particle size, and a lower than expected increase in CRP levels were observed in 51 subjects within the statin subpopulation that had baseline LDL levels greater than 70 mg/dl (Tables 48- 55). The number of subjects in the non-statin subpopulation was too low to allow for a detailed statistical analysis of the combined effect of A-002 and statins versus the effect of either compound alone. However, once additional non-statin controls are obtained, it is expected that a synergistic decrease in LDL levels similar to that observed following twice daily A-002 administration (Example 4) will be observed in subjects receiving A-002 once a day. Table 39' Changes in serum LDL concentration in statin subpopulation following A-002 administration:
Figure imgf000121_0002
Figure imgf000122_0001
Table 40 Changes in serum non-HDL cholesterol concentration in statin subpopulation following A-002 administration
Figure imgf000122_0002
Table 41 Changes in serum total cholesterol concentration in statin subpopulation following A-002 administration
Figure imgf000122_0003
Table 42 Changes in serum small LDL particle concentration in statin subpopulation following A-002 administration
Placebo
40
773 5 nmol/L
37
-6 5 nmol/L
-1 0%
Figure imgf000123_0001
Table 43 Changes in serum oxidized LDL concentration in statin subpopulation following A-002 administration
Figure imgf000123_0002
Table 44 Changes in serum TG concentration in statin subpopulation following A-002 administration
Figure imgf000124_0001
Table 45 Changes in serum ApoB concentration in statin subpopulation following A-002 administration
Figure imgf000124_0002
Table 46 Changes in LDL particle size in statin subpopulation following A-002 administration
Figure imgf000124_0003
Figure imgf000125_0001
Figure imgf000125_0002
Table 47: Changes in serum CRP concentration in statin subpopulation following A-002 administration
Figure imgf000125_0003
Table 48. Changes in serum LDL concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/d! following A-002 administration:
Figure imgf000125_0004
Table 49: Changes in serum non-HDL cholesterol concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
Figure imgf000126_0001
Table 50: Changes in serum total cholesterol concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
Figure imgf000126_0002
Table 51 " Changes in serum small LDL particle concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
Figure imgf000127_0001
Table 52: Changes in serum oxidized LDL concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
Figure imgf000127_0002
Table 53: Changes in serum ApoB concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration.
Figure imgf000128_0001
Table 54: Changes in LDL particle size in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration.
Figure imgf000128_0002
Table 55: Changes in serum CRP concentration in statin subpopulation with baseline serum LDL levels greater than 70 mg/dl following A-002 administration:
Figure imgf000128_0003
Figure imgf000129_0001
[00115] As stated above, the foregoing is merely intended to illustrate various embodiments of the present invention. The specific modifications discussed above are not to be construed as limitations on the scope of the invention, it will be apparent to one skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the invention, and it is understood that such equivalent embodiments are to be included herein. All references cited herein are incorporated by reference as if fully set forth herein.
REFERENCES Boekholdt et al 2005 Arterioscler Thromb Vase Biol 25 839-846 Bostrom et al 2007 Arterioscler Thromb Vase Biol 27 600-606 Camejo et al 1998 Atherosclerosis 139 205-222 Chait, A , et al 2005 J Lipid Res 46 389-403 Daugherty et al 2000 J CIm Invest 105 1605-1612 Elinder et al 1997 Arterioscler Thromb Vase Biol 17 2257-2263 Hakala et al 2001 Arterioscler Thromb Vase Biol 21 1053-1058 Hartford et al 2006 J Cardiol 108 55-62 Ivandic et al 1999 Arterioscler Thromb Vase Biol 19 1284-1290 Jialal, I 1998 Clin Chem 44 1827-1832 Ktmura-Matsumoto et al Atherosclerosis Epub March 10, 2007 Kugiyama et al 1999 Circulation 100 1280-1284 Liu et al 2003 Eur Heart J 24 1824-1832 Mallat et al 2007 Arterioscler Thromb Vase Biol 27 1 177-1 183 Mallat et al 2005 J Am Coll Cardiol 46 1249-1257 Menschikowski et al 1995 Atherosclerosis 118 173-181 Nijmeijer et al 2002 Cardiovasc Res 53 138-146 Pruzanski et al 1998 J Lipid Res 39 2150-2160 Ramoner et al 2005 Blood 105 3583 Rosengren, B , et al 2006 Arterioscler Thromb Vase Biol 26 1579-
Sartipy et al 1999 J Biol Chem 274 25913-25920 Szmitko et al 2003 Circulation 108 2041 Tietge et al 2000 J Biol Chem 275 10077-10084

Claims

What is claimed is
1 A method of treating dyslipidemia in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more sPLA^ inhibitors
2 The method of claim 1 , wherein said administration of one or more SPLA2 inhibitors results in a decrease in cholesterol levels
3 The method of claim 2, wherein said administration of one or more SPLA2 inhibitors results in a decrease in total cholesterol levels
4 The method of claim 2, wherein said administration of one or more SPLA2 inhibitors results in a decrease in non-HDL cholesterol levels
5 The method of claim 2, wherein said administration of one or more SPLA2 inhibitors results in a decrease in LDL levels
6 The method of claim 5, wherein said administration of one or more SPLA2 inhibitors results in a decrease in LDL particle levels
7 The method of claim 6, wherein said administration of one or more SPLA2 inhibitors results in a decrease in small LDL particle levels
8 The method of claim 5, wherein said administration of one or more SPLA2 inhibitors results in a decrease in oxidized LDL levels
9 The method of claim 5, wherein said administration of one or more SPLA2 inhibitors results in a decrease in apolipoprotein B levels
10 The method of claim 1 , wherein said administration of one or more SPLA2 inhibitors results in an increase in LDL particle size 1 1 The method of claim 1 , wherein said administration of one or more sPLA? inhibitors results in an increase in HDL levels
12 The method of claim 2, wherein said administration of one or more sPLA? inhibitors results in an increase in HDL/LDL ratio
13 The method of claim 1 , wherein said administration of one or more sPLA2 inhibitors results in a decrease in triglyceride levels
14 The method of claim 1 , wherein said administration of one or more SPLA2 inhibitors results in a decrease in levels of one or more inflammatory markers
15 The method of claim 14, wherein said one or more inflammatory markers are selected from the group consisting of SPLA2 CRP, and IL-6
16 The method of claim 1 , wherein said one or more sPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs co-crystals solvates, or prodrug derivatives thereof
17 The method of claim 16, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 ,2- dιoxoethyi)-2-methyI-1-(phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
18 The method of claim 1 , wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day 19 The method of claim 18, wherein said administration of one or more sPLA; inhibitors is carried out twice per day
20 The method of claim 1 , wherein said administration of one or more SPLA2 inhibitors is carried out once per day
21 A method of decreasing cholesterol levels in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more sPLA? inhibitors, wherein said administration results in a decrease in cholesterol levels
22 The method of claim 21 , wherein said administration of one or more SPLA2 inhibitors results in a decrease in total cholesterol levels
23 The method of claim 21 , wherein said administration of one or more SPLA2 inhibitors results in a decrease in non-HDL cholesterol levels
24 The method of claim 21 , wherein said administration of one or more SPLA2 inhibitors results in a decrease in LDL levels
25 The method of claim 24, wherein said administration of one or more SPLA2 inhibitors results in a decrease in LDL particle levels
26 The method of claim 25, wherein said administration of one or more sPLA2 inhibitors results in a decrease in small LDL particle levels
27 The method of claim 24, wherein said administration of one or more SPLA2 inhibitors results in a decrease in oxidized LDL levels
28 The method of claim 24, wherein said administration of one or more sPLA2 inhibitors results in a decrease in apolipoprotein B levels 29 The method of claim 21 , wherein said administration of one or mote sPLA? inhibitors results in an increase in LDL particle size
30 The method of claim 21 , wherein said administration of one or more sPLA? inhibitors results in an increase in HDL/LDL ratio
31 The method of claim 21 , wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs, co-crystals, solvates, or prodrug derivatives thereof
32 The method of claim 31 , wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 ,2-dιoxoethyi)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
33 The method of claim 21 , wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
34 The method of claim 33, wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
35 The method of claim 21 , wherein said administration of one or more SPLA2 inhibitors is carried out once per day
36 A method of decreasing triglyceride levels in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more SPLA2 inhibitors, wherein said administration results in a decrease in triglyceride levels 37 The method of claim 36, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl)oxy)acetic acid and pharmaceutically acceptable salts, polymorphs, co-crystals, solvates, or prodrug derivatives thereof
38 The method of claim 37, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amino-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
39 The method of claim 36, wherein said administration of one or more SPLA2 inhibitors is earned out two or more times a day
40 The method of claim 39, wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
41 The method of claim 36 wherein said administration of one or more SPLA2 inhibitors is carried out once per day
42 A method of increasing HDL levels in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more sPLA2 inhibitors wherein said administration results in an increase in HDL levels
43 The method of claim 42, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethy!)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs, co-crystals, solvates or prodrug derivatives thereof 44 The method of claim 43, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
45 The method of claim 42, wherein said administration of one or more sPLAi inhibitors results in an increase in HDL/LDL ratio
46 The method of claim 42, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
47 The method of claim 46, wherein said administration of one or more SPLΛ2 inhibitors is carried out twice per day
48 The method of claim 42, wherein said administration of one or more SPLA2 inhibitors is carried out once per day
49 A method of treating cardiovascular disease or a condition associated with cardiovascular disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more SPLA2 inhibitors
50 The method of claim 49, wherein said cardiovascular disease is selected from the group consisting of atherosclerosis, coronary artery disease, coronary heart disease, conditions associated with coronary artery disease or coronary heart disease cerebrovascular disease, conditions associated with cerebrovascular disease, peripheral vascular disease, conditions associated with peripheral vascular disease, aneurysm, vasculitis, venous thrombosis, diabetes mellitus, and metabolic syndrome
51 The method of claim 49, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1 - (phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs co-crystals, solvates, or prodrug derivatives thereof
52 The method of claim 51 , wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (pheny!methyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
53 The method of claim 49, wherein administration of said one or more SPLA2 inhibitors results in a decrease in levels of one or more inflammatory markers
54 The method of claim 53, wherein said one or more inflammatory markers are selected from the group consisting of SPLA2, CRP, and IL-6
55 The method of claim 49, wherein said administration of one or more sPLA? inhibitors is carried out two or more times a day
56 The method of claim 55, wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
57 The method of claim 49, wherein said administration of one or more sPLA2 inhibitors is carried out once per day 58 A method of treating metabolic syndrome in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more sPLA? inhibitors
59 The method of claim 58, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-y!)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs, co-crystals, solvates or prodrug derivatives thereof
60 The method of claim 59, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
61 The method of claim 58 wherein administration of said one or more SPLA2 inhibitors results in a decrease in levels of one or more inflammatory markers
62 The method of claim 61 , wherein said one or more inflammatory markers are selected from the group consisting of SPLA2 CRP, and IL-6
63 The method of claim 58, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
64 The method of claim 63, wherein said administration of one or more sPLA? inhibitors is carried out twice per day
65 The method of claim 58, wherein said administration of one or more SPLA2 inhibitors is carried out once per day 66 A composition comprising one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD
67 The composition of claim 66, wherein said one or more compounds used in the treatment of CVD comprise one or more statins
68 The composition of claim 67, wherein said one or more statins are selected from the group consisting of atorvastatin, ceπvastatin, fluvastatin, lovastatin, mevastatin, pravastatin pravastatin, rosuvastatin, simvastatin, ezetimibe plus simvastatin, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug derivatives thereof
69 The composition of claim 66 wherein said one or more compounds used in the treatment of CVD comprise one or more statin combination drugs
70 The composition of claim 69, wherein said one or more statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine atorvastatin plus CP-529414 atorvastatin plus APA-01 simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK-0524A lovastatin plus extended release niacin rosuvastatin plus fenofibrate pravastatin plus fenofibrate, and statin plus TAK-457
71 The composition of claim 66 wherein said one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers calcium channel blockers, and antithrombotics
72 The composition of claim 66, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)- 2-ethyi-1-(phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts solvates, stereoisomers, or prodrug derivatives thereof
73 The composition of claim 72, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
74 The composition of claim 66 further comprising one or more pharmaceutically acceptable carriers
75 A method of treating dyslipidemia in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more sPLA2 inhibitors and a therapeutically effective amount of one or more compounds used in the treatment of CVD
76 The method of claim 75, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in cholesterol levels 77 The method of claim 76, wherein said administration of one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD results in a decrease in total cholesterol levels
78 The method of claim 76, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in non-HDL cholesterol levels
79 The method of claim 76, wherein said administration of one or more SPLΛ2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in LDL levels
80 The method of claim 79, wherein said administration of one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD results in a decrease in LDL particle levels
81 The method of claim 80, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in small LDL particle levels
82 The method of claim 79, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in oxidized LDL levels
83 The method of claim 79, wherein said administration of one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD results in a decrease in apolipoprotein B levels 84 The method of claim 75 wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an increase in LDL particle size
85 The method of claim 75, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an increase in HDL levels
86 The method of claim 75, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an increase in HDL/LDL ratio
87 The method of claim 75, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in triglyceride levels
88 The method of claim 75, wherein administration of said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in levels of one or more inflammatory markers
89 The method of claim 88, wherein said one or more inflammatory markers are selected from the group consisting of SPLA2 CRP and IL-6
90 The method of claim 75, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1 - (phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs, co-crystals solvates, or prodrug derivatives thereof
91 The method of claim 90, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
92 The method of claim 75, wherein said one or more compounds used in the treatment of CVD comprise one or more statins
93 The method of claim 92, wherein said one or more statins are selected from the group consisting of atorvastatin, ceπvastatin fluvastatin, lovastatin, mevastatin, pravastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe plus simvastatin, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug derivatives thereof
94 The method of claim 75 wherein said one or more compounds used in the treatment of CVD comprise one or more statin combination drugs
95 The method of claim 94, wherein said one or more statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate pravastatin plus fenofibrate, and statin plus TAK-457
96 The method of claim 75, wherein said one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics
97 The method of claim 75, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered simultaneously
98 The method of claim 97, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered in the same formulation
99 The method of claim 75, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered sequentially
100 The method of claim 75, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
101 The method of claim 100, wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
102 The method of claim 75, wherein said administration of one or more SPLA2 inhibitors is carried out once per day
103 A method of decreasing cholesterol levels in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more sPLA2 inhibitors and one or more compounds used in the treatment of CVD, wherein said administration results in a decrease in cholesterol levels
104 The method of claim 103, wherein said administration of one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD results in a decrease in total cholesterol levels
105 The method of claim 103 wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in non-HDL cholesterol levels
106 The method of claim 103, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in LDL levels
107 The method of claim 106, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in LDL particle levels
108 The method of claim 107, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in small LDL particle levels
109 The method of claim 106, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in oxidized LDL levels
1 10 The method of claim 106, wherein said administration of one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD results in a decrease in apolipoprotein B levels 1 11 The method of claim 103 wherein said administration of one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD results in an increase in LDL particle size
1 12 The method of claim 103, wherein said administration of one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD results in an increase in HDL/LDL ratio
1 13 The method of claim 103, wherein said one or more sPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)- 2-ethyl-1-(phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts polymorphs, co-crystals, solvates or prodrug derivatives thereof
1 14 The method of claim 1 13, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndoi-4-yl)oxy)acetιc acid N- morpholmo ethyl ester
115 The method of claim 103, wherein said one or more compounds used in the treatment of CVD comprise one or more statins
1 16 The method of claim 1 15, wherein said one or more statins are selected from the group consisting of atorvastatin ceπvastatin fluvastatin lovastatin, mevastatin, pravastatin, pravastatin, rosuvastatin, simvastatin ezetimibe plus simvastatin, and pharmaceutically acceptable salts, solvates stereoisomers, or prodrug derivatives thereof 1 17 The method of claim 103, wherein said one or more compounds used in the treatment of CVD comprise one or more statin combination drugs
1 18 The method of claim 1 17, wherein said one or more statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414 atorvastatin plus APA-01 , simvastatin plus ezetimibe simvastatin plus extended release niacin simvastatin plus MK-0524A lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457
1 19 The method of claim 103, wherein said one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors squalene synthase inhibitors, ACE inhibitors angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics
120 The method of claim 103 wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered simultaneously
121 The method of claim 120, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered in the same formulation 122 The method of claim 103, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered sequentially
123 The method of claim 103, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
124 The method of claim 123, wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
125 The method of claim 103, wherein said administration of one or more SPLA2 inhibitors is carried out once per day
126 A method of decreasing triglyceride levels in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more sPLA2 inhibitors and one or more compounds used in the treatment of CVD, wherein said administration results in a decrease in triglyceride levels
127 The method of claim 126, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dioxoethyl)- 2-ethyl-1-(phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts polymorphs, co-crystals, solvates, or prodrug derivatives thereof
128 The method of claim 127, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ({3-(2-amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
129 The method of claim 126, wherein said one or more compounds used in the treatment of CVD comprise one or more statins
130 The method of claim 129, wherein said one or more statins are selected from the group consisting of atorvastatin cerivastatin fluvastatin, lovastatin, mevastatin, pravastatin, pravastatin, rosuvastatin simvastatin ezetimibe plus simvastatin and pharmaceutically acceptable salts solvates, stereoisomers, or prodrug derivatives thereof
131 The method of claim 126, wherein said one or more compounds used in the treatment of CVD comprise one or more statin combination drugs
132 The method of claim 131 wherein said one or more statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine atorvastatin plus CP-529414 atorvastatin plus APA-01 , simvastatin plus ezetimibe simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate pravastatin plus fenofibrate, and statin plus TAK-457.
133 The method of claim 126, wherein said one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfei protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotics
134 The method of claim 126, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered simultaneously
135 The method of claim 134 wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered in the same formulation
136 The method of claim 126, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered sequentially
137 The method of claim 126, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
138 The method of claim 137, wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
139 The method of claim 126, wherein said administration of one or more SPLA2 inhibitors is carried out once per day
140 A method of increasing HDL levels in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD, wherein said administration results in an increase in HDL levels 141 The method of claim 140, wherein said one or more sPLA; inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)- 2-ethyl-1-(phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs, co-crystals, solvates, or prodrug derivatives thereof
142 The method of claim 141 , wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i /-/-ιndol-4-yl)oxy)acetιc acid N- morpholmo ethyl ester
143 The method of claim 140, wherein said one or more compounds used in the treatment of CVD comprise one or more statins
144 The method of claim 143, wherein said one or more statins are selected from the group consisting of atorvastatin, ceπvastatin fluvastatin, iovastatin, mevastatin, pravastatin pravastatin, rosuvastatin, simvastatin ezetimibe plus simvastatin, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug derivatives thereof
145 The method of claim 140, wherein said one or more compounds used in the treatment of CVD comprise one or more statin combination drugs
146 The method of claim 145, wherein said one or more statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414 atorvastatin plus APA-01 , simvastatin plus ezetimibe, simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibtate, pravastatin plus fenofibrate, and statin plus TAK-457
147 The method of claim 140, wherein said one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors ACE inhibitors, angiotensin H receptor antagonists, beta-adrenergic blockers calcium channel blockers and antithrombotics
148 The method of claim 140, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered simultaneously
149 The method of claim 148 wherein said one or more sPLA/ inhibitors and one or more compounds used in the treatment of CVD are administered in the same formulation
150 The method of claim 140, wherein said one or more sPLA, inhibitors and one or more compounds used in the treatment of CVD are administered sequentially
151 The method of claim 140, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day 152 The method of claim 151 , wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
153 The method of claim 140, wherein said administration of one or more sPLA? inhibitors is carried out once per day
154 The method of claim 140, wherein said administration of one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in an increase in HDL/LDL ratio
155 A method of treating cardiovascular disease or a condition associated with cardiovascular disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more SPLA2 inhibitors and a therapeutically effective amount of one or more statins
156 The method of claim 155, wherein said cardiovascular disease is selected from the group consisting of atherosclerosis, coronary artery disease, coronary heart disease, conditions associated with coronary artery disease or coronary heart disease, cerebrovascular disease, conditions associated with cerebrovascular disease, peripheral vascular disease, conditions associated with peripheral vascular disease, aneurysm vasculitis, venous thrombosis, diabetes mellitus, and metabolic syndrome
157 The method of claim 155, wherein said one or more sPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)- 2-ethyl-1-(phenylmethyl)-1 H-mdol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs, co-crystals solvates, or prodrug derivatives thereof 158 The method of claim 157, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyi)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yi]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
159 The method of claim 155, wherein said one or more compounds used in the treatment of CVD comprise one or more statins
160 The method of claim 159, wherein said one or more statins are selected from the group consisting of atorvastatin ceπvastatin, fluvastatin, lovastatin, mevastatin, pravastatin, pravastatin, rosuvastatin simvastatin ezetimibe plus simvastatin, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug derivatives thereof
161 The method of claim 155, wherein said one or more compounds used in the treatment of CVD comprise one or more statin combination drugs
162 The method of claim 161 , wherein said one or more statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine atorvastatin plus CP-529414 atorvastatin plus APA-01 simvastatin plus ezetimibe simvastatin plus extended release niacin, simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate pravastatin plus fenofibrate, and statin plus TAK-457
163 The method of claim 155, wherein said one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics
164 The method of claim 155, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered simultaneously
165 The method of claim 164, wherein said one or more sPLA? inhibitors and one or more compounds used in the treatment of CVD are administered in the same formulation
166 The method of claim 155, wherein said one or more sPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered sequentially
167 The method of claim 155, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
168 The method of claim 167, wherein said administration of one or more sPLA? inhibitors is carried out twice per day
169 The method of claim 155, wherein said administration of one or more sPLA? inhibitors is carried out once per day 170 The method of claim 155, wherein administration of said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in levels of one or more inflammatory markers
171 The method of claim 170, wherein said one or more inflammatory markers are selected from the group consisting of sPLA?, CRP, and IL-6
172 A method of treating metabolic syndrome in a subject in need thereof comprising administering to said subject a therapeutically effective amount of one or more SPLA2 inhibitors and a therapeutically effective amount of one or more statins
173 The method of claim 172, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)- 2-ethyl-1-(phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs, co-crystals, solvates, or prodrug derivatives thereof
174 The method of claim 173, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 2-dιoxoethyl)-2-ethyl-1- {phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 2- dιoxoethyl)-2-methyl-1-(phenylmethyl)-1H-ιndol-4-yl)oxy)acetιc acid N- morpholino ethyl ester
175 The method of claim 172, wherein said one or more compounds used in the treatment of CVD comprise one or more statins
176 The method of claim 175, wherein said one or more statins are selected from the group consisting of atorvastatin, ceπvastatin fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin ezetimibe plus simvastatin, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug derivatives thereof
177 The method of claim 172, wherein said one or more compounds used in the treatment of CVD comprise one or more statin combination drugs
178 The method of claim 177, wherein said one or more statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe, atorvastatin plus amlodipine, atorvastatin plus CP-529414 atorvastatin plus APA-01 simvastatin plus ezetimibe, simvastatin plus extended release niacin simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate pravastatin plus fenofibrate, and statin plus TAK-457
179 The method of claim 172, wherein said one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors angiotensin Il receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics
180 The method of claim 172, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered simultaneously 181 The method of claim 180, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered in the same formulation
182 The method of claim 172, wherein said one or more sPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered sequentially
183 The method of claim 172, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
184 The method of claim 183, wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
185 The method of claim 172, wherein said administration of one or more SPLA2 inhibitors is carried out once per day
186 The method of claim 172, wherein administration of said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD results in a decrease in levels of one or more inflammatory markers
187 The method of claim 186, wherein said one or more inflammatory markers are selected from the group consisting of SPLA2 CRP, and IL-6
188 A method of increasing the effectiveness of one or more compounds used in the treatment of CVD in a subject comprising administering one or more sPI_A2 inhibitors to said subject
189 The method of claim 188, wherein said one or more SPLA2 inhibitors are selected from the group consisting of ((3-(2-Amιno-1 ,2-dιoxoethyl)- 2-ethyl-1-(phenylmethyl)-1 H-ιndol-4-yl)oxy)acetιc acid and pharmaceutically acceptable salts, polymorphs, co-crystals, solvates, or prodrug derivatives thereof
190 The method of claim 189, wherein said prodrug derivatives are selected from the group consisting of [[3-(2-Amιno-1 ,2-dιoxoethyl)-2-ethyl-1- (phenylmethyl)-1 H-ιndol-4-yl]oxy]acetιc acid methyl ester and ((3-(2-amιno-1 ,2- dιoxoethyl)-2-methyl-1 -(phenylmethyl)-i H-indol-4-yl)oxy)acetιc acid N- morphoiino ethyl ester
191 The method of claim 188, wherein said one or more compounds used in the treatment of CVD comprise one or more statins
192 The method of claim 191 , wherein said one or more statins are selected from the group consisting of atorvastatin ceπvastatin fluvastatin, lovastatin, mevastatin, pravastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe plus simvastatin, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug derivatives thereof
193 The method of claim 188, wherein said one or more compounds used in the treatment of CVD comprise one or more statin combination drugs
194 The method of claim 193, wherein said one or more statin combination drugs are selected from the group consisting of atorvastatin plus ezetimibe atorvastatin plus amlodipine, atorvastatin plus CP-529414, atorvastatin plus APA-01 , simvastatin plus ezetimibe simvastatin plus extended release niacin simvastatin plus MK-0524A, lovastatin plus extended release niacin, rosuvastatin plus fenofibrate, pravastatin plus fenofibrate, and statin plus TAK-457 195 The method of claim 188, wherein said one or more compounds used in the treatment of CVD comprise one or more non-statin compounds selected from the group consisting of bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors microsomal triglyceride transfer protein (MTP) inhibitors, squalene synthase inhibitors ACE inhibitors, angiotensin I! receptor antagonists, beta-adrenergic blockers, calcium channel blockers, and antithrombotics
196 The method of claim 188, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered simultaneously
197 The method of claim 196, wherein said one or more SPLA2 inhibitors and one or more compounds used in the treatment of CVD are administered in the same formulation
198 The method of claim 188 wherein said one or more sPLA^ inhibitors and one or more compounds used in the treatment of CVD are administered sequentially
199 The method of claim 188, wherein said administration of one or more SPLA2 inhibitors is carried out two or more times a day
200 The method of claim 199, wherein said administration of one or more SPLA2 inhibitors is carried out twice per day
201 The method of claim 188, wherein said administration of one or more SPLA2 inhibitors is carried out once per day
PCT/US2008/062577 2007-05-03 2008-05-02 Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase a2 (spla2) inhibitors and spla2 inhibitor combination therapies WO2008137803A1 (en)

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EP08747605A EP2154958A4 (en) 2007-05-03 2008-05-02 Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase a2 (spla2) inhibitors and spla2 inhibitor combination therapies
BRPI0811486-2A2A BRPI0811486A2 (en) 2007-05-03 2008-05-02 CARDIOVASCULAR DISEASE TREATMENT AND DISLIPIDEMIA USING SECRETORY PHOSPHOLIPASE A2 INHIBITORS (SPLA2) AND SPLA2 INHIBITOR COMBINATION THERAPIES
CN200880023061A CN101742907A (en) 2007-05-03 2008-05-02 Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase A2 (SPLA2) inhibitors and spla2 inhibitor combination therapies
JP2010507578A JP2010526152A (en) 2007-05-03 2008-05-02 Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase A2 (SPLA2) inhibitor and SPLA2 inhibitor combination therapy
EA200971020A EA200971020A1 (en) 2007-05-03 2008-05-02 TREATMENT OF CARDIOVASCULAR DISEASE AND DYSLIPIDEMIA WITH THE USE OF SECRETARY PHOSPHOLIPASE A SPLA INHIBITORS AND SPLA INHIBITOR TREATMENT METHODS
MX2009011925A MX2009011925A (en) 2007-05-03 2008-05-02 Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase a2 (spla2) inhibitors and spla2 inhibitor combination therapies.
AU2008247451A AU2008247451A1 (en) 2007-05-03 2008-05-02 Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase A2 (SPLA2) inhibitors and SPLA2 inhibitor combination therapies
CA002686157A CA2686157A1 (en) 2007-05-03 2008-05-02 Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase a2 (spla2) inhibitors and spla2 inhibitor combination therapies
IL201897A IL201897A0 (en) 2007-05-03 2009-11-03 Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase a2 (spla2) inhibitors and spla2 inhibitor combination therapies

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US96959107P 2007-08-31 2007-08-31
US60/969,591 2007-08-31
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