KR20100109840A - Treatment of cardiovascular disease and dyslipidemia using secretory phospholipase a2 (spla2) inhibitors and spla2 inhibitor combination therapies - Google Patents

Abstract

Administration of sPLA ₂ inhibitors has been shown to reduce cholesterol levels, atherosclerotic plaque formation and aortic aneurysms in mice, and reduce cholesterol and triglyceride levels in humans. Interestingly, it has been found that administration of an sPLA ₂ inhibitor reduces cholesterol levels even when the inhibitor is administered only once daily. Accordingly, provided herein are methods for treating dyslipidemia, CVD, and conditions associated with CVD such as atherosclerosis and metabolic syndrome by administering one or more sPLA ₂ inhibitors. Significantly, administration of sPLA ₂ inhibitors and various compounds used in the treatment of CVD, such as statins, even further reduces LDL and LDL particle levels in a synergistic manner. In addition, administration of sPLA ₂ inhibitors and statins synergistically reduces plaque area. Thus, it is also possible to treat one or more sPLA ₂ inhibitors and compositions comprising one or more compounds used in the treatment of CVD, such as statins, and conditions associated with dyslipidemia, CVD, and CVD, such as atherosclerosis and metabolic syndrome. Provided herein are methods of using such compositions.

 SPLA2 inhibitor, statins, cholesterol

Description

TREATMENT OF CARDIOVASCULAR DISEASE AND DYSLIPIDEMIA USING SECRETORY PHOSPHOLIPASE A2 (SPLA2) INHIBITORS AND SPLA2 THEHIRAPI THE

Cross Reference to Related Application

This application is directed to US Provisional Application No. 11 / 874,869, filed Oct. 18, 2007, US Provisional Patent Application No. 60 / 969,591, filed Aug. 31, 2007, and US Provisional Filed May 3, 2007. Claim the benefit of patent application 60 / 915,910. The disclosures of each of these applications are incorporated herein by reference in their entirety, including the drawings.

In 2004, more than 75 million Americans were estimated to have 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 the coronary arteries that supply blood to the heart harden and narrow due to atherosclerosis. Various therapeutic options are currently used for the treatment of CVD and conditions associated with CVD. Many of these therapeutic options work by lowering cholesterol levels, especially LDL levels. Among the most popular and effective treatment options are statins, a class of compounds that inhibit cholesterol biosynthesis and prevent the formation of arterial plaques. Statin administration has been shown to lower LDL and triglyceride levels and substantially reduce coronary-related events and death due to CVD. However, statin therapy alone is insufficient to fully treat CVD. Thus, there is a need in the art for more effective methods of treating CVD and conditions associated with CVD.

Summary of the Invention

In certain embodiments, a method of treating dyslipidemia in a subject in need of treatment of dyslipidemia is provided by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors. In certain embodiments, the one or more sPLA ₂ inhibitors are administered in a composition further comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, administration of one or more sPLA ₂ inhibitors reduces cholesterol and / or triglyceride levels. In this particular embodiment, administration of one or more sPLA ₂ inhibitors reduces total cholesterol, non-HDL cholesterol, LDL, LDL particles, LDL small particles, oxidized LDL and / or ApoB levels. In certain embodiments, administration of one or more sPLA ₂ inhibitors increases HDL levels and / or LDL particle size. In certain embodiments, administration of one or more sPLA ₂ inhibitors reduces the level of one or more inflammatory markers. In this particular embodiment, inflammatory markers may include, but are not limited to, sPLA ₂ , CRP, and / or IL-6. In certain embodiments, administration of one or more sPLA ₂ inhibitors improves the HDL / LDL ratio. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, a method of reducing cholesterol levels in a subject in need thereof is provided by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors. In certain embodiments, the one or more sPLA ₂ inhibitors are administered in a composition further comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, administration of one or more sPLA ₂ inhibitors reduces total cholesterol, non-HDL cholesterol, LDL, LDL particles, LDL small particles, oxidized LDL and / or ApoB levels. In certain embodiments, administration of one or more sPLA ₂ inhibitors improves the HDL / LDL ratio. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, a method of reducing triglyceride levels in a subject in need thereof is provided by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors. In certain embodiments, the one or more sPLA ₂ inhibitors are administered in a composition further comprising one or more pharmaceutically acceptable carriers. In this particular embodiment, the at least one sPLA ₂ inhibitor comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors may be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, methods are provided for increasing HDL levels in a subject in need of increasing HDL levels by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors. In certain embodiments, the one or more sPLA ₂ inhibitors are administered in a composition further comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, administration of one or more sPLA ₂ inhibitors improves the HDL / LDL ratio. In certain embodiments, the improvement in the HDL / LDL ratio is further performed by a decrease in LDL levels. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, a method of treating a condition associated with CVD or CVD in a subject in need thereof is provided by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors. In certain embodiments, the one or more sPLA ₂ inhibitors are administered in a composition further comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg. In certain embodiments, administration of one or more sPLA ₂ inhibitors reduces the level of one or more inflammatory markers. In this particular embodiment, inflammatory markers may include, but are not limited to, sPLA ₂ , CRP, and / or IL-6. In certain embodiments, the condition associated with CVD or CVD includes atherosclerosis, metabolic syndrome, coronary artery disease, coronary heart disease, cerebrovascular disease, peripheral vascular disease, and / or coronary artery disease, coronary heart disease, cerebrovascular Conditions associated with a disease or peripheral vascular disease are included.

In certain embodiments, a method of treating metabolic syndrome in a subject in need thereof is provided by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors. In certain embodiments, the one or more sPLA ₂ inhibitors are administered in a composition further comprising one or more pharmaceutically acceptable carriers. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg. In certain embodiments, administration of one or more sPLA ₂ inhibitors reduces the level of one or more inflammatory markers. In this particular embodiment, inflammatory markers may include, but are not limited to, sPLA ₂ , CRP, and / or IL-6.

In certain embodiments, compositions are provided that include one or more sPLA ₂ 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 sPLA ₂ inhibitors comprises A-001 or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the one or more statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, stereoisomers, and precursors thereof Drug derivatives. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, Lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents.

In certain embodiments, a method of treating dyslipidemia in a subject in need of treatment of dyslipidemia by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of a therapeutically effective amount of CVD. This is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001 or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the one or more statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, stereoisomers, and precursors thereof Drug derivatives. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, Lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces cholesterol levels and / or triglyceride levels. In this particular embodiment, administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD results in total cholesterol, non-HDL cholesterol, LDL, LDL particles, LDL small particles, oxidized LDL and / or ApoB levels. Decreases. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD increases HDL levels and / or LDL particle size. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD improves the HDL / LDL ratio. In certain embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered simultaneously. In this particular embodiment, one or more sPLA ₂ inhibitors and 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 agent (s) may further comprise one or more pharmaceutically acceptable carriers. In other embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered sequentially. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces the level of one or more inflammatory markers. In this particular embodiment, inflammatory markers may include, but are not limited to, sPLA ₂ , CRP, and / or IL-6.

In certain embodiments, a method of reducing cholesterol levels 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 for the treatment of a therapeutically effective amount of CVD is disclosed. Is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001 or a pharmaceutically acceptable prodrug, salt, polymorph co-crystal or solvate. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the one or more statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, stereoisomers, and precursors thereof Drug derivatives. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK -0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD results in total cholesterol, non-HDL cholesterol, LDL, LDL particles, LDL small particle levels, oxidized LDL and / or ApoB levels. Decreases. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD increases the LDL particle size. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD improves the HDL / LDL ratio. In certain embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered simultaneously. In this particular embodiment, one or more sPLA ₂ inhibitors and 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 agent (s) may further comprise one or more pharmaceutically acceptable carriers. In other embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered sequentially. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, a method of reducing triglyceride levels in a subject in need of a reduction in triglyceride levels by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of a therapeutically effective amount of CVD is disclosed. Is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. A-001 In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the one or more statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, stereoisomers thereof And prodrug derivatives. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, Lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In certain embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered simultaneously. In this particular embodiment, one or more sPLA ₂ inhibitors and 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 agent (s) may further comprise one or more pharmaceutically acceptable carriers. In other embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered sequentially. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, a method of increasing HDL levels in a subject in need of an increase in HDL levels by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of a therapeutically effective amount of CVD is disclosed. Is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In this particular embodiment, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the one or more statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, stereoisomers, and precursors thereof Drug derivatives. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, Lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD improves the HDL / LDL ratio. In certain embodiments, the improvement in the HDL / LDL ratio is further performed by a decrease in LDL levels. In certain embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered simultaneously. In this particular embodiment, one or more sPLA ₂ inhibitors and 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 agent (s) may further comprise one or more pharmaceutically acceptable carriers. In other embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered sequentially. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD to ameliorate a condition associated with CVD or CVD in a subject in need of treatment of a condition associated with CVD or CVD. Methods of treatment are provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the one or more statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, stereoisomers, and precursors thereof Drug derivatives. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, Lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In certain embodiments, administration of one or more sPLA ₂ inhibitors reduces the level of one or more inflammatory markers. In certain embodiments, inflammatory markers may include, but are not limited to, sPLA ₂ , CRP, and / or IL-6. In certain embodiments, the condition associated with CVD or CVD includes atherosclerosis, metabolic syndrome, coronary artery disease, coronary heart disease, cerebrovascular disease, peripheral vascular disease, and / or coronary artery disease, coronary heart disease, cerebrovascular Included but are not limited to diseases or conditions associated with peripheral vascular disease. In certain embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered simultaneously. In this particular embodiment, one or more sPLA ₂ inhibitors and 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 agent (s) may further comprise one or more pharmaceutically acceptable carriers. In other embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered sequentially. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject once daily. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, a method of treating metabolic syndrome in a subject in need thereof is provided by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the one or more statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, stereoisomers, and precursors thereof Drug derivatives. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, Lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In certain embodiments, administration of one or more sPLA ₂ inhibitors reduces the level of one or more inflammatory markers. In this particular embodiment, inflammatory markers may include, but are not limited to, sPLA ₂ , CRP, and / or IL-6. In certain embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered simultaneously. In this particular embodiment, one or more sPLA ₂ inhibitors and 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 agent (s) may further comprise one or more pharmaceutically acceptable carriers. In other embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered sequentially. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, methods are provided for increasing the efficacy of a compound used in the treatment of CVD in a subject by administering at least one sPLA ₂ inhibitor to the subject. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, the compound used for the treatment of CVD can be a statin or statin combination drug. In this particular embodiment, the statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, stereoisomers, and prodrug derivatives thereof. It may be selected from the group consisting of. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK- 0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the compounds used for the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, Non-statin compounds selected from the group consisting of squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In certain embodiments, one or more sPLA ₂ inhibitors may be administered simultaneously with the compound used to treat CVD. In this particular embodiment, the one or more sPLA ₂ inhibitors and the 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 agent (s) may further comprise one or more pharmaceutically acceptable carriers. In other embodiments, the one or more sPLA ₂ inhibitors and the compounds used in the treatment of CVD may be administered sequentially. In certain embodiments, one or more sPLA ₂ inhibitors may be administered to a subject two or more times a day, and in such specific embodiments, one or more sPLA ₂ inhibitors are administered twice daily. In other embodiments, the one or more sPLA ₂ inhibitors can be administered to the subject on a daily basis. In certain embodiments, one or more sPLA ₂ inhibitors can be administered in a dosage of about 50 to about 500 mg.

In certain embodiments, 1 in the manufacture of a medicament for the treatment of dyslipidemia in a subject, treatment of CVD and conditions associated with CVD, lowering cholesterol levels, lowering triglyceride levels, increasing HDL levels and improving HDL / LDL ratio Use of more than one sPLA ₂ inhibitor is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, the medicament further comprises one or more pharmaceutically acceptable carriers.

In certain embodiments, in the manufacture of a medicament for the treatment of dyslipidemia in a subject, treatment of CVD and conditions associated with CVD, lowering cholesterol levels, lowering triglyceride levels, increasing HDL levels and / or improving HDL / LDL ratios. The use of one or more sPLA ₂ inhibitors of and one or more compounds used in the treatment of CVD is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the one or more sPLA ₂ inhibitors comprises A-002, a prodrug of A-001. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the one or more statins are atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin, pitavastatin, and various salts, solvates, conformations thereof Isomers and prodrug derivatives. In this particular embodiment, the statin combination drug is atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, Lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In certain embodiments, the medicament further comprises one or more pharmaceutically acceptable carriers.

With reference to the drawings and the study of the following description, further embodiments and aspects will become apparent in addition to the exemplary embodiments described above.

1: Effect of A-002 administration on body weight in mice. ApoE ^{− / −} mice were administered vehicle alone, 30 mg / kg A-002 or 90 mg / kg A-002 twice daily for 16 weeks. Body weight was measured once a week.

2: Effect of A-002 administration on plasma total cholesterol levels in mice. ApoE ^{− / −} mice were administered vehicle alone, 30 mg / kg A-002 or 90 mg / kg A-002 twice daily for 16 weeks. Total plasma cholesterol levels were measured at weeks 0, 4, 8, 12 and 16 weeks.

Figure 3: Effect of A-002 administration on atherosclerotic plaque coverage in mice. ApoE ^{− / −} mice were administered vehicle alone, 30 mg / kg A-002 or 90 mg / kg A-002 twice daily for 16 weeks. At week 16 the aortic plaque coverage was measured.

4: Effect of A-002 administration on angiotensin II-mediated atherosclerotic plaque formation and aortic aneurysm. ApoE ^{− / −} mice were administered saline and aqueous angiotensin II in aqueous vehicle, angiotensin II in acacia vehicle, or angiotensin II in acacia vehicle and 30 mg / kg A-002. At 4 weeks, the aortic plaque coverage was measured.

Figure 5: En surface lesions in A-002 and / or statin dosing group. Various doses of A-002, statin, or A-002 and statins were administered over 12 weeks to high-fat ApoE ^-/- mice, and the en surface lesion area was measured using digital imaging. Lesion size is expressed as percent coverage of the entire tissue sample. A: low dose A-002; B: high dose A-002; C: statins; D: low dose A-002 and statins; E: high dose A-002 and statins; And F: vehicle alone.

6: Total plasma cholesterol levels in A-002 and / or statin dosing group. High-fat dietary ApoE ^-/- mice were administered various doses of A-002, statin, or A-002 and statins over 12 weeks, and total cholesterol levels were measured. A: low dose A-002; B: high dose A-002; C: statins; D: low dose A-002 and statins; E: high dose A-002 and statins; And F: vehicle alone.

7: HDL levels in A-002 and / or statin dosing group. High-fat dietary ApoE ^-/- mice were dosed with various doses of A-002, statin, or A-002 and statins over 12 weeks, and HDL levels were measured. A: low dose A-002; B: high dose A-002; C: statins; D: low dose A-002 and statins; E: high dose A-002 and statins; And F: vehicle alone.

8: A-002 / simvastatin combination tablet preparation protocol.

9: HPLC profile. A. Simvastatin. B. A-002. C. A-002 / Simvastatin Combination Tablet # 19. D. A-002 / Simvastatin Combination Tablet # 27.

The following description of the invention is merely illustrative of various embodiments of the invention. Accordingly, the specific modifications examined are not to be construed as limitations on the scope of the invention. It will be apparent to those skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the present invention, and such equivalent embodiments will be included herein.

Abbreviations :

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 / minute; CHD, coronary heart disease; CRP, C-reactive protein; CVD, cardiovascular disease; ECG, electrocardiogram; ERN, sustained release niacin; HDL, high density lipoprotein; HMG-CoA, hydroxymethyl glutaryl coenzyme A; HPLC, high performance liquid chromatography; ICAM-1, intercellular adhesion molecule 1; IDL, medium density lipoprotein; IL, interleukin (eg, IL-6, IL-8); ITT, subject; LDL, low density lipoprotein; LPA, lysophosphatidic acid; MCP-1, monocyte chemotactic protein-1; MI, myocardial infarction; MIP-1α, macrophage inflammatory protein 1 alpha; MTP, microsomal triglyceride transfer protein; PAD, peripheral arterial disease; PAF, platelet activating factor; PLA ₂ , phospholipase A ₂ ; QD, once daily; sPLA ₂ , secretory phospholipase A ₂ ; TEAE, adverse effects appearing untimely upon treatment; TG, triglycerides; TIA, transient ischemic attack; TNFα, tumor necrosis factor alpha; VCAM-1, vascular cell adhesion molecule 1; VLDL, ultra low density lipoprotein.

As used herein in connection with a condition, the terms “treat”, “treating” or “treatment” may be used to prevent a condition, slow the onset or progress of an ecology, reduce the risk of developing the condition, To prevent or delay the progression of associated symptoms, to reduce or terminate the symptoms associated with a condition, to fully or partially recover a condition, or some combination thereof. For example, with respect to atherosclerosis, “treatment” can refer to a reduction in the likelihood of diffusion of atherosclerotic plaque deposits, a reduction in the rate of diffusion of deposits, a reduction in the number or size of existing deposits, or improved plaque stability. have. Likewise, “treatment” in connection with dyslipidemia can refer to a decrease in lipid levels, cholesterol levels and / or triglyceride (TG) levels.

As used herein, the term "subject" refers to any mammal, preferably a human.

In certain embodiments, a 'subject in need' is a subject diagnosed with CVD or exhibiting one or more conditions associated with CVD, a subject diagnosed with, or exhibiting, one or more conditions associated with CVD in the past, or genetic Refers to a subject who appears to be at risk of developing one or more conditions associated with CVD or CVD in the future due to environmental or environmental factors As used herein, "cardiovascular disease" or "CVD" includes, for example, atherosclerosis (coronary atherosclerosis). With sclerosis and carotid atherosclerosis), coronary artery disease (CAD), coronary heart disease (CHD), conditions associated with CAD and CHD, conditions associated with cerebrovascular disease and cerebrovascular disease, peripheral vascular disease and peripheral vascular disease and Associated conditions, aneurysms, vasculitis, venous thrombosis, diabetes mellitus and metabolic syndrome. As used herein, “state associated with CAD and CHD” includes, for example, angina and myocardial infarction (MI; heart failure). As used herein, “state associated with cerebrovascular disease” includes, for example, transient ischemic attack (TIA). And stroke, as used herein, include, for example, lameness. As used herein, "condition associated with CVD" includes, for example, dyslipidemia, such as hyperlipidemia (elevated) Lipid levels), hypercholesterolemia (elevated cholesterol levels), and hypertriglyceridemia (elevated TG levels), elevated glucose levels, low HDL / LDL ratios, and hypertension. A subject in need may be a subject exhibiting dyslipidemia, or a subject who exhibited dyslipidemia in the past or at risk of developing dyslipidemia in the future. In the fetus, the subject may exhibit elevated cholesterol levels, or may be at risk of showing elevated cholesterol levels in the past or at elevated levels in the future. Elevated triglyceride levels may be present, or there may be a risk of exhibiting elevated triglyceride levels in the past or elevated levels of triglycerides in the future. In certain embodiments, a 'subject in need' may have a condition associated with inflammation, may have been diagnosed with such a condition in the past, or may be at risk of 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 such embodiments, the "subject in need a ~ 'may be at risk of developing a nd or may receive the or can exhibit an elevated level of sPLA _2, the past rise sPLA ₂ levels, or increase sPLA _2. In other embodiments, a 'subject in need' may exhibit sPLA ₂ levels that fall within the normal range. In certain embodiments, a 'subject in need' may exhibit elevated levels of one or more additional markers associated with inflammation, including CRP, IL-6, MCP-1, TNFα, IL-8, ICAM -1, VCAM-I and MIP-1α are included, but are not limited to these.

As used herein, the term "cholesterol level" refers to blood cholesterol levels, serum cholesterol levels, plasma cholesterol levels, or cholesterol levels from another biological fluid. As used herein, a decrease in cholesterol levels 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. As used herein, a decrease in LDL may refer to a decrease in total LDL, a decrease in LDL particles, a decrease in LDL particles, a decrease in oxidized LDL levels and / or a decrease in ApoB levels. As used herein, a decrease in VLDL may refer to a decrease in total VLDL, or a decrease in the level of one or more of VLDL subparticles V1 to V6. As used herein, an improvement in the HDL / LDL ratio refers to any increase in the ratio of HDL to LDL and can be performed by decreasing the LDL level, increasing the HDL level, or some combination thereof. As used herein, an increase in LDL particle size refers to an increase in average particle size.

As used herein, the term "elevated cholesterol level" refers to acceptable normal limit levels, such as the National Heart Lung and Blood Institute (NHLBI), the National Cholesterol Education Program (NCEP). Cholesterol levels above the level declared by)). Accepted normal limit cholesterol levels can vary from subject to subject based on a variety of risk factors, such as the history of CVD. In certain embodiments, a subject exhibiting elevated cholesterol levels can have a blood LDL level of at least 70 mg / dL. In this particular embodiment, a subject exhibiting elevated cholesterol levels may have a blood LDL of at least 100 mg / dL, in another embodiment at least 160 mg / dL, in another embodiment at least 190 mg / dL. In certain embodiments, a subject exhibiting elevated cholesterol levels can have a total cholesterol level in the blood of at least 200 mg / dL. In this particular embodiment, the subject exhibiting elevated cholesterol levels can have total cholesterol in the blood of at least 240 mg / dl.

As used herein, the term “triglyceride level” refers to triglyceride levels in blood, serum triglyceride levels, plasma triglyceride levels, or triglyceride levels from another biological fluid. As used herein, the term "elevated triglyceride level" refers to triglyceride levels above the acceptable normal limit level. Acceptable normal limit triglyceride levels can vary from subject to subject based on a variety of risk factors, such as the history of CVD. In certain embodiments, a subject exhibiting elevated triglyceride levels can have a blood triglyceride level of at least 150 mg / dL. In this particular embodiment, the subject exhibiting elevated triglyceride levels is at least 200 mg / dL, in other embodiments at least 300 mg / dL, in other embodiments at least 400 mg / dL, in another embodiment at least 500 mg / dL May have triglyceride levels in the blood.

As used herein, the term "statin" refers to any compound that inhibits HMG-CoA reductase, an enzyme that promotes the conversion of HMG-CoA to mevalonate.

As used herein, the term “sPLA ₂ inhibitor” refers to any compound or prodrug thereof that inhibits the activity of sPLA ₂ .

As used herein, a “therapeutically effective amount” of a composition is an amount of the composition that produces a desired therapeutic effect, such as treating a target condition, in a subject. The exact therapeutically effective amount is the amount of the composition that will yield the most effective result in terms of therapeutic efficacy in a given subject. The amount will vary depending on various factors, including the specific (eg, active, pharmacokinetic, pharmacodynamic, and bioavailable) of the therapeutic composition, the physiological condition of the subject (eg, weight, sex, type and stage of disease, History, general physical condition, responsiveness to a given dosage, and other current 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 the therapeutically effective amount through routine experimentation, ie, monitoring the subject's response to administration of the composition and adjusting the dosage accordingly. For further guidance, see, eg, 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, 11 ^th Edition, McGraw-Hill, New York, NY, 2006. The entire disclosure is incorporated herein by reference.

As used herein, “pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substance, composition or vehicle that is involved in carrying or delivering a compound of interest from one tissue organ or body part to another tissue, organ or body part. . Such carriers include, for example, liquid, solid or semisolid fillers, solvents, surfactants, diluents, excipients, adjuvants, binders, buffers, dissolution aid solutions, encapsulating materials, sequestrants, dispersants, preservatives, lubricants, disintegrants, thickeners, Emulsifiers, antimicrobials, antioxidants, stabilizers, colorants, or some combination thereof. Each component of the carrier must be "pharmaceutically acceptable" in that it must be compatible with other components of the composition and suitable for contact with any tissue, organ or body part it encounters, which means that it is a risk of toxicity, irritation. , Allergic reactions, immunity, or any other complications that excessively surpass its therapeutic benefit. Examples of pharmaceutically acceptable carriers for use in the pharmaceutical compositions disclosed herein include diluents such as microcrystalline cellulose or lactose (eg, anhydrous lactose, lactose fast flo), binders such as gelatin, polyethylene glycol , Waxes, microcrystalline cellulose, synthetic gums such as polyvinylpyrrolidone, or cellulose based polymers such as hydroxypropyl cellulose (eg hydroxypropyl methylcellulose (HPMC)), lubricants such as magnesium stearate, calcium Stearate, stearic acid, or microcrystalline cellulose, disintegrants such as starch, crosslinked polymers, or cellulose (eg, croscarmellose sodium (CCNa), fillers such as silicon dioxide, titanium dioxide, microcrystalline cellulose, Or powdered cellulose, surfactants or emulsifiers such as polysorbates (eg polysorbate 20, 40, 60 or 80; Span 20, 40, 60, 65 or 80), antioxidants such as butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gal Or ascorbic acid (in its free acid or salt form), buffers such as phosphate or citrate buffers, sequestrants such as ethylenediaminetetraacetic acid (EDTA), ethylene glycol tetraacetic acid (EGTA), or edetate disodium, dispersant Such as sodium carboxymethylcellulose, hydroxypropyl methylcellulose, povidone, or polyvinylpyrrolidone, dissolution aids such as calcium carbonate, and excipients such as water, saline, dextrose, glycerol, or ethanol, citric acid, calcium metabisulse Pit, lactic acid, malic acid, succinic acid or tartaric acid are included, but are not limited thereto.

Metabolic syndrome is a disorder characterized by a group of metabolic risk factors. Such elements include, for example, dyslipidemia, abdominal obesity, elevated blood pressure (hypertension), insulin resistance or glucose intolerance, prethrombotic state, and proinflammatory state. Subjects are generally classified as having metabolic syndrome if they meet three of the following five criteria. 1) Abdominal obesity (women over 35 inches waist circumference, men over 40 inches), 2) low HDL levels (women below 50 mg / dl, men below 40 mg / dl), 3) high blood pressure (130 / 85 mmHg or more) or current antihypertensive prescription treatment, 4) hypertriglyceridemia (TG levels above 150 mg / dL) and 5) fasting glucose disorders (blood glucose levels above 110 mg / dL). Metabolic syndrome is associated with elevated levels of various inflammatory markers such as CRP or IL-6. Subjects with metabolic syndrome have an increased risk of developing CAD, CHD, CAD, and CHD, and type 2 diabetes.

Over time, hypercholesterolemia and hypertriglyceridemia can lead to the development of atherosclerotic plaque on the inner artery lining through an atherosclerosis process which in turn results in atherosclerosis. Atherosclerosis significantly reduces blood flow through the arteries, which in turn results in the development of CAD, CHD, and conditions associated with CAD and CHD.

Reduction of cholesterol levels, in particular LDL levels and / or reduction of TG levels, have been shown to delay the onset of atherosclerosis and reduce progression, thereby reducing the risk of developing CAD and CHD. In certain cases, moderate cholesterol and / or TG reduction may be achieved through diet control. In other cases, however, a moderate reduction requires the administration of one or more compounds used for the treatment of CVD. Compounds used to treat CVD include compounds that lower cholesterol levels and / or increase HDL levels, such as statins, bile acid sequestrants, such as cholestyramine resin (Questran®), prevalites ( Prevalite®), Cholestipol Hydrochloride (Colestid®), or Colesevelam Hydrochloride (WelChol®, Cholestagel®) Fibrate, such as bezafibrate (Bezalip®), cipropibrate (Modalim®), clofibrate, gemfibrozil (Lopid (Registered trademark)), or fenofibrate (Antara (registered trademark), TriCor (registered trademark), ABT-335), niacin or niacin derivatives such as xantinol niacinate, niacin immediate- Release type (Niacor®), sustained release niacin ( ERN) (Niaspan®), niaspan MF or niaspan CF, or sustained release niacin combinations (eg, sustained release niacin and DP-1 antagonist laropiprant (MK-0524) , A 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 combinations of AEGR-733 and AEGR-733 (eg, AEGR-733 and ezetimibe), squalene synthase inhibitors such as rapamystat acetate (TAK-475) and rapamystat acetate combinations ( For example, TAK-475 and one or more statins), and various other compounds such as dextrose Shin, ISIS 301012, cardioprotectants such as MC-1 antibodies, glycoprotein IIb / IIIa inhibitors such as tyropiban hydrochloride (Aggrastat®), TG100-115, AEGR 773, AEGR 427, stanol 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 ricinopril, captopril, enalapril, nitrosated ACE inhibitors, or ACE inhibitors. Combination (eg, a combination of ricinopril and MC-1 antibody, MC-4232), angiotensin II receptor antagonist, nitrosized angiotensin II receptor antagonist, or angiotensin II receptor antagonist combination (eg, Angiotensin receptor blocker (ARB) and combinations referred to as MC-1, MC-4262), beta-adrenergic blockers or nitrified beta-adrenergic blockers, calcium channel blockers, or antithrombotic agents such as aspirin or nitrosified Aspirin is included.

Among the most well-known and commonly used compounds used in the treatment of CVD are statins. Statins are compounds that inhibit HMG-CoA reductase from promoting the conversion of HMG-CoA to mevalonate, a rate-limiting step in the cholesterol biosynthetic pathway. Thus, statins act as potential lipid lowering agents. Statin administration significantly reduces blood LDL levels and moderately reduces blood TG levels. It has also been suggested that statins can prevent CVD by improving endothelial function, regulating inflammatory responses, maintaining plaque stability, and preventing thrombus formation. Examples of statins that may be used with the compositions and methods disclosed herein include atorvastatin or atorvastatin calcium (Lipitor® or Torrvast®; for example, US Pat. No. 4,681,893 or 5,273,995) and atorvastatin combinations (e.g., atorvastatin and amlodipine (commercially available as Norvasc®), a combination sold as Caduet®, for example, the United States) See Patent No. 6,455,574; atorvastatin and CP-529414 (available under torcetrapib®); atorvastatin and APA-01; atorvastatin and ezetimibe), cerivastatin (Lipobay®) Or commercially available as Baycol®, fluvastatin (available under Lescol®; US Pat. No. 4,739,073), lovastatin (Mevacor®) ) Or as Altocor® (see, eg, US Pat. No. 4,231,938), lovastatin combinations (eg, lovastatin and niaspan®, Advicor) Combination sold as a trademark), mevastatin, pitavastatin (commercially available as Livalo® or Pitava®), pravastatin (Pravachol ( Commercially available as trademark®, Mevalotin®, Selektine® or Lipostat®; see eg US Pat. No. 4,346,227), pravastatin combination Water (eg pravastatin and fenofibrate), rosuvastatin (commercially available as Crestor®), rosuvastatin combination (eg rosuvastatin and tricor®) , Simvastatin (Zocor® or Lipex®) Commercially available as U.S. Pat.Nos. 4,444,784, 4,916,239 and 4,820,850, and simvastatin combinations (e.g., simvastatin and ezetimibe, Vytorin®) Combinations; See, eg, US Pat. No. 7,229,982; Simvastatin and niaspan®, a combination commercially available as Simcor®, a combination of simvastatin and MK-0524A, MK-0524B), as well as various pharmaceutically acceptable compounds of the compounds listed above Salts, solvates, salts, stereoisomers, prodrug derivatives or nitro derivatives are included, but are not limited to these. In some cases, for example simvastatin, the active form of statin is a metabolite formed in the subject's body after administration. In other cases, statins are administered in their active form.

Phospholipase A ₂ (PLA ₂ ) is a family of enzymes that promotes hydrolysis of sn-2 fatty acyl ester bonds of phospholipids to produce free fatty acids and lysophospholipids such as arachidonic acid (AA) and lysophosphatidylcholine. AA can then be converted to eicosanoids such as prostaglandins, leukotriene, thromboxane, and lipoxin, while lysophosphatidylcholine can be metabolized to lysophosphatidine acid (LPA) or platelet-activating factor (PAF). PLA ₂ s has been classified into several groups based on factors such as calcium required for cell localization, amino acid sequence, molecular mass, and enzyme activity (Ramoner 2005).

Secretory phospholipase A ₂ (sPLA ₂ ) is a subgroup of extracellular or secreted PLA ₂ that plays a role in inflammation induction. Elevated levels of sPLA ₂ type IIA, IID, IIE, IIF, III, V and X have been observed at all stages of atherosclerosis development and are involved in atherosclerosis based on their ability to degrade phospholipids (Kimura- Kimura-Matsumoto 2007). sPLA ₂ type IIA was found to be expressed in vascular smooth muscle cells and foam cells of human atherosclerotic lesions, and this expression was recognized to correlate with the development of atherosclerosis (Menschikowski 1995; Eliner ( Elinder) 1997). Transgenic mice expressing high levels of human type IIA sPLA ₂ increase LDL levels, reduce HDL levels, atherosclerotic lesions (Ivandic 1999; Tietge 2000), and given a high fat diet. Atherosclerosis develops at a higher rate than normal mice (Ivandick 1999). Treatment with sPLA ₂ modifies the LDL lipoproteins to have higher affinity for extracellular matrix proteins (Camejo 1998; Sartipy 1999; Hakala 2001), in the arterial wall. Increase the retention of LDL particles. There is also some evidence that sPLA ₂ remodels HDL, causing HDL catabolism (Pruzanski 1998). The increased expression of sPLA ₂ type V is indicated sikindago increased atherosclerosis in mice Meanwhile, sPLA ₂ type V were sikindago reduce atherosclerosis (rosen Glenn (Rosengren) 2006; Boss Tromso (Bostrom) 2007).

In addition, sPLA ₂ expression is correlated with increased risk of developing CAD. Higher circulating levels of sPLA ₂ and sPLA ₂ type IIA were observed especially in documented CAD patients than in control patients (Kugiyama 1999; Liu 2003; Boekholdt 2005; Chait) 2005; Hartford 2006). In addition, higher circulating levels of sPLA ₂ have been found to provide accurate prognostic measures of the onset of CAD in healthy individuals. 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 only type IIA concentrations (malat ( Mallat) 2005). It has also been suggested that sPLA ₂ may have a deleterious effect on the regulation of ischemic events. This is largely based on the discovery of sPLA ₂ deposition in the necrotic centers of infarcted human myocardium (Nijmeijer 2002).

As disclosed herein, administration of the sPLA ₂ inhibitor A-002, a prodrug form of A-001, reduces plasma total cholesterol levels, increases plasma HDL levels, reduces atherosclerotic plaque formation and aortic aneurysm in mice. . Twice daily administration of A-002 in humans with CVD reduces serum LDL, LDL particles, LDL small particles, total cholesterol and TG levels. A decrease in LDL was observed in subgroups showing elevated baseline LDL levels as well as in diabetic subgroups, while a decrease in TG levels was observed in metabolic syndrome subgroups. In addition, it has been found that administration of A-002 reduces serum levels of inflammatory markers sPLA ₂ , CRP and IL-6. Surprisingly, similar results were obtained in a single daily administration of A-002, which resulted in reduction of LDL, non-HDL cholesterol, total cholesterol, LDL small particles, oxidized LDL, triglyceride and ApoB levels and an increase in LDL particle size. It was. In addition, once-daily dosing of A-002 prevented a significant increase in CRP levels observed in the placebo group. Administration of sPLA ₂ inhibitors reduces total cholesterol levels, atherosclerotic plaque formation and aortic aneurysms, and in humans total cholesterol, non-HDL cholesterol, LDL, LDL particles, LDL small particles, oxidized LDL particles, TG and ApoB levels Based on the results of the experiments disclosed herein, which show a decrease in the number of cells and increased LDL particle size in humans, the administration of a therapeutically effective amount of one or more sPLA ₂ inhibitors is determined by CVD, and conditions associated with CVD, such as dyslipidemia, atherosclerosis Sclerosis metabolic syndrome, CAD, CHD, and conditions associated with CAD and CHD can be used.

Provided herein are methods of treating CVD and CVD associated conditions in a subject in need of treatment of CVD and CVD related conditions by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors in certain embodiments. In this particular embodiment, administration of one or more sPLA ₂ inhibitors can result in a decrease in cholesterol levels, a decrease in TG levels, an increase in LDL particle size, and / or an improvement in HDL / LDL ratio, among other effects. Accordingly, also provided herein are methods of treating dyslipidemia in a subject in need thereof. In certain embodiments, the one or more sPLA ₂ inhibitors for use in this method include A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, cocrystal or solvate of A-001. In this particular embodiment, the pharmaceutically acceptable prodrug is A-002. In certain embodiments, administration of one or more sPLA ₂ inhibitors may result in the reduction of one or more markers associated with inflammation. Such markers include, but are not limited to, sPLA ₂ , CRP, and IL-6. Further, herein disclosed are methods for treating conditions and / or dyslipidemia associated with methods disclosed herein, such as CVD, CVD, or total cholesterol, LDL, non-HDL cholesterol, LDL particles, LDL small particles, oxidized LDL, ApoB, and / Or compositions comprising one or more sPLA ₂ inhibitors for use to lower triglyceride levels or raise HDL levels. In certain embodiments, such compositions further comprise one or more pharmaceutically acceptable carriers.

Compositions comprising one or more sPLA ₂ inhibitors for use in the methods disclosed herein can be administered to a subject on a single basis or in multiple doses. In embodiments in which such compositions are provided in multiple administrations, the compositions may be administered at set intervals over a predetermined, predetermined period of time, or indefinitely or until a certain therapeutic level is reached, such as a subject having cholesterol below a certain limit. It may be administered until the level is indicated. In certain embodiments, one or more sPLA ₂ inhibitors may be administered at least once a day to once a week, once a month, or once every few months. In certain embodiments, one or more sPLA ₂ inhibitors may be administered twice daily, and in other embodiments, one or more sPLA ₂ inhibitors may be administered once daily. As disclosed herein, administration of A-002 twice daily and once daily resulted in a significant decrease in serum lipid levels.

In certain embodiments, a kit comprising one or more sPLA ₂ inhibitors is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001, and in such specific embodiments, An acceptable prodrug is A-002. In certain embodiments, the kits provide instructions for use, such as dosage or administration instructions.

As disclosed herein, twice daily administration of A-002 has been shown to further reduce total cholesterol levels in statin treated mice, and LDL, LDL particles and LDL small particle levels in humans. Likewise, A-002 has been shown to further reduce serum LDL levels in ezetimibe treated humans. Similar results were obtained when A-002 was administered once daily with statins. These results indicate that administration of the sPLA ₂ inhibitor unexpectedly further reduces cholesterol levels in subjects previously treated with another compound used for the treatment of CVD, such as statins. As further disclosed herein, administration of A-002 and statins resulted in an unexpected synergistic decrease in total cholesterol levels and aortic lesion formation in mice and LDL and LDL particle size in humans. A synergistic decrease in LDL after co-administration of A-002 and statins was observed in the entire statin subpopulation. In addition, although synergism was shown between A-002 and each individual statin in the general statin subgroup, statistical analysis of this effect was complicated by a limited number of trials and placebo subjects for each statin. These results indicate that the synergistic decrease in LDL levels caused by co-administration of A-002 and statins is not limited to one particular statin, but rather occurs over the full range of statins. Administration of A-002 and ezetimibe results in a similar synergistic decrease in LDL levels, indicating that the synergy between A-002 and the compound used to treat CVD is not limited to statins. Thus, herein, by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of a therapeutically effective amount of CVD, such as statins, CVD and associated with CVD, including dyslipidemia and atherosclerosis Methods of treating CVD and conditions associated with CVD, including dyslipidemia and atherosclerosis, are provided in a subject in need thereof. Also provided herein are methods of increasing the efficacy of a compound, such as statin, used in the treatment of CVD, by administering the compound used in the treatment of CVD with one or more sPLA ₂ inhibitors.

In certain embodiments herein, treatment of dyslipidemia in a subject in need of treatment of dyslipidemia by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of a therapeutically effective amount of CVD. A method is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001, and in such specific embodiments, An acceptable prodrug is A-002. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the at least one statin is selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin and pitavastatin, and the statin combination drug is combined with atorvastatin Ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibin Pravastatin and fenofibrate, and statins and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin M receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In this particular embodiment, the one or more compounds used in the treatment of CVD include ezetimibe. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more statins reduces cholesterol levels, and in such specific embodiments, the decrease in cholesterol levels occurs after administration of one or more sPLA ₂ inhibitors or one or more statins alone. Greater than observed. In this particular embodiment, the decrease in cholesterol levels is synergistic, meaning that the decrease is greater than the expected side effects of the one or more sPLA ₂ inhibitors and the one or more statins. In this particular embodiment, administration of the one or more sPLA ₂ inhibitors and the one or more statins reduces LDL levels, increases HDL levels, or improves the HDL / LDL ratio by both.

In certain embodiments herein, in a subject in need of treatment of a condition associated with CVD or CVD by administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of a therapeutically effective amount of CVD. A method of treating CVD or a condition associated with CVD is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001, and in such specific embodiments, An acceptable prodrug is A-002. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the at least one statin is selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin and pitavastatin, and the statin combination drug is combined with atorvastatin Ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibin Pravastatin and fenofibrate, and statins and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In this particular embodiment, the one or more compounds used in the treatment of CVD include ezetimibe. In certain embodiments, treating CVD or a condition associated with CVD may be associated with a decrease in cholesterol levels. However, in other embodiments, treatment of certain forms of CVD may not be associated with a concomitant decrease in cholesterol levels. For example, sPLA ₂ inhibitors and statin administration can reduce atherosclerotic plaque formation without measurable reduction of cholesterol levels through mechanisms such as inhibition of inflammation. In such embodiments, treatment of CVD may be associated with a decrease in the level of one or more inflammatory markers such as sPLA ₂ , CRP and / or IL-6. In certain embodiments, administration of one or more sPLA ₂ inhibitors and one or more statin combinations results in a greater degree of treatment than observed after administration of one or more sPLA ₂ inhibitors or statins alone. In this particular embodiment, the degree of treatment is synergistic, meaning that the degree of treatment is greater than the expected side effects of the one or more sPLA ₂ inhibitors and one or more statins.

In certain embodiments, provided herein are methods for increasing the efficacy of a compound used in the treatment of CVD by administering the compound used in the treatment of CVD with one or more sPLA ₂ inhibitors. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001, and in such specific embodiments, An acceptable prodrug is A-002. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the at least one statin is selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin and pitavastatin, and the statin combination drug is combined with atorvastatin Ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibin Pravastatin and fenofibrate, and statins and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In this particular embodiment, the one or more compounds used in the treatment of CVD include ezetimibe. As used herein, an increase in the efficacy of a compound used in the treatment of CVD refers to an increase in the therapeutic effect of the compound, a decrease in the dosage of the compound required to achieve a particular level of therapeutic effect, or some combination thereof. For example, an increase in the efficacy of a statin as used herein may refer to a greater decrease in LDL levels after administration of a particular dose of statin, a decrease in the amount of statin dose required to cause a specific decrease in LDL levels, or some combination thereof. have.

Likewise, in certain embodiments, methods are provided for increasing the efficacy of sPLA ₂ inhibitors by administering one or more compounds used in the treatment of CVD. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001, and in such specific embodiments, An acceptable prodrug is A-002. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the at least one statin is selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin and pitavastatin, and the statin combination drug is combined with atorvastatin Ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibin Pravastatin and fenofibrate, and statins and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In this particular embodiment, the one or more compounds used in the treatment of CVD include ezetimibe.

In certain embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD, such as one or more statins, may be administered to the subject separately, ie as separate compositions. In such embodiments, one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD may be administered simultaneously or sequentially. In addition, one or more sPLA ₂ inhibitors and 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 the sPLA ₂ inhibitor and / or statins are provided in multiple doses, one or both are anywhere from at least once a day to once a week, monthly It may be administered once or once every few months. In certain embodiments, one or more sPLA ₂ inhibitors and / or statins may be administered twice daily, and in another preferred embodiment, one or more sPLA ₂ inhibitors and / or statins may be administered once daily. .

In certain embodiments, a kit comprising one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD is provided. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001, and in such specific embodiments, An acceptable prodrug is A-002. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the at least one statin is selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin and pitavastatin, and the statin combination drug is combined with atorvastatin Ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibin Pravastatin and fenofibrate, and statins and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. Within the kit, the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD may be divided into separate compartments, for example, the kit may comprise a plurality of bottles or packets, where each bottle Or the packet contains one or more sPLA ₂ inhibitors or one or more compounds used for the treatment of CVD. In other embodiments, one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD can be found in a single, non-dividing vessel. In certain embodiments, the kit provides instructions for use, such as dosage or administration instructions.

In certain embodiments, provided herein are pharmaceutical compositions comprising a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used to treat a therapeutically effective amount of CVD. In certain embodiments, the one or more sPLA ₂ inhibitors comprises A-001, or a pharmaceutically acceptable prodrug, salt, polymorph, co-crystal or solvate of A-001, and in such specific embodiments, An acceptable prodrug is A-002. In certain embodiments, the one or more compounds used in the treatment of CVD include one or more statins or statin combination drugs. In this particular embodiment, the at least one statin is selected from the group consisting of atorvastatin, simvastatin, rosuvastatin, lovastatin, pravastatin, cerivastatin, fluvastatin, mevastatin and pitavastatin, and the statin combination drug is combined with atorvastatin Ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibin Pravastatin and fenofibrate, and statins and TAK-457. In certain embodiments, the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer protein (MTP) ) At least one non-statin compound selected from the group consisting of inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. In this particular embodiment, the one or more compounds used in the treatment of CVD include ezetimibe.

Pharmaceutical compositions comprising one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD, such as one or more statins, may be administered to a subject on a single basis or in multiple doses. In embodiments in which such compositions are provided in multiple administrations, the compositions may be administered at set intervals over a predetermined, predetermined period of time, or indefinitely or until a certain therapeutic level is reached, such as a subject having cholesterol below a certain limit. Administration until levels, triglyceride levels, or inflammatory marker levels are indicated. In certain embodiments, the composition may be administered at least once a day to once a month or once every few months. In this particular embodiment, the composition is administered once or twice daily.

One or more of sPLA ₂ inhibitor as disclosed herein, at least one compound used in the CVD treatment, or one pharmaceutical composition comprising at least one compound used in the treatment of at least one sPLA ₂ inhibitors and CVD is oral, aerosol Can be delivered to a subject by any route of administration known in the art including, but not limited to, enteral, nasal, ocular, parenteral or transdermal (eg, topical creams or ointments, patches). . "Parenteral" includes orbital inferior, intraarterial injection, intraepithelial, intracardiac, intradermal, intramuscular, intraperitoneal, intrapulmonary, intravertebral, intestinal, intradural, intrauterine, intravenous, subarachnoid, subcapsular, subcutaneous Refers to the route of administration generally associated with injection, including transmucosal or transmucosal membranes. As described herein, sPLA ₂ inhibitors, statins, or combined sPLA ₂ inhibitors and statin pharmaceutical compositions can be in any pharmaceutically acceptable form, including, for example, solid, liquid, solution, suspension, emulsion, dispersion, micelle, or liposome forms. It may be administered in the form. Injectable preparations include sterile solutions for immediate injection, sterile dry soluble products such as subcutaneous tablets, lyophilized powders for immediate combination with the solvent immediately before use, sterile suspensions for immediate injection, and sterile dry for immediate combination with the vehicle immediately before use. Insoluble products and sterile emulsions may be included. The solution can be aqueous or non-aqueous. In certain embodiments, the composition may comprise one or more pharmaceutically acceptable carriers, or may be administered with one or more pharmaceutically acceptable carriers.

In certain embodiments, a pharmaceutical comprising one or more of sPLA ₂ inhibitor, at least one compound used in the CVD treatment, or one at least one compound used in the treatment of at least one sPLA ₂ inhibitors and CVD, as described herein The composition may be formed in oral dosage units such as tablets, pills or capsules. Such oral dosage units may comprise the active ingredient (eg A-002 and one or more statins) and one or more pharmaceutically acceptable carriers. As disclosed herein, the possibility of such oral dosage units has been demonstrated by producing tablet batches comprising A-002 and simvastatin as active ingredients. Each tablet was formulated with 250 mg A-002 and 40 mg simvastatin. Pharmaceutically acceptable carriers used to formulate tablets include anhydrous lactose, lactose fast flow, and microcrystalline cellulose as diluent, hydroxypropyl cellulose as binder, croscarmellose sodium as disintegrant, butylated hydroxy as antioxidant Anisole, magnesium stearate as lubricant and polysorbate 80 as surfactant were included. Water was used as the solvent when formulating the tablet. The final tablet contained two high concentrations of the active ingredient as measured by HPLC analysis, which means that the sPLA ₂ inhibitor and one or more compounds used for the treatment of CVD, such as one or more statins, can be formulated in a single oral dosage unit. It is present. Certain tablet formulations disclosed herein are provided by way of example only. Those skilled in the art will appreciate that the therapeutically acceptable carriers employed in the formulations may vary and such modifications are routine in the art. Likewise, the active ingredient may vary. As disclosed herein, administration of various statins in conjunction with A-002 results in a synergistic decrease in serum lipid levels. Thus, in certain embodiments, A-002 includes, but is not limited to, atorvastatin or atorvastatin calcium, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, and / or simvastatin May be combined with any statin known in the art. In certain embodiments, oral dosage units may comprise a coating surrounding the active ingredient and the pharmaceutically acceptable carrier (s).

In certain embodiments, as disclosed herein, comprising one or more sPLA ₂ inhibitors, one or more compounds used in the treatment of CVD, or one or more compounds used in the treatment of CVD with one or more sPLA ₂ inhibitors The pharmaceutical composition may be administered via a time-release delivery vehicle, such as a time-release oral dosage unit. As used herein, “time-release vehicle” refers to any delivery vehicle that releases an active agent (ie, A-002 and one or more statins) at or after a dose or over a period of time rather than immediately after administration. Time-release can be obtained by coating on the vehicle that dissolves over a set timeframe after administration. In certain embodiments, the time-release vehicle can include a multi-layer coating with alternating multiple layers of the active ingredient such that each layer of the coating releases a particular dose of active ingredient as it dissolves. In other embodiments, sPLA ₂ inhibitors, statins, or combined sPLA ₂ inhibitors and statin pharmaceutical compositions can be administered via an immediate-release delivery vehicle.

A therapeutically effective amount of a compound for use in the treatment of an sPLA ₂ inhibitor or CVD for use in the methods or compositions disclosed herein may be determined individually for each compound. For example, statins or statin combination drugs may be administered or included in pharmaceutical compositions in dosages well known in the art to reduce cholesterol levels. Those skilled in the art will appreciate that in embodiments in which the one or more compounds used for the treatment of CVD are combined in a single composition with one or more sPLA ₂ inhibitors, the amount of the compound used in the treatment of CVD that constitutes a therapeutically effective amount is 1 It will be appreciated that due to the interaction between more than one sPLA ₂ inhibitor, it may differ from the amount of compound that constitutes a therapeutically effective amount of the compound when administered alone. For example, the effective dosage of statins for use in combination therapy may be lower than the standard dosage of statins when administered alone. In such situations, one skilled 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 sPLA ₂ 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 / 1 serving. In this particular embodiment, the therapeutically effective amount of the sPLA ₂ inhibitor may be about 25 to about 5,000 mg / 1 batch, and in this particular embodiment, the therapeutically effective amount may be about 50 to about 500 mg / 1 batch.

In certain embodiments, sPLA ₂ inhibitor for use in the compositions and methods disclosed herein may best indole-based sPLA ₂ inhibition, which means that contains the indole nucleus to the compound having the structure.

Various indole sPLA ₂ inhibitors are known in the art. For example, indole-based sPLA ₂ inhibitors that can be used with the present invention include U.S. Pat.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) include, but are not limited to, the entire disclosure above Included with reference to. Methods for preparing indole-based sPLA ₂ inhibitors are described, for example, in US Pat. Nos. 5,986,106 (Khau), 6,265,591 (Anderson) and 6,380,397 (Anderson), the entire disclosure of which is Incorporated herein by reference. SPLA ₂ inhibitors for use in the present invention can be produced using this synthesis or using any other synthesis known in the art. In certain embodiments, the sPLA ₂ inhibitor for use in the present invention may be an sPLA ₂ type IIA, type V, and / or type X inhibitor. Various examples of indole sPLA ₂ inhibitors are shown below. This example is provided only as a description of the type of inhibitor that may be used with the present invention and thus is not meant to be limiting. Those skilled in the art will appreciate that a variety of other indole sPLA ₂ inhibitors may be used.

In certain embodiments, sPLA ₂ inhibitors for use in the present invention comprise 1H-indole-3-glyoxylamide compounds having the structure: and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, Tautomers or optical isomers.

Where

Each X is independently oxygen or sulfur,

R ₁ is selected from the group consisting of (a), (b) and (c), wherein

(a) is a C ₇ -C ₂₀ alkyl, C ₇ -C ₂₀ alkenyl, C ₇ -C ₂₀ alkynyl, carbocyclic radical or heterocyclic radical,

(b) is a member of (a) substituted with one or more independently selected non-interfering substituents,

(c) is a-(L) -R ₈₀ group, wherein-(L)-is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen and sulfur, wherein-(L)- The combination of atoms in (i) only carbon and hydrogen, (ii) only sulfur, (iii) only oxygen, (iv) only nitrogen and hydrogen, (v) only carbon, hydrogen and sulfur, and (vi) only carbon , Hydrogen and oxygen, wherein R ₈₀ 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- (C ₁ -C ₂ alkyl), -S- (C _1- 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, non-interfering substituents and-(L _a )-(acidic groups), wherein-(L _a )-is an acid linker having an acid linker length of 1-4 Provided that at least one of R ₄ and R ₅ must be-(L _a )-(acidic group),

R ₆ and R ₇ are each independently selected from hydrogen, non-interfering substituents, carbocyclic radicals, carbocyclic radicals substituted with non-interfering substituents, heterocyclic radicals and heterocyclic radicals substituted with non-interfering substituents,

Provided that for any of the R ₁ , R ₆ and R ₇ groups the carbocyclic radical is cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, Nil, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl represented by the formula (bb) and related bibenzylyl homologues ,

Wherein n is a number from 1 to 8, provided that for any of the R ₁ , R ₆ and R ₇ groups the heterocyclic radical is pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenyl Imidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphthenyl, di Benzothiaphenyl, indazolyl, imidazo (1.2-A) pyridinyl, benzotriazolyl, anthranyl, 1,2-benzisoxazolyl, benzoxazolyl, benzotriazolyl, purinyl, pyridinyl, dipyridyl, Phenylpyridinyl, benzylpyridinyl, pyrimidinyl, phenylpyrimidinyl, pyrazinyl, 1,3,5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl and quinoxalinyl and Provided that in the R ₁ , R ₂ , R ₄ , R ₅ , R ₆ and R ₇ groups, the non-interfering substituents are 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 -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, toluyl, xylenyl, non Phenyl, 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 alkyl Carbonyl, C ₂ -C ₁₂ alkylcarbonylamino, C ₂ -C ₁₂ alkoxyamino, C ₂ -C ₁₂ alkoxyaminocarbonyl, C ₂ -C ₁₂ alkylamino, C ₁ -C ₆ alkylthio, C _2- C ₁₂ alkylthiocarbonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₂ -C ₆ haloalkoxy, C ₁ -C ₆ haloalkylsulfonyl, C ₂ -C ₆ haloalkyl , C ₁ -C ₆ hydroxyalkyl, -C (O) O (C ₁ -C ₆ alkyl),-(CH ₂ ) _n -O- (C ₁ -C ₆ alkyl), benzyloxy, phenoxy, phenyl Thio,-(CONHSO ₂ R), -CHO, amino, amidino, bromo, carbamyl, carboxyl, carvalkoxy,-(CH ₂ ) _n -CO ₂ H, chloro, cyano, cyanoguanidinyl , Fluoro, guanidino, hydrazide , Hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO ₃ H, thioacetal, thiocarbonyl and C ₁ -C ₆ carbonyl, wherein n Is 1 to 8.

In this particular embodiment,-(L)-has the formula:

Wherein R ₈₁ and R ₈₂ are each independently selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, carboxy carboalkoxy and halo, p is a number from 1 to 5, Z is a bond,-(CH ₂ )-, -O-, -N (C ₁ -C ₁₀ alkyl)-, -NH-, and -S-.

In this particular embodiment, R ₄ is-(L _a )-(acid group) and the acid linker-(L _a )-has the formula:

Wherein Q is selected from the group consisting of-(CH ₂ )-, -O-, -NH- and -S-, R ₈₃ and R ₈₄ are each hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₁ Independently from the group consisting of —C ₁₀ alkaryl, C ₁ -C ₁₀ aralkyl, hydroxy and halo.

In this particular embodiment wherein R ₅ is-(L _a )-(acid group), the acid linker-(L _a )-has the formula:

Wherein r is a number from 2 to 7, s is 0 or 1, Q is selected from the group consisting of-(CH ₂ )-, -O-, -NH- and -S-, R ₈₅ and R ₈₆ is each independently selected from the group consisting of hydrogen, C ₁ -C ₁₀ alkyl, aryl, C ₁ -C ₁₀ alkaryl, C ₁ -C ₁₀ aralkyl, carboxy, carvalkoxy and halo.

In certain embodiments, the 1H-indole-3-glyoxylamide compound for use in the present invention is ((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] Oxy] acetic acid methyl ester, ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, di-2 -((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) propanoic acid, ((3- (2- Amino-1,2-dioxoethyl) -1-((1,1'-biphenyl) -2-ylmethyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1-((1,1'-biphenyl) -3-ylmethyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid, ( (3- (2-amino-1,2-dioxoethyl) -1-((1,1'-biphenyl) -4-ylmethyl) -2-methyl-1H-indol-4-yl) oxy) Acetic acid, ((3- (2-amino-1, 2-dioxoethyl) -1-((2,6-dichlorophenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) Acetic acid, ((3- (2-amino-1, 2-dioxoethyl) -1- (4- (fluorophenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -2-methyl-1-((1-naphthalenyl) methyl) -1H-indol-4-yl) oxy) acetic acid, ((3 -(2-amino-1,2-dioxoethyl) -1-((3-chlorophenyl) methyl) -2-ethyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2- Amino-1,2-dioxoethyl) -1-((1,1'-biphenyl) -2-ylmethyl) -2-ethyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1-((1,1'-biphenyl) -2-ylmethyl) -2-propyl-1H-indol-4-yl) oxy) acetic acid, ( (3- (2-amino-1,2-dioxoethyl) -2-cyclopropyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino- 1,2-dioxoethyl) -1-((1,1'-biphenyl) -2-ylmethyl) -2-cyclopropyl-1H-indol-4-yl) oxy) acetic acid and 4-((3 -(2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-5-yl) oxy) butanoic acid, or a pharmaceutically acceptable salt, solvate thereof, I'm Drug is selected from the group consisting of derivatives, racemates, tautomers, or optical isomers.

In certain embodiments, sPLA ₂ inhibitors for use in the present invention comprise 1H-indole-3-glyoxylamide compounds having the structure: and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers thereof Isomers or optical isomers.

Where

Both X are oxygen,

및

로 이루어진 군으로부터 선택되며,R ₁ is

And

Is selected from the group consisting of

Wherein R ₁₀ is a radical independently selected from halo, C ₁ -C ₁₀ alkoxy, —S— (C ₁ -C ₁₀ alkyl) and C ₁ -C ₁₀ haloalkyl, t is a number from 0 to 5,

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, non-interfering substituents and-(L _a )-(acidic groups), wherein-(L _a )-is an acid linker, provided that the acid at R ₄ The linker-(L _a )-

및

And

로 이루어진 군으로부터 선택되고,

Selected from the group consisting of

Provided that the acid linker-(L _a )-in R ₅

및

And

로 이루어진 군으로부터 선택되며,

Is selected from the group consisting of

Provided that 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 ₁₀ aralkyl, carboxy carvalkoxy and halo doedoe, with the proviso that, R ₄ and R ₅ at least one of the - (L _a) - (acidic group) must be and, R ₄ or R ₅ in - (L _a) - (acidic group) on the (acidic group) is - 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, and non-interfering substituents are 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 -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, toluyl, 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 alkyl Carbonylamino, C ₂ -C ₁₂ alkoxyamino, C ₂ -C ₁₂ alkoxyaminocarbonyl, C ₂ -C ₁₂ alkylamino, C ₁ -C ₆ alkylthio, C ₂ -C ₁₂ alkylthiocarbonyl, C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₂ -C ₆ haloalkoxy, C ₁ -C ₆ can roal kilsul sulfonyl, C ₂ -C ₆ haloalkyl, C ₁ -C ₆ hydroxyalkyl , -C (O) O (C ₁ -C ₆ alkyl),-(CH ₂ ) _n -O- (C ₁ -C ₆ alkyl), benzyloxy, phenoxy, phenylthio,-(CONHSO ₂ R), -CHO, amino, amino No, bromo, carbamyl, carboxyl, carbalkoxy _{alkoxy, - (CH 2) n -CO} 2 of H, chloro, cyano, cyano Noguchi not pyridinyl, fluoro, guanidino, hydrazide, hydrazino, Hydra Map, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO ₃ H, thioacetal, thiocarbonyl and C ₁ -C ₆ carbonyl, wherein n is 1 to 8 .

In certain embodiments, the 1H-indole-3-glyoxylamide compound for use in the present invention comprises ((3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) Oxy) acetic acid methyl ester, di-2-((3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) propane Acid, di-2-((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) propanoic acid methyl ester, ((3- (2-amino-1,2-dioxoethyl) -1-((1,1'-biphenyl) -2-ylmethyl) -2-methyl-1H-indol-4-yl) oxy ) Acetic acid, ((3- (2-amino-1, 2-dioxoethyl) -1-((1,1'-biphenyl) -2-ylmethyl) -2-methyl-1H-indole-4- Yl) oxy) acetic acid methyl ester, ((3- (2-amino-1, 2-dioxoethyl) -1-((1,1'-biphenyl) -3-ylmethyl) -2-methyl-1H -Indol-4-yl) oxy) acetic acid, ((3- (2-amino-1, 2-dioxoethyl) -1-((1,1'-biphenyl) -3- Methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid methyl ester, ((3- (2-amino-1,2-dioxoethyl) -1-((1,1'-biphenyl) ) -4-ylmethyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1-((1,1 ') -Biphenyl) -4-ylmethyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid methyl ester, ((3- (2-amino-1, 2-dioxoethyl) -1- ( (2,6-dichlorophenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1-((2 , 6-dichlorophenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid methyl ester, ((3- (2-amino-1,2-dioxoethyl) -1- (4- (Fluorophenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1- (4- (fluoro) Phenyl) methyl) -2-methyl-1H-indol-4-yl) oxy) acetic acid methyl ester, ((3- (2-amino-1,2-dioxoethyl) -2-methyl-1-((1 -Naphthalenyl) methyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -2-meth -1-((1-naphthalenyl) methyl) -1H-indol-4-yl) oxy) acetic acid methyl ester ((3- (2-amino-1,2-dioxoethyl) -1-((3 -Chlorophenyl) methyl) -2-ethyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1-((3-chlorophenyl) Methyl) -2-ethyl-1H-indol-4-yl) oxy) acetic acid methyl ester, ((3- (2-amino-1,2-dioxoethyl) -1-((1,1'-biphenyl) ) -2-ylmethyl) -2-ethyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1-((1,1 ') -Biphenyl) -2-ylmethyl) -2-ethyl-1H-indol-4-yl) oxy) acetic acid methyl ester ((3- (2-amino-1, 2-dioxoethyl) -1-(( 1,1'-biphenyl) -2-ylmethyl) -2-propyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1 -((1,1'-biphenyl) -2-ylmethyl) -2-propyl-1H-indol-4-yl) oxy) acetic acid methyl ester, ((3- (2-amino-1,2-di Oxoethyl) -2-cyclopropyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) 2-cyclopropyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid methyl ester, ((3- (2-amino-1,2-dioxoethyl) -1-((1 , 1'-biphenyl) -2-ylmethyl) -2-cyclopropyl-1H-indol-4-yl) oxy) acetic acid, ((3- (2-amino-1,2-dioxoethyl) -1 -((1,1'-biphenyl) -2-ylmethyl) -2-cyclopropyl-1H-indol-4-yl) oxy) acetic acid methyl ester, 4-((3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-5-yl) oxy) butanoic acid, 4-((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-5-yl) oxy) butanoic acid tert-butyl ester, or a pharmaceutically acceptable salt, solvate, prodrug derivative, racemate, tautomer thereof Or optical isomers.

In certain embodiments, sPLA ₂ inhibitors for use in the present invention comprise 1H-indole-3-glyoxylamide compounds having the structure: and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers thereof Isomers or optical isomers.

Where

Each X is independently oxygen or sulfur,

R ₁ is selected from groups (a), (b) and (c), wherein

(a) is a C ₇ -C ₂₀ alkyl, C ₇ -C ₂₀ alkenyl, C ₇ -C ₂₀ alkynyl, carbocyclic radical or heterocyclic radical,

(b) is a member of (a) substituted with one or more independently selected non-interfering substituents,

(c) is a-(L) -R ₈₀ group, wherein-(L)-is a divalent linking group of 1 to 12 atoms selected from carbon, hydrogen, oxygen, nitrogen and sulfur, wherein-(L)- The combination of atoms in (i) only carbon and hydrogen, (ii) only sulfur, (iii) only oxygen, (iv) only nitrogen and hydrogen, (v) only carbon, hydrogen and sulfur, and (vi) only carbon , Hydrogen and oxygen, wherein R ₈₀ 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- (C ₁ -C ₂ alkyl), -S- (C _1- C ₂ alkyl), and non-interfering substituents 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, non-interfering substituents and-(L _a )-(acidic group) groups, wherein-(L _a )-is an acid linker having an acid linker length of 1-4 Provided that at least one of R ₄ and R ₅ must be-(L _a )-(acidic group),

R ₆ and R ₇ are each independently 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 Is selected.

In certain embodiments, sPLA ₂ inhibitors for use in the present invention comprise 1H-indole-3-glyoxylamide compounds having the structure: and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers thereof Methyl ester prodrug derivatives of isomers or optical isomers.

Where

Both X are oxygen,

및

로 이루어진 군으로부터 선택되며,R ₁ is

And

Is selected from the group consisting of

Wherein R ₁₀ is a radical independently selected from halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, -S- (C ₁ -C ₁₀ alkyl) and C ₁ -C ₁₀ haloalkyl, t is 0 to Is the number of 5,

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, non-interfering substituents and-(L _a )-(acidic groups), wherein-(L _a )-is an acid linker, provided that the acid at R ₄ The linker-(L _a )-

및

And

로 이루어진 군으로부터 선택되고,

Selected from the group consisting of

Provided that the acid linker-(L _a )-in R ₅

및

And

로 이루어진 군으로부터 선택되며,

Is selected from the group consisting of

Wherein 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 ₁₀ aralkyl, carboxy, carvalkoxy and halo doedoe, with the proviso that, R ₄ and R ₅ at least one of the - (L _a) - (acidic group) must be and, R ₄ or R ₅ in - (L _a) - (acidic group) on the (acidic group) is - 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, and non-interfering substituents are 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 -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, toluyl, 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 alkoxyaminocarbonyl, C ₂ -C ₁₂ alkylamino, C ₁ -C ₆ alkylthio, C ₂ -C ₁₂ alkylthiocarbonyl. C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₂ -C ₆ haloalkoxy, C ₁ -C ₆ can roal kilsul sulfonyl, C ₂ -C ₆ haloalkyl, C ₁ -C ₆ hydroxy Oxyalkyl, -C (O) O (C ₁ -C ₆ alkyl),-(CH ₂ ) _n -O- (C ₁ -C ₆ alkyl), benzyloxy, phenoxy, phenylthio,-(CONHSO ₂ R ), -CHO, amino, amidino, bromo, carbamyl, carboxyl, carvalkoxy,-(CH ₂ ) _n -CO ₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino , Hydrazide, hydrazino hydrazido, hydroxy, hydroxyamino, iodo, nitro phosphono, -SO ₃ H, thioacetal, thiocarbonyl and C ₁ -C ₆ carbonyl, wherein n is 1-8.

In certain embodiments, sPLA ₂ inhibitors for use in the present invention comprise 1H-indole-3-glyoxylamide compounds having the structure: and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers thereof (Acyloxy) alkyl esters of isomers or optical isomers.

Where

Both X are oxygen,

및

로 이루어진 군으로부터 선택되며,R ₁ is

And

Is selected from the group consisting of

Wherein R ₁₀ is a radical independently selected from halo, C ₁ -C ₁₀ alkyl, C ₁ -C ₁₀ alkoxy, -S- (C ₁ -C ₁₀ alkyl) and C ₁ -C ₁₀ haloalkyl, t is 0 to Is the number of 5,

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, non-interfering substituents and-(L _a )-(acidic groups), wherein-(L _a )-is an acid linker, provided that the acid at R ₄ The linker-(L _a )-

및

And

로 이루어진 군으로부터 선택되고,

Selected from the group consisting of

Provided that the acid linker-(L _a )-in R ₅

및

And

로 이루어진 군으로부터 선택되며,

Is selected from the group consisting of

Wherein 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 ₁₀ aralkyl, carboxy, carvalkoxy and halo doedoe, with the proviso that, R ₄ and R ₅ at least one of the - (L _a) - (acidic group) must be and, R ₄ or R ₅ in - (L _a) - (acidic group) on the (acidic group) is - 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, and non-interfering substituents are 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 -C ₈ cycloalkyl, C ₃ -C ₈ cycloalkenyl, phenyl, toluyl, 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 alkoxyaminocarbonyl, C ₂ -C ₁₂ alkylamino, C ₁ -C ₆ alkylthio, C ₂ -C ₁₂ alkylthiocarbonyl. C ₁ -C ₆ alkylsulfinyl, C ₁ -C ₆ alkylsulfonyl, C ₂ -C ₆ haloalkoxy, C ₁ -C ₆ haloalkylsulfonyl, C ₂ -C ₆ haloalkyl, C ₁ -C ₆ hydroxide Oxyalkyl, -C (O) O (C ₁ -C ₆ alkyl),-(CH ₂ ) _n -O- (C ₁ -C ₆ alkyl), benzyloxy, phenoxy, phenylthio,-(CONHSO ₂ R ), -CHO, amino, amidino, bromo, carbamyl, carboxyl, carvalkoxy,-(CH ₂ ) _n -CO ₂ H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino , Hydrazide, hydrazino hydrazido, hydroxy, hydroxyamino, iodo, nitro phosphono, -SO ₃ H, thioacetal, thiocarbonyl and C ₁ -C ₆ carbonyl, wherein n is 1-8.

In certain embodiments, sPLA ₂ inhibitors for use in the present invention are substituted tricyclics having the structure: and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

Where

R ₁ is selected from the group consisting of -NHNH ₂ and -NH ₂ ,

로 이루어진 군으로부터 선택되며,R ₂ is selected from the group consisting of —OH and —0 (CH ₂ ) _m R ₅ , wherein R ₅ is H, —CO ₂ H, —CO ₂ (C ₁ -C ₄ alkyl), —SO ₃ H, -SO ₃ (C ₁ -C ₄ alkyl), tetrazolyl, -CN, -NH ₂ , -NHSO ₂ R ₁₅ , -CONHSO ₂ R ₁₅ , phenyl, -CO ₂ H or -CO ₂ (C ₁ -C ₄ Phenyl substituted with alkyl, and

Is selected from the group consisting of

Wherein R ₆ and R ₇ are each independently selected from the group consisting of -OH, -O (C ₁ -C ₄ ) alkyl, and R ₁₅ is from the group consisting of-(C ₁ -C ₆ ) alkyl and -CF ₃ M is 1 to 3,

R ₃ is _{H, -O (C 1 -C 4} ) alkyl, halo, - (C ₁ -C ₆₎ alkyl, phenyl, - (C ₁ -C _{4) alkylphenyl, - (C 1 - C 6} ) alkyl , Phenyl substituted with halo or -CF ₃ , -CH ₂ OSi (C ₁ -C ₆ ) alkyl, furyl, thiophenyl,-(C ₁ -C ₆ ) hydroxyalkyl and-(CH ₂ ) _n R ₈ It is selected from the group consisting of wherein R ₈ is _{H, -CONH 2, -NR 9 R} 10, -CN , and is selected from the group consisting of phenyl, where R ₉ and R ₁₀ are each independently - (C ₁ -C ₄ ) Alkyl or -phenyl (C ₁ -C ₄ ) alkyl, n is 1 to 8,

R ₄ is H,-(C ₅ -C ₁₄ ) alkyl,-(C ₃ -C ₁₄ ) cycloalkyl, pyridyl, phenyl, phenyl substituted with-(C ₁ -C ₆ ) alkyl, halo, -CF ₃ , -OCF ₃ ,-(C ₁ -C ₄ ) alkoxy, -CN,-(C ₁ -C ₄ ) alkylthio, phenyl (C ₁ -C ₄ ) alkyl,-(C ₁ -C ₄ ) alkylphenyl, Phenyl, phenoxy or naphthyl,

A is selected from the group consisting of phenyl and pyridyl, wherein nitrogen is in the 5-, 6-, 7- or 8-position,

Z is cyclohexenyl, phenyl, pyridyl (where nitrogen is in the 1-, 2- or 3-position) and sulfur and oxygen in the 1-, 2- or 3-position and 1-, 2-, 3- or 4 Is selected from the group consisting of 6-membered heterocyclic rings having one heteroatom selected from the group consisting of nitrogen at the position, or one carbon on the heterocyclic ring is optionally substituted with ═O and is either A or Z I am a heterocyclic ring.

In certain embodiments, sPLA ₂ inhibitors for use in the present invention are substituted tricyclics having the structure: and pharmaceutically acceptable salts, solvates, prodrug derivatives, racemates, tautomers, or optical isomers thereof.

Where

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 ,

로 이루어진 군으로부터 선택되며,R ₂ is selected from the group consisting of —OH and —0 (CH ₂ ) _m R ₅ , wherein R ₅ is H, —CO ₂ H, —CONH ₂ , —CO ₂ (C ₁ -C ₄ alkyl),- SO ₃ H, -SO ₃ (C ₁ -C ₄ alkyl), tetrazolyl, -CN, -NH ₂ , -NHSO ₂ R ₁₅ , -CONHSO ₂ R ₁₅ , phenyl, -CO ₂ H or -CO ₂ (C Phenyl substituted with _1- C ₄ ) alkyl, and

Is selected from the group consisting of

Wherein R ₆ and R ₇ are each independently selected from the group consisting of -OH, -O (C ₁ -C ₄ ) alkyl, and R ₁₅ is from the group consisting of-(C ₁ -C ₆ ) alkyl and -CF ₃ M is 1 to 3,

R ₃ is _{H, -O (C 1 -C 4} ) alkyl, halo, - (C ₁ -C ₆₎ alkyl, phenyl, - (C ₁ -C _{4) alkylphenyl, - (C 1 - C 6} ) alkyl , Phenyl substituted with halo or -CF ₃ , -CH ₂ OSi (C ₁ -C ₆ ) alkyl, furyl, thiophenyl,-(C ₁ -C ₆ ) hydroxyalkyl and-(CH ₂ ) _n R ₈ is selected from the group consisting of wherein R ₈ is _{H, -CONH 2, -NR 9 R} 10, -CN , and is selected from the group consisting of phenyl, where R ₉ and R ₁₀ is H, -CF _3, phenyl, respectively, - Independently selected from the group consisting of (C ₁ -C ₄ ) alkyl,-(C ₁ -C ₄ ) alkylphenyl and -phenyl (C ₁ -C ₄ ) alkyl, n is 1 to 8,

R ₄ is H,-(C ₅ -C ₁₄ ) alkyl,-(C ₃ -C ₁₄ ) cycloalkyl, pyridyl, phenyl, phenyl substituted with-(C ₁ -C ₆ ) alkyl, halo, -CF ₃ , -OCF ₃ ,-(C ₁ -C ₄ ) alkoxy, -CN,-(C ₁ -C ₄ ) alkylthio, phenyl (C ₁ -C ₄ ) alkyl,-(C ₁ -C ₄ ) alkylphenyl, Phenyl, phenoxy or naphthyl.

In certain embodiments, sPLA ₂ inhibitors for use in the present invention comprise {9-[(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, 9-benzyl-5,7-dimethoxy -1,2,3,4-tetrahydrocarbazole-4-carboxylic acid hydrazide, 9-benzyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole-4-carbox Amide, [9-benzyl-4-carbamoyl-7-methoxy-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, [9-benzyl-4-carbamoyl-7 -Methoxycarbazol-5-yl] oxyacetic acid, methyl [9-benzyl-4-carbamoyl-7-methoxycarbazol-5-yl] oxyacetic acid, 9-benzyl-7-methoxy-5- Cyanomethyloxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide, 9-benzyl-7-methoxy-5- (1H-tetrazol-5-yl-methyl) oxy)- 1,2,3,4-tetrahydrocarbazole-4-carboxamide, {9-[(phenyl) methyl] -5-carbamoyl-2-methyl-carbazol-4-yl} oxyacetic acid , {9-[(3-fluorophenyl) methyl] -5-carbamoyl-2-methyl Rbazol-4-yl} oxyacetic acid, {9-[(3-methylphenyl) methyl] -5-carbamoyl-2-methylcarbazol-4-yl} oxyacetic acid, {9-[(phenyl) methyl] -5-Carbamoyl-2- (4-trifluoromethylphenyl) -carbazol-4-yl} oxyacetic acid, 9-benzyl-5- (2-methanesulfonamido) ethyloxy-7-methoxy- 1,2,3,4-tetrahydrocarbazole-4-carboxamide, 9-benzyl-4- (2-methanesulfonamido) ethyloxy-2-methoxycarbazole-5-carboxamide, 9 -Benzyl-4- (2-trifluoromethanesulfonamido) ethyloxy-2-methoxycarbazole-5-carboxamide, 9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy -1,2,3,4-tetrahydrocarbazole-4-carboxamide, 9-benzyl-4-methanesulfonamidoylmethyloxy-carbazole-5-carboxamide, [5-carbamoyl- 2-pentyl-9- (phenylmethyl) carbazol-4-yl] oxyacetic acid, [5-carbamoyl-2- (1-methylethyl) -9- (phenylmethyl) carbazol-4-yl] oxy Acetic acid, [5-carbamoyl-9- (phenyl Tyl) -2-[(tri (1-methylethyl) silyl) oxymethyl] carbazol-4-yl] oxyacetic acid, [5-carbamoyl-2-phenyl-9- (phenylmethyl) carbazole-4 -Yl] oxyacetic acid, [5-carbamoyl-2- (4-chlorophenyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid, [5-carbamoyl-2- (2- Furyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid, [5-carbamoyl-9- (phenylmethyl) -2-[(tri (1-methylethyl) silyl) oxymethyl] carbox Bazol-4-yl] oxyacetic acid, {9-[(2-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-trifluoromethylphenyl) Methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-benzylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9- [ (1-naphthyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-cyanophenyl) methyl] -5-carbamoylcarbazol-4-yl} Oxyacetic acid, {9-[(3-cyanophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxya Acid, {9-[(3,5-dimethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, (9-[(3-iodophenyl) methyl] -5-carba Moylcarbazol-4-yl} oxyacetic acid, (9-[(2-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2,3-difluoro Rophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2,6-difluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} Oxyacetic acid, {9-[(2,6-dichlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-biphenyl) methyl] -5-carba Moylcarbazol-4-yl} oxyacetic acid, {9-[(2-biphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid methyl ester, [9-benzyl-4-carba Moyl-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, {9-[(2-pyridyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(3-pyridyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, [9-benzyl -4-carbamoyl-8-methyl-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, [9-benzyl-5-carbamoyl-1-methylcarbazole-4- Yl] oxyacetic acid, [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, [9-benzyl-4-carba Moyl-8-chloro-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid [5-carbamoyl-9- (phenylmethyl) -2-[[(propen-3-yl ) Oxy] methyl] carbazol-4-yl] oxyacetic acid, [5-carbamoyl-9- (phenylmethyl) -2-[(propyloxy) methyl] carbazol-4-yl] oxyacetic acid, 9- Benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -1,2,3,4-tetrahydrocarbazole-4-carboxamide, 9-benzyl-7-methoxy-5- Cyanomethyloxy-carbazole-4-carboxamide, 9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl-methyl) oxy) -carbazole-4-carboxamide, 9-benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -carbazole-4-carboxamide, [ 9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, {9-[(phenyl) methyl] -5-carbamoyl-2-methyl -Carbazol-4-yl} oxyacetic acid, {9-[(3-fluorophenyl) methyl] -5-carbamoyl-2-methylcarbazol-4-yl} oxyacetic acid, {9-[(3 -Methylphenyl) methyl] -5-carbamoyl-2-methylcarbazol-4-yl} oxyacetic acid, {9-[(phenyl) methyl] -5-carbamoyl-2- (4-trifluoromethylphenyl ) -Carbazol-4-yl} oxyacetic acid, 9-benzyl-5- (2-methanesulfonamido) ethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4-car Voxamide, 9-benzyl-4- (2-methanesulfonamido) ethyloxy-2-methoxycarbazole-5-carboxamide, 9-benzyl-4- {2-trifluoromethanesulfonamido) Ethyloxy-2-methoxycarbazole-5-carboxamide, 9-benzyl-5-methanesulfonamidoylmethyloxy-7-methoxy-1,2,3,4-tetrahydrocarbazole-4- Carboxamide, 9-benzyl-4-methanesulfonamidoylmethyloxy-car Bazol-5-carboxamide, [5-carbamoyl-2-pentyl-9- (phenylmethyl) carbazol-4-yl] oxyacetic acid, [5-carbamoyl-2- (1-methylethyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid, [5-carbamoyl-9- {phenylmethyl) -2-[(tri (1-methylethyl) silyl) oxymethyl] carbazole- 4-yl] oxyacetic acid, [5-carbamoyl-2-phenyl-9- (phenylmethyl) carbazol-4-yl] oxyacetic acid, [5-carbamoyl-2- (4-chlorophenyl)- 9- (phenylmethyl) carbazol-4-yl] oxyacetic acid, [5-carbamoyl-2- (2-furyl) -9- (phenylmethyl) carbazol-4-yl] oxyacetic acid, [5- Carbamoyl-9- (phenylmethyl) -2-[(tri (1-methylethyl) silyl) oxymethyl] carbazol-4-yl] oxyacetic acid, {9-[(3-fluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(3-chlorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(3 -Phenoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-fluoro Phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-trifluoromethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid , {9-[(2-benzylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(3-trifluoromethylphenyl) methyl] -5-carbamoylcar Bazol-4-yl} oxyacetic acid, {9-[(1-naphthyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-cyanophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(3-cyanophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[( 2-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(3-methylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, { 9-[(3,5-dimethylphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(3- iodophenyl) methyl] -5-carbamoylcarbazole -4-yl} oxyacetic acid, {9-[(2-chlorophenyl) methyl] -5-carr Moylcarbazol-4-yl} oxyacetic acid, {9-[(2,3-difluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2, 6-difluorophenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2,6-dichlorophenyl) methyl] -5-carbamoylcarbazole-4- Ylacetic acid, {9-[(3-trifluoromethoxyphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-biphenyl) methyl] -5 -Carbamoylcarbazol-4-yl} oxyacetic acid, {9-[(2-biphenyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid methyl ester, [9-benzyl-4 -Carbamoyl-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, {9-[(2-pyridyl) methyl] -5-carbamoylcarbazol-4-yl} Oxyacetic acid, {9-[(3-pyridyl) methyl] -5-carbamoylcarbazol-4-yl} oxyacetic acid, [9-benzyl-4-carbamoyl-8-methyl-1,2, 3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, [9-benzyl-5-carbamoyl -1-methylcarbazol-4-yl] oxyacetic acid, [9-benzyl-4-carbamoyl-8-fluoro-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, [9-benzyl-5-carbamoyl-1-fluorocarbazol-4-yl] oxyacetic acid, [9-benzyl-carbamoyl-5-chloro-1,2,3,4-tetrahydrocarbazole -5-yl] oxyacetic acid, [9-benzyl-5-carbamoyl-1-chlorocarbazol-4-yl] oxyacetic acid, [9-[(cyclohexyl) methyl] -5-carbamoylcarbazole -4-yl] oxyacetic acid, [9-[(cyclopentyl) methyl] -5-carbamoylcarbazol-4-yl] oxyacetic acid, [5-carbamoyl-9- (phenylmethyl) -2- (2-thienyl) carbazol-4-yl] oxyacetic acid, [5-carbamoyl-9- (phenylmethyl) -2-[[(propen-3-yl) oxy] methyl] carbazole-4 -Yl] oxyacetic acid, [5-carbamoyl-9- (phenylmethyl) -2-[(propyloxy) methyl] carbazol-4-yl] oxyacetic acid, 9-benzyl-7-methoxy-5- ((Carboxamidomethyl) oxy) -1,2,3,4-tetrahydrocarbazole-4-car Samide, 9-benzyl-7-methoxy-5-cyanomethyloxy-carbazole-4-carboxamide, 9-benzyl-7-methoxy-5-((1H-tetrazol-5-yl- Methyl) oxy) -carbazole-4-carboxamide, 9-benzyl-7-methoxy-5-((carboxamidomethyl) oxy) -carbazole-4-carboxamide, [9-benzyl- 4-carbamoyl-1,2,3,4-tetrahydrocarbazol-5-yl] oxyacetic acid, (R, S)-(9-benzyl-4-carbamoyl-1-oxo-3-thia -1,2,3,4-tetrahydrocarbazol-5-yl) oxyacetic acid, (R, S)-(9-benzyl-4-carbamoyl-3-thia-1,2,3,4- Tetrahydrocarbazol-5-yl) oxyacetic acid, 2- (4-oxo-5-carboxamido-9-benzyl-9H-pyrido [3,4-b] indolyl) acetic acid chloride, [N- Benzyl-1-carbamoyl-1-aza-1,2,3,4-tetrahydrocarbazol-8-yl] oxyacetic acid, 4-methoxy-6-methoxycarbonyl-10-phenylmethyl-6 , 7,8,9-tetrahydropyrido [1,2-a] indole, (4-carboxamido-9-phenylmethyl-4,5-dihydrothiopyrano [3,4- b] indol-5-yl) oxyacetic acid, 3,4-dihydro-4-carboxamidol-5-methoxy-9-phenylmethylpyrano [3,4-b] indole, 2-[(2 , 9-bis-benzyl-4-carbamoyl-1,2,3,4-tetrahydro-betacarboline-5-yl) oxy] acetic acid, 2- [4-oxo-5-carboxamido- 9- (2-methylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (3-methylbenzyl) -9H- Pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-methylbenzyl) -9H-pyrido [3,4-b] indolyl ] Acetic acid, 2- [4-oxo-5-carboxamido-9- (4-tert-butylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo -5-Carboxamido-9-pentafluorobenzyl-9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2- Fluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid 2- [4-oxo-5-carboxamido-9- (3-fluorobenzyl) -9H-pyrido [3 , 4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-fluoro Lobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2,6-difluorobenzyl) -9H-pyri Fig. [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (3,4-difluorobenzyl) -9H-pyrido [3,4-b ] Indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2,5-difluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2 -[4-oxo-5-carboxamido-9- (3,5-difluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5 -Carboxamido-9- (2,4-difluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9 -(2,3-difluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- [2- (trifluoro Rhomethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- [2- (trifluoromethyl) benzyl]- 9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- [3- (triflu Rhomethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- [4- (trifluoromethyl) benzyl]- 9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- [3,5-bis (trifluoromethyl) benzyl] -9H-pyri Do [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- [2,4-bis (trifluoromethyl) benzyl] -9H-pyrido [ 3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (a-methylnaphthyl) -9H-pyrido [3,4-b] indolyl] acetic acid , 2- [4-oxo-5-carboxamido-9- (b-methylnaphthyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5- Carboxamido-9- (3,5-dimethylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2 , 4-dimethylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2-phenylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (3-phenylbenzyl) -9H-pi Lido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-phenylbenzyl) -9H-pyrido [3,4-b] indolyl] Acetic acid, 2- [4-oxo-5-carboxamido-9- (1-fluorenylmethyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo- 5-carboxamido-9- (2-fluoro-3-methylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido -9- (3-benzoylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2-phenoxybenzyl)- 9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (3-phenoxybenzyl) -9H-pyrido [3,4-b ] Indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-phenoxybenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4 -Oxo-5-carboxamido-9- [3- [2- (fluorophenoxy) benzyl]]-9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo -5-Carboxamido-9- [3- [4- (fluorophenoxy) benzyl]]-9H-pyrido [3,4-b] indolyl] acetic acid, 2- [ 4-oxo-5-carboxamido-9- [2-fluoro-3- {trifluoromethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4 -Oxo-5-carboxamido-9- [2-fluoro-4- (trifluoromethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4- Oxo-5-carboxamido-9- [2-fluoro-5- (trifluoromethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo -5-Carboxamido-9- [3-fluoro-5- (trifluoromethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo- 5-Carboxamido-9- [4-fluoro-2- (trifluoromethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5 -Carboxamido-9- [4-fluoro-3- (trifluoromethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5- Carboxamido-9- [2-fluoro-6- (trifluoromethyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carbox Voxamido-9- (2,3,6-trifluorobenzyl)- 9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2,3,5-trifluorobenzyl) -9H-pyrido [ 3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2,4,5-trifluorobenzyl) -9H-pyrido [3,4-b ] Indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2,4,6-trifluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid , 2- [4-oxo-5-carboxamido-9- (2,3,4-trifluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4 -Oxo-5-carboxamido-9- (3,4,5-trifluorobenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5- Carboxamido-9- [3- (trifluoromethoxyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9 -[4- (trifluoromethoxyl) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- [4-methoxy (Tetrafluoro) benzyl] -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carbox Sumido-9- (2-methoxybenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (3-meth Oxybenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-methoxybenzyl) -9H-pyrido [3 , 4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-ethylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-isopropylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carr Voxamido-9- (3,4,5-trimethoxybenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9 -(3,4-methylenedioxybenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-methoxy- 3-methylbenzyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (3,5-dimethoxybenzyl) -9H- Pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2,5-dimethoxybenzyl) -9H-pyri [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (4-ethoxybenzyl) -9H-pyrido [3,4-b] indolyl] Acetic acid, 2- [4-oxo-5-carboxamido-9- (cyclohexylmethyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carbox Voxamido-9- (cyclopentylmethyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9-ethyl-9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (1-propyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2-propyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido Figure 9- (1-Butyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (2-butyl) -9H- Pyrido [3,4-b]) indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9-isobutyl-9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- [2- (1-phenylethyl)]-9H-pyrido [3,4-b] indolyl] acet , 2- [4-oxo-5-carboxamido-9- [3- (1-phenylpropyl)]-9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo -5-Carboxamido-9- [4- (1-phenylbutyl)]-9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido -9- (1-pentyl) -9H-pyrido [3,4-b] indolyl] acetic acid, 2- [4-oxo-5-carboxamido-9- (1-hexyl) -9H-pyri Fig. [3,4-b] indolyl] acetic acid, 4-[(9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazol-6-yl) oxy] butyric acid, 3- [(9-benzyl-4-carbamoyl-1,2,3,4-tetrahydrocarbazol-6-yl) oxy] propylphosphonic acid, 2-[(9-benzyl-4-carbamoyl-1 , 2,3,4-tetrahydrocarbazol-6-yl) oxy] methylbenzoic acid, 3-[(9-benzyl-4-carbamoyl-7-n-octyl-1,2,3,4-tetra Hydrocarbazol-6-yl) oxy] propylphosphonic acid, 4-[(9-benzyl-4-carbamoyl-7-ethyl-1,2,3,4-tetrahydrocarbazol-6-yl) oxy ] Butyric acid, 3-[(9-benzyl-4-carbamoyl-7-ethyl-1,2,3,4-tetrahydrocarbazole- 6-yl) oxy] propylphosphonic acid, 3-[(9-benzyl-4-carbamoyl-7-ethyl-1,2,3,4-tetrahydrocarbazol-6-yl) oxy] propylphosphonic acid , (S)-(+)-4-[(9-benzyl-4-carbamoyl-7-ethyl-1,2,3,4-tetrahydrocarbazol-6-yl) oxy] butyric acid, 4- [9-benzyl-4-carbamoyl-6- (2-cyanoethyl) -1,2,3,4-tetrahydrocarbazol-6-yl] oxybutyric acid, 4- [9-benzyl-4- Carboxamido-7- (2-phenylethyl) -1,2,3,4-tetrahydrocarbazol-6-yl] oxybutyric acid, 4- [9-benzyl-4-carboxamidocarbazole- 6-yl] oxybutyric 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] oxybutyric acid, 9-benzyl-7-methoxy-5-sia Nomethyloxy-1,2,3,4-tetrahydrocarbazole-4-carboxamide, [9-benzyl-4-carbamoyl-8-methyl-carbazol-5-yl] oxyacetic acid and [9 Ben Vagin-carbamoyl-carbazol-5-yl] oxyacetic acid, or a pharmaceutically acceptable salt, solvate, prodrug derivative, racemate, tautomer or optical isomer thereof.

In certain preferred embodiments, the sPLA ₂ inhibitor for use in the present invention comprises ((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenyl), also referred to herein as Compound A-001. Methyl) -1H-indol-4-yl) oxy) acetic acid. Compound A-001, also referred to in the art as S-5920 or LY315920, has the following structure.

A-001 antagonically inhibits sPLA ₂ .

In certain other preferred embodiments, the sPLA ₂ inhibitors for use in the present invention comprise [[3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- ( Phenylmethyl) -1H-indol-4-yl] oxy] acetic acid methyl ester. Compound A-002 has the following structure.

Compound A-002, sometimes referred to in the art as S-3013 or LY333013, is a prodrug form of A-001 that is rapidly absorbed and hydrolyzed to A-001 after administration to a subject.

In certain other preferred embodiments, the sPLA ₂ inhibitor for use in the present invention is {9-[(phenyl) methyl] -5-carbamoylcarbazol-4-yl} oxy, also referred to herein as Compound A-003 or LY433771. Acetic acid. Compound A-003 has the following structure.

In another preferred embodiment, the sPLA ₂ inhibitor for use in the present invention is ((3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl), also referred to herein as compound 421079. ) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl ester. Compound 421079 has the following structure.

Like A-002, compound 421079 is a prodrug of A-001.

The following examples are provided to better illustrate the claimed invention and are not to be construed as limiting the scope of the invention. In the sense that specific materials are mentioned, they are for illustrative purposes only and are not intended to limit the invention. Those skilled in the art can develop equivalent means or reactants without departing from the scope of the present invention without having to practice creative competence. Of course, many modifications may be made to the procedures described herein while still remaining within the scope of the present invention. It is the intention of the inventors that such modifications fall within the scope of the present invention.

Example 1: Effect of A-002 Administration on Plasma Cholesterol Levels and Atherosclerotic Plaque Formation in Mice:

Male ApoE ^{− / −} mice were optionally fed a high fat diet (21% fat, 0.15% cholesterol, 19.5% casein) for 2 weeks to accommodate the diet. Plasma cholesterol levels and body weight were measured to obtain baseline levels, and based on these measurements, mice were randomly divided into three groups of 20 animals. After the acclimation period, mice were maintained on a high fat diet and A-002 (30 mg / kg or 90 mg / kg) or vehicle (5% acacia) alone was administered by oral gavage twice a day for 16 weeks.

Plasma cholesterol levels and body weights were measured 4, 8, 12 and 16 weeks after the start of A-002 administration. Comparison of the measurements between test and control mice at each time point was performed using the post-Bonferroni test for significance after the two-way ANOVA for repeated measurements.

At the end of week 16, mice were killed and plasma samples, heart tissue, and aorta were harvested up to a distance of approximately 3 mm from the heart to the iliac branch. The aorta was placed on a microscope slide and stained with Oil Red O for atherosclerotic lesion size scanning and image analysis. Vascular images were captured using a Microtek Scanmaker 9600XL scanner (Microtec, Carson, Calif.) And Photoshop 6.0 software (Adobe Systems Inc., San Jose, Calif.). Atherosclerotic plaque coverage was quantified for the overall length of blood vessels, including arches, using Image-Pro plus software. Blood vessels were also analyzed for plaque coverage in the descending abdominal aorta starting from the first intercostal branching region to the iliac bifurcation (no arch). Plaque area is expressed as a percentage of the aortic surface. To assess the significance of the atherosclerotic plaque area between the test and control mice, the Bonferroni post test was used after the one-way variance assay.

A total of three groups of mice (control, 30 mg / kg A-002 and 90 mg / kg A-002) had similar baseline weights (FIG. 1). Body weight increased by approximately 155%, 150% and 141% for control, 30 mg / kg A-002 and 90 mg / kg A-002 mice, respectively, during the 16 week test period (FIG. 1). There was no statistically significant difference in body weight between the three groups.

Baseline total plasma cholesterol levels did not differ significantly between the three groups (FIG. 2). At 4 weeks, mice administered A-002 at the same dose showed a significant decrease in total cholesterol. The effect was consistent throughout the rest of the 16 weeks of testing. At week 16, changes in total cholesterol from baseline were + 15%, -10% and -12% in control, 30 mg / kg A-002 and 90 mg / kg A-002 mice, respectively (FIG. 2). There was no apparent dose-response effect.

Control mice showed approximately 13% plaque coverage in aortic tissue at week 16 (FIG. 3). 30 mg / kg A-002 and 90 mg / kg A-002 mice showed 6.3% and 6.8% plaque coverage, respectively (FIG. 3). Thus, A-002 treatment significantly reduced plaque area.

Example 2: Effect of A-002 on Angiotensin II-Mediated Atherosclerotic Plaque Formation and Aneurysms:

An enhanced atherosclerosis mouse model was used to determine the effect of A-002 administration on atherosclerosis and aneurysm formation. Angiotensin II and water, angiotensin and 5% acacia, or saline infusion and water were administered twice daily for 4 weeks to ApoE ^-/- mice adapted to the same high fat diet used in Example 1. Angiotensin II has been shown to promote atherosclerosis and aneurysm formation in apoE deficient mice (Daugherty 2000). At the end of the testing period, plaque coverage was assessed by three independent inspectors, and their estimates were averaged to determine plaque coverage.

Angiotensin II and water or 5% acacia resulted in similar proportions of plaque coverage (FIG. 4) and aneurysms (Table 1). Administration of 30 mg / kg A-002 twice daily significantly reduced plaque area and aortic level aneurysm in Angiotensin II / Acacia mice (FIG. 4).

Effect of A-002 Administration on Aneurysm Ratio Treated group Aneurysm rate (%) Angiotensin II + 5% Acacia 22% (2/9) Angiotensin + Water 25% (5/20) Saline and water 0% (0/25) Angiotensin II + 5% Acacia + 30 mg / kg A-002 0% (0/16)

Example 3: Effect of A-002, or A-002 and Statins on lesion formation and composition in mice:

Body weight, plasma total cholesterol and plasma HDL levels were measured in six groups of 12 ApoE ^{− / −} mice. The mice were then given a high fat diet for 12 weeks to form significant fatty atherosclerotic plaques. High fat diets include casein (195 g / kg), DL-methionine (3 g / kg), sucrose (341.44 g / kg), corn starch (150 g / kg), anhydrous milk fat (210 g / kgg), cholesterol (1.5 g / kg), cellulose (50 g / kg), mineral mix AIN-76 (Teklad; 35 g / kg), calcium carbonate (4 g / kg), vitamin mix (teclad # 40060; 10 g / kg), ethoxyquine (antioxidant; 0.04 g / kg), and also 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 and 0.02 g / kg pravastatin (group D), high dose A-002 and 0.02 g / kg pravastatin (group E) or vehicle alone (group F) (TD.88137, Harlan Teklad, Madison, Wisconsin). Mice were dosed with diets A to F blindly and optionally fed. The diet was initially prepared assuming that each mouse weighs 22.5 g and eats 4.5 g per day. Based on body weight and feed consumption, diets were adjusted over 12 weeks of treatment to adjust body weight to 26 g and feed intake to 2.5 g per day. Doses of A-002 were chosen to cover a 100-fold range based on pharmacokinetics in ApoE ^{− / −} mice as well as toxicology and efficacy already observed in this model.

After 12 weeks, mice were killed and plasma heart tissue and aortic tissue were harvested. Surface lesion size was measured via digital imaging analysis. The percent lesion coverage for each dosage group is summarized in Table 2 and FIG. 5. Plaque area (measured as surface lesion) was reduced in mice receiving statins in combination with A-002 alone, statins alone, or in combination with A-002. The reduction in plaque area in mice administered A-002 and statins was significantly greater than that in mice administered compounds alone (Table 2, Group D vs. Groups A and C, Group E vs. Groups B and C). compare). In addition, the reduction in plaque area in mice administered A-002 and statins was significantly greater than the sum of the decreases in plaque area in mice administered A-002 alone and mice administered statins alone (Table 2, the sum of the change in the mean of the surface lesions relative to the control group (ie -4.210%) in the group D and the change in the mean of the surface lesions relative to the control group in the group A and Group C (i.e., -2.241% and -0.813% Sum, or -3.054%)). Thus, administration of A-002 and statins reduces plaque area in a synergistic manner.

Plasma total cholesterol and HDL levels were measured. Average levels of total cholesterol decreased in mice administered A-002 alone or in combination with statins (Table 3, FIG. 6). Administration of high dose A-002 and statins resulted in much lower total cholesterol than administration of high dose A-002 or statin alone (Table 3, Group E vs. Groups B and C; FIG. 6). Mean levels of HDL increased in mice administered A-002 at the same dose (Table 4). The increase was much greater in mice administered high dose A-002 and statins than in mice administered high dose A-002 or statin alone (Table 4, Group E vs. Groups B and C; FIG. 7).

Example 4 Effect of A-002, or A-002 and Statin Administration on Serum Lipid Levels in Humans:

In the United States, 204 human subjects with CVD, particularly stable coronary artery disease, randomly received 50 mg, 100 mg, 250 mg or 500 mg over an 8-week administration period twice daily via oral administration of placebo or A-002. Dosing was by dose. Levels of various lipid and inflammatory markers were measured at the beginning of the experiment and at the end of 4 and / or 8 weeks. For a data set of normal distributions, the mean levels of lipid or inflammatory markers were analyzed. For data sets of nonnormal distributions, the median level was analyzed. Administration of A-002 at all doses tested resulted in mean levels of serum LDL (Table 5), LDL particles (Table 6), LDL small particles (Table 7), total cholesterol (Table 8) and TG (Table 9) and sPLA The median level of ₂ (Table 10) was reduced. In addition, administration of A-002 reduced the moderate level of CRP (Table 11). The magnitude of the decrease in observed LDL particles, LDL small particles and CRP levels is particularly noteworthy because subjects treated with placebo showed an increase in these markers during the experiment. (Tables 6, 7 and 11).

The median baseline LDL concentration was 72.0 mg / dL in 204 US ITT population subjects. A-002 administration significantly reduced mean LDL levels in 97 subpopulation subjects with baseline LDL levels above the median concentration (Table 12). In addition, administration of A-002 reduced mean serum LDL levels in 53 subpopulation subjects with diabetes (Table 13).

A decrease in mean LDL particle size was observed in a subset of the US population that received statins during the experiment (Table 14), indicating that administration of A-002 and statins reduced LDL small particles even more than statin alone. Likewise, a decrease in mean serum LDL levels was observed in a subset of 81 subsets of the statin treated group that exhibited elevated baseline LDL levels (ie, baseline LDL levels above 72 mg / dL) (Table 15).

The combined effect of A-002 and statin administration on LDL levels was tested in a population of 332 subjects. The population consisted of the original 204 US subjects and an additional 128 Ukrainian subjects with stable CAD who received placebo or A-002 following the same protocol as the US subjects. A decrease in mean serum LDL levels was observed in the statin subset at weeks 4 and 8 (Table 16), indicating that administration of A-002 and statins reduced serum LDL levels even more than administration of statins alone. Similarly, A-002 is ezetimibe, AEGR-733 / ezetimibe, Colesevelam hydrochloride (Wellcol®), MK-0524A (Cordabitive®), lisinopril / MC LDL levels were reduced in subjects administered various non-statin compounds used for the treatment of CVD, including the -1 antibody (MC-4232) and angiotensin receptor blocker (ARB) / MC-1 (MC-4262).

Comparison of the statin subpopulation results with those in the subjects who did not receive statins indicated that administration of A-002 and statins significantly reduced mean serum LDL small particles and LDL levels than the expected side effects of A-002 and statins. (Table 17 is compared to Table 14 and Table 18 to Table 16). In the US population, mean serum LDL particle levels were A-002 compared to 3.25% reduction in subjects administered with A-002 alone (Table 17) and 13.26% reduction in subjects administered statins alone (Table 14). The reduction was 9.00% at week 8 in subjects receiving 002 and statins (Table 14). These results are summarized in Table 20. In the U.S. and Ukrainian combination population, mean serum LDL levels were 6.93% decrease in subjects administered A-002 alone (Table 18) and 3.36% decrease in subjects administered statins alone (Table 16), Attenuation was reduced by 14.04% at week 4 in subjects administered A-002 and statins (Table 16). At week 8, mean serum LDL levels were A-002 compared to a 4.22% decrease in subjects administered A-002 alone (Table 18) and a 2.15% decrease in subjects administered statins alone (Table 16). It was reduced by 12.48% in subjects treated with and statins (Table 16). These results are also summarized in Table 20. Thus, administration of A-002 and statins reduces LDL and LDL small particle levels in a synergistic manner.

In addition, this synergy was observed in subjects of the US population having baseline LDL concentrations of 72 mg / dl or higher (compare Table 19 to Table 15). Mean serum LDL levels were administered A-002 and statins compared to 8.23% reduction in subjects administered A-002 alone (Table 19) and 4.40% reduction in subjects administered statins alone (Table 15). It decreased by 16.27% at 8 weeks in one subject (Table 15). These results are summarized in Table 20.

Serum LDL data for subjects of the statin subset were divided based on the specific statins administered to each subject. Significantly indicated statins include atorvastatin, rosuvastatin, simvastatin, lovastatin, pravastatin and fluvastatin, as well as the statin combination drug simvastatin / ezetimibe (Vytorin®), atorvastatin / ezetimibe, Atorvastatin / amlodipine (carduet®), lovastatin / sustained release niacin (adbicor®), rosuvastatin / tricor®, rosuvastatin / ABT-335, simvastatin / sustained release niacin (Simcor®), simvastatin / MK-0524A (MK-0524B), pravastatin / fenofibrate, atorvastatin / APA-01 and TAK-457 / statin. Statin and statin combination dosages were varied in each individual statin subgroup. The number of test and placebo subjects from each individual statin subgroup from the larger statin subgroup was too small for detailed statistical analysis. However, some statin subgroups of atorvastatin, rosuvastatin, and simvastatin, for example, showed the same synergistic decrease in LDL levels observed in the statin subpopulation. These results indicate that the synergy observed between A-002 and statins is not limited to specific statins.

The synergistic effects of the compounds used in the treatment of A-002 and CVD on LDL levels were not limited to statins. For example, 30 subjects from the ITT population were administered ezetimibe at a dose of 10 mg during the A-002 test procedure. Administration of A-002 reduced mean serum LDL levels in the ezetimibe subgroup after 8 weeks (Table 21), indicating that administration of A-002 and ezetimibe significantly reduced LDL levels than administration of ezetimibe alone. (See Table 21). As with the statin subset, administration of A-002 and ezetimibe resulted in a synergistic decrease in mean LDL levels that was much greater than the expected side effects of A-002 and ezetimibe (Table 22).

Serum TG, CRP and IL-6 levels were measured at week 8 in 86 subjects from the ITT population diagnosed with metabolic syndrome. Administration of A-002 reduced the serum levels of each of these markers (Tables 23-25). Subjects receiving placebo showed an increase in CRP and IL-6 levels (Tables 24-25).

Example 5: A-002 and Statin Combination Tablets:

Fixed dose tablets containing A-002 and one or more statins can be produced using methods known in the art. For example, fixed dose tablets containing a therapeutically effective amount of A-002 (eg, 250 or 500 mg) and a therapeutically effective amount of statins (eg, 10, 20, 40 or 80 mg) are shown in Table 26. It can be produced using the formulation as shown. Those skilled in the art will appreciate that additional ingredients may be added to such generic formulations. For example, compounds such as calcium carbonate can be added to the formulation to enhance solubility and solubility. Likewise, one of ordinary skill in the art will recognize that such formulations are merely examples of generic A-002 / statin formulations and that the nature and weight of the components mentioned in the formulations may vary without undue experimentation.

Generic A-002 / Statin Formulations ingredient Typical weight percentage A-002 Depends on desired dosage Statins Depends on desired dosage Anhydrous lactose 20-50% Lactose Monohydrate 20-50% Hydroxypropyl cellulose 2 to 6% Croscarmellose sodium 0.5 to 5% Polysorbate 80 0.1 to 3% Microcrystalline cellulose 5 to 20% Magnesium stearate 0.25 to 3%

To demonstrate the possibility of including both A-002 and statins in a single formulation, fixed dose tablets containing 250 mg A-002 and 40 mg simvastatin (commercially available under Zocor®) were produced. Unit and batch formulations for these tablets are shown 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 commercial form of simvastatin (Jocor®).

Unit preparations for A-002 / simvastatin tablets ingredient function Mg / tablet A-002 Active ingredient 250 Simvastatin Active ingredient 40 Anhydrous lactose diluent 119.18 Lactose Fast Flo diluent 59.58 Hydroxypropyl cellulose (HPC) Binder 13.5 Croscarmellose sodium
(Divided into two equal parts for internal / external granules) Disintegrant 24.3 Polysorbate 80 Surfactants 0.54 Butylated Hydroxyanisole (BHA) Antioxidant 0.01% Microcrystalline Cellulose 200 (MCC) diluent 70.20 Magnesium stearate slush 2.70 Purified water menstruum - Total tablet weight 580 mg

Batch formulation for A-002 / simvastatin tablets ingredient function g / batch A-002 Active ingredient 259 Simvastatin Active ingredient 41 Anhydrous lactose diluent 123 Lactose Fast Flo diluent 62 Hydroxypropyl cellulose (HPC) Binder 14 Croscarmellose sodium
(Divided into two equal parts for internal / external granules) Disintegrant 6.6 / 8.4 Polysorbate 80 Surfactants One Butylated Hydroxyanisole (BHA) Antioxidant 0.1 Microcrystalline Cellulose 200 (MCC) diluent 62 Magnesium stearate slush 2.5 Purified water menstruum 93 Batch size 673 g

A process diagram detailing one method of making the tablet is shown in FIG. 8. BHA, Polysorbate 80 and purified water were mixed to produce a granulation fluid, which was stored overnight. Lactose anhydride, lactose fast flow and one portion of croscarmellose sodium are weighed, screened through a coarse mesh, then combined with A-002 and simvastatin (which can also be sieved if necessary), using a mixer Dry blended at low speed for 1-2 minutes. In certain embodiments of the above protocols, microcrystalline cellulose may be included in the dry mix. Hydroxypropyl cellulose was combined with the granulation fluid to significantly increase the viscosity. The resulting solution was slowly added to the mixer containing the A-002 / simvastatin mix. During the addition, the mixing speed was gradually increased. The granulation endpoint was reached when the fine granules formed while the mass was not wet or sticky.

The granules were screened through a coarse mesh on a foiled tray and placed in an oven at 50 ° C. and ambient humidity for approximately 3 hours. After drying (and any grinding and / or sieving), the granules were placed in a low density polyethylene (LDPE) bag. Approximately 1/4 of the dried granules were pre-blended with microcrystalline cellulose and magnesium stearate in a small bag, and then the remaining granules were combined with the pre-blend in a mixer. Two portions of croscarmellose sodium were added and the entire mixture was mixed for a few minutes. Approximately 580 mg of the final blend was weighed into a tablet press and pressed at 200 to 2500 psi (Carver press) to make tablets. The resulting tablets were weighed individually and the average weight was approximately 0.6 g. The color of the tablets was off-white to light brown.

Two representative purifications (Nos. 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 both purifications are shown in FIG. 9 and summarized in Table 29. The tablets maintained high potency (ie, high concentrations of A-002 and simvastatin), demonstrating the possibility of producing A-002 / statin combination tablets for the treatment of various conditions.

HPLC analysis of A-002 / simvastatin combination tablets Tablet number weight % A-002 (RT: 28.5 min) % Simvastatin (RT: 44.5 min) 19 0.64 g 92% 89% 27 0.60 g 88% 86%

Film coatings can be applied to A-002 / statin combination tablets using methods well known in the art. In one such method, a coating suspension is prepared by adding a film coating mixture, such as Opadry YS-1-18027-A, to purified water in a mixing vessel. The mixing rate was reduced to avoid foaming and the suspension was mixed for at least 60 minutes until uniform. After mixing, the suspension was degassed for at least 60 minutes. A coater such as Accela Coater was installed and calculated based on the number and size of tablets to be coated with the theoretical amount of coating suspension to be sprayed. Tablets are loaded onto the coating pan, nozzle air pressure (approximately 80-100 psi), spray air pressure (approximately 25-45 psi), pattern air pressure (approximately 20-40 psi), delivery rate (approximately 300-400 g / min), Fan speed (approximately 4 to 10 rpm) and dew point setting (approximately 5 to 15 ° C.) were checked. Turn on the fan, gun-to-bed distance (approximately 6 to 10 inches), feed air temperature (approximately 58 ° C), exhaust air temperature (approximately 45 ° C), air volume inlet (approximately 1500 cfm) and vice versa The fan pressure difference was checked. The tablets were preheated and the number of samples weighed to determine the average core tablet weight. The coating solution was sprayed onto the tablets with gentle mixing. At various intervals of approximately 5-15 minutes, the average tablet weight was recalculated. Once the target tablet weight was reached, the feed temperature was reduced to approximately 45 ° C. and the pan was tapped at intervals of approximately five minutes to dry the tablet. The feed temperature was reduced to approximately 30 ° C. and the tablets were knocked by hand for approximately 10 minutes or longer. The coated tablets were then discharged from the coating pan.

Example 6: Dosing once a day of A-002 or A-002 with statins:

CVD, in particular over 135 human subjects over 18 years of age with stable CAD, randomized to placebo or two doses (250 mg or 500 mg) of A-002 once daily for oral administration over a period of 8 weeks Administered. 89 of the subjects received A-002, while 46 of the subjects received placebo. Subjects who received statins or other compounds used for the treatment of CVD at the start of the experiment continued to receive the therapy throughout the experiment. 121 of 135 subjects received statins during the experiment. There was little variation in age, height, weight or BMI among the dosing groups.

Levels of various lipid and inflammatory markers were measured at the start of the experiment and 2, 4 and / or 8 weeks after the start of A-002 administration. In addition, plasma A-002 levels were measured at various intervals. Lipids measured included LDL, LDL small particles, oxidized LDL, non-HDL cholesterol, total cholesterol, ApoB and triglycerides. In addition, the level of the inflammatory marker CRP was measured. Lipid and inflammatory marker levels at each time point were compared to baseline measurements to determine the effect of A-002 administration. For a data set of normal distributions, the mean levels of lipid or inflammatory markers were analyzed. For data sets of nonnormal distributions, the median level was analyzed. In addition, the LDL particle size was evaluated.

Subjects in the ITT population who received A-002 at the same dose received mean serum LDL, non-HDL cholesterol and total cholesterol levels (Tables 30-32, respectively) at week 8, and intermediate LDL small particles, oxidized LDL, TG and ApoB levels. A significant decrease in (Tables 33-36) is shown. In addition, subjects administered A-002 showed 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 observed in subjects receiving placebo (Table 38).

In addition, the average serum LDL, non-HDL cholesterol and total cholesterol levels observed in the ITT population, and decreases in intermediate LDL small particles, oxidized LDL, TG and ApoB levels, increase in mean LDL particle size, and expected increase in median CRP levels A lower increase was observed at week 8 in the subset of 121 subjects who received statins during the experiment (Tables 39-47, respectively), indicating that A-002 and statins were much more therapeutic for these markers than statins alone. It shows the effect. Similarly, baseline LDL levels above 70 mg / dL are less than expected increases in LDL, non-HDL cholesterol, total cholesterol, LDL small particles, oxidized LDL and ApoB levels, an increase in LDL particle size, and an increase in CRP levels. Were observed in 51 subjects in the statin subgroup with Tables (Tables 48-55). The number of subjects in the non-statin subgroup was too small for a detailed statistical analysis of the combined effects of A-002 and statins on the effect of the same compound alone. However, if additional non-statin controls were obtained, a synergistic decrease in LDL levels similar to that observed after two A-002 administrations per day (Example 4) was observed in subjects receiving A-002 once a day It is expected to be.

As mentioned above, the foregoing is only for describing various embodiments of the present invention. The specific modifications discussed above should not be construed as limitations on the scope of the invention. It will be apparent to those skilled in the art that various equivalents, changes, and modifications may be made without departing from the scope of the present invention, and such equivalent embodiments will be included herein. References cited herein are incorporated by reference as if fully set forth herein.

references

Claims (201)

A method of treating dyslipidemia in a subject comprising administering a therapeutically effective amount of one or more sPLA ₂ inhibitors to the subject in need of treatment of dyslipidemia. The method of claim 1, wherein administration of the one or more sPLA ₂ inhibitors reduces cholesterol levels. The method of claim 2, wherein administration of the one or more sPLA ₂ inhibitors reduces total cholesterol levels. The method of claim 2, wherein administration of the one or more sPLA ₂ inhibitors reduces non-HDL cholesterol levels. The method of claim 2, wherein administration of the one or more sPLA ₂ inhibitors reduces LDL levels. The method of claim 5, wherein administration of the one or more sPLA ₂ inhibitors reduces LDL particle levels. The method of claim 6, wherein administration of the one or more sPLA ₂ inhibitors reduces LDL small particle levels. The method of claim 5, wherein administration of the one or more sPLA ₂ inhibitors reduces oxidized LDL levels. The method of claim 5, wherein administration of the one or more sPLA ₂ inhibitors reduces apolipoprotein B levels. The method of claim 1, wherein administration of the one or more sPLA ₂ inhibitors increases the LDL particle size. The method of claim 1, wherein administration of the one or more sPLA ₂ inhibitors increases HDL levels. The method of claim 2, wherein administration of the one or more sPLA ₂ inhibitors increases the HDL / LDL ratio. The method of claim 1, wherein administration of the one or more sPLA ₂ inhibitors reduces triglyceride levels. The method of claim 1, wherein administration of the one or more sPLA ₂ inhibitors reduces the level of one or more inflammatory markers. The method of claim 14, wherein the one or more inflammatory markers are selected from the group consisting of sPLA ₂ , CRP, and IL-6. The method of claim 1, wherein the one or more sPLA ₂ inhibitors are ((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 17. The method of claim 16, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl)-2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. The method of claim 1, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. The method of claim 18, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. The method of claim 1, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. A method of reducing cholesterol levels in a subject comprising administering a therapeutically effective amount of at least one sPLA ₂ inhibitor to a subject in need thereof. The method of claim 21, wherein administration of the one or more sPLA ₂ inhibitors reduces total cholesterol levels. The method of claim 21, wherein administration of the one or more sPLA ₂ inhibitors reduces non-HDL cholesterol levels. The method of claim 21, wherein administration of the one or more sPLA ₂ inhibitors reduces LDL levels. The method of claim 24, wherein administration of the one or more sPLA ₂ inhibitors reduces LDL particle levels. The method of claim 25, wherein administration of the one or more sPLA ₂ inhibitors reduces LDL small particle levels. The method of claim 24, wherein administration of the one or more sPLA ₂ inhibitors reduces oxidized LDL levels. The method of claim 24, wherein administration of the one or more sPLA ₂ inhibitors reduces apolipoprotein B levels. The method of claim 21, wherein administration of the one or more sPLA ₂ inhibitors increases the LDL particle size. The method of claim 21, wherein administration of the one or more sPLA ₂ inhibitors increases the HDL / LDL ratio. The method of claim 21, wherein the at least one sPLA ₂ inhibitor is ((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 32. The method of claim 31, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. The method of claim 21, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. The method of claim 33, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. The method of claim 21, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. A method of reducing triglyceride levels in a subject comprising administering a therapeutically effective amount of one or more sPLA ₂ inhibitors to a subject in need of a decrease in triglyceride levels. The method of claim 36, wherein the one or more sPLA ₂ inhibitors are ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 38. The method of claim 37, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl)-2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. The method of claim 36, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. The method of claim 39, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. The method of claim 36, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. A method of increasing HDL levels in a subject comprising administering a therapeutically effective amount of one or more sPLA ₂ inhibitors to a subject in need of an increase in HDL levels. The method of claim 42, wherein the at least one sPLA ₂ inhibitor is ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. The method of claim 43, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. The method of claim 42, wherein administration of the one or more sPLA ₂ inhibitors increases the HDL / LDL ratio. The method of claim 42, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. The method of claim 46, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. The method of claim 42, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. A method of treating a condition associated with cardiovascular disease or cardiovascular disease in a subject comprising administering a therapeutically effective amount of one or more sPLA ₂ inhibitors to a subject in need of treatment of the cardiovascular disease or condition associated with the cardiovascular disease. The method of claim 49, wherein the cardiovascular disease is a condition associated with atherosclerosis, coronary artery disease, coronary heart disease, coronary heart disease or coronary heart disease, cerebrovascular disease, condition associated with cerebrovascular disease, peripheral vascular disease, A condition associated with peripheral vascular disease, aneurysm, vasculitis, venous thrombosis, diabetes mellitus and metabolic syndrome. The method of claim 49, wherein the one or more sPLA ₂ inhibitors is ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. The prodrug derivative according to claim 51, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1,2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. The method of claim 49, wherein administration of the one or more sPLA ₂ inhibitors reduces the level of one or more inflammatory markers. The method of claim 53, wherein the one or more inflammatory markers are selected from the group consisting of sPLA ₂ , CRP, and IL-6. The method of claim 49, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. The method of claim 55, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. The method of claim 49, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. A method of treating metabolic syndrome in a subject comprising administering a therapeutically effective amount of one or more sPLA ₂ inhibitors to the subject in need thereof. The method of claim 58, wherein the one or more sPLA ₂ inhibitors is ((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 60. The method of claim 59, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. The method of claim 58, wherein administration of the one or more sPLA ₂ inhibitors reduces the level of one or more inflammatory markers. The method of claim 61, wherein the one or more inflammatory markers are selected from the group consisting of sPLA ₂ , CRP, and IL-6. 59. The method of claim 58, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. The method of claim 63, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. The method of claim 58, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. A composition comprising at least one sPLA ₂ inhibitor and at least one compound used for the treatment of CVD. 67. The composition of claim 66, wherein the at least one compound used for the treatment of CVD comprises at least one statin. 68. The method of claim 67, wherein the one or more statins are atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe and simvastatin, and pharmaceutically acceptable thereof A composition selected from the group consisting of salts, solvates, stereoisomers or prodrug derivatives. 67. The composition of claim 66, wherein the at least one compound used in the treatment of CVD comprises at least one statin combination drug. 70. The method of claim 69, wherein the one or more statin combination drugs are atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. 67. The method of claim 66, wherein the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer proteins A composition comprising at least one non-statin compound selected from the group consisting of (MTP) inhibitors, squalene synthase inhibitors, ACE inhibitors, angiotensin II receptor antagonists, beta-adrenergic blockers, calcium channel blockers and antithrombotic agents. 67. The method of claim 66, wherein the at least one sPLA ₂ inhibitor is ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and a pharmaceutically acceptable salt, solvate, stereoisomer or prodrug derivative thereof. 73. The method of claim 72, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl A composition selected from the group consisting of esters. 67. The composition of claim 66, further comprising at least one pharmaceutically acceptable carrier. A method of treating dyslipidemia in a subject comprising administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of a therapeutically effective amount of CVD to a subject in need thereof. Way. 76. The method of claim 75, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces cholesterol levels. The method of claim 76, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD reduces total cholesterol levels. The method of claim 76, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD reduces non-HDL cholesterol levels. The method of claim 76, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces LDL levels. The method of claim 79, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD reduces LDL particle levels. 81. The method of claim 80, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces LDL small particle levels. The method of claim 79, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces oxidized LDL levels. 80. The method of claim 79, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces apolipoprotein B levels. 76. The method of claim 75, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD increases the LDL particle size. 76. The method of claim 75, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD increases HDL levels. 76. The method of claim 75, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD increases the HDL / LDL ratio. 76. The method of claim 75, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces triglyceride levels. 76. The method of claim 75, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces the level of one or more inflammatory markers. 89. The method of claim 88, wherein said at least one inflammatory marker is selected from the group consisting of sPLA ₂ , CRP, and IL-6. 76. The method of claim 75, wherein the one or more sPLA ₂ inhibitors are ((3- (2-amino-1,2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 91. The method of claim 90, wherein said prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. 76. The method of claim 75, wherein the at least one compound used for the treatment of CVD comprises at least one statin. 95. The method of claim 92, wherein the one or more statins are atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe and simvastatin, and pharmaceutically acceptable thereof Salt, solvate, stereoisomer or prodrug derivative. 76. The method of claim 75, wherein the one or more compounds used for the treatment of CVD comprises one or more statin combination drugs. 95. The method according to claim 94, wherein the one or more statin combination drugs are atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. 76. The method of claim 75, wherein the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer proteins (MTP) inhibitor, squalene synthase inhibitor, ACE inhibitor, angiotensin II receptor antagonist, beta-adrenergic blocker, calcium channel blocker and antithrombotic agent. 76. The method of claim 75, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered simultaneously. 98. The method of claim 97, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered in the same formulation. 76. The method of claim 75, wherein the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD are administered sequentially. The method of claim 75, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. 101. The method of claim 100, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. The method of claim 75, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. Administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD to a subject in need of a decrease in cholesterol levels, wherein said administration reduces cholesterol levels, A method of reducing cholesterol levels in said subject. 107. The method of claim 103, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces total cholesterol levels. 107. The method of claim 103, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces non-HDL cholesterol levels. 107. The method of claim 103, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces LDL levels. 107. The method of claim 106, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces LDL particle levels. 107. The method of claim 107, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces LDL small particle levels. 107. The method of claim 106, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces oxidized LDL levels. 107. The method of claim 106, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces apolipoprotein B levels. 107. The method of claim 103, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD increases the LDL particle size. 107. The method of claim 103, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD increases the HDL / LDL ratio. 107. The method of claim 103, wherein the at least one sPLA ₂ inhibitor is ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 116. The prodrug derivative of claim 113, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. 107. The method of claim 103, wherein the at least one compound used for the treatment of CVD comprises at least one statin. 116. The method of claim 115, wherein the one or more statins are atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe and simvastatin, and pharmaceutically acceptable Salt, solvate, stereoisomer or prodrug derivative. 107. The method of claim 103, wherein the at least one compound used for the treatment of CVD comprises at least one statin combination drug. 118. The method of claim 117, wherein the one or more statin combination drugs are atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. 103. The method of claim 103, wherein the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer proteins (MTP) inhibitor, squalene synthase inhibitor, ACE inhibitor, angiotensin II receptor antagonist, beta-adrenergic blocker, calcium channel blocker and antithrombotic agent. 107. The method of claim 103, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered simultaneously. 121. The method of claim 120, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered in the same formulation. 107. The method of claim 103, wherein the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD are administered sequentially. 103. The method of claim 103, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. 123. The method of claim 123, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. 103. The method of claim 103, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. Administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD to a subject in need of a decrease in triglyceride levels, wherein said administration reduces triglyceride levels. Reducing triglyceride levels in said subject. 126. The method of claim 126, wherein the at least one sPLA ₂ inhibitor is ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 127. The method of claim 127, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. 126. The method of claim 126, wherein the one or more compounds used for the treatment of CVD comprises one or more statins. 131. The method of claim 129, wherein the one or more statins are atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe and simvastatin, and pharmaceutically acceptable thereof Salt, solvate, stereoisomer or prodrug derivative. 126. The method of claim 126, wherein the one or more compounds used in the treatment of CVD comprises one or more statin combination drugs. 134. The method of claim 131, wherein the one or more statin combination drugs are atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. 126. The method of claim 126, wherein the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer proteins (MTP) inhibitor, squalene synthase inhibitor, ACE inhibitor, angiotensin II receptor antagonist, beta-adrenergic blocker, calcium channel blocker and antithrombotic agent. 126. The method of claim 126, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered simultaneously. 134. The method of claim 134, wherein said one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered in the same formulation. 126. The method of claim 126, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered sequentially. 126. The method of claim 126, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. 138. The method of claim 137, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. 126. The method of claim 126, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. Administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD to a subject in need of an increase in HDL levels, wherein the administration is to increase HDL levels, Increasing the HDL level in the subject. 141. The method of claim 140, wherein the one or more sPLA ₂ inhibitors are ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 141. The prodrug derivative of claim 141 wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. 141. The method of claim 140, wherein the at least one compound used for the treatment of CVD comprises at least one statin. 143. The method of claim 143, wherein the at least one statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe and simvastatin, and pharmaceutically acceptable thereof Salt, solvate, stereoisomer or prodrug derivative. 141. The method of claim 140, wherein the one or more compounds used for the treatment of CVD comprises one or more statin combination drugs. 145. The method of claim 145, wherein the one or more statin combination drugs are atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. 141. The method of claim 140, wherein the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer proteins (MTP) inhibitor, squalene synthase inhibitor, ACE inhibitor, angiotensin II receptor antagonist, beta-adrenergic blocker, calcium channel blocker and antithrombotic agent. 141. The method of claim 140, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered simultaneously. 148. The method of claim 148, wherein said one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered in the same formulation. 141. The method of claim 140, wherein the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD are administered sequentially. 141. The method of claim 140, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. 151. The method of claim 151, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. 141. The method of claim 140, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. 141. The method of claim 140, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD increases the HDL / LDL ratio. A cardiovascular disease or cardiovascular disease, comprising administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and a therapeutically effective amount of one or more statins to a subject in need of treatment of a cardiovascular disease or a condition associated with cardiovascular disease How to treat a condition associated with. 155. The method of claim 155, wherein the cardiovascular disease is associated with atherosclerosis, coronary artery disease, coronary heart disease, coronary heart disease or coronary heart disease, cerebrovascular disease, condition associated with cerebrovascular disease, peripheral vascular disease, A condition associated with peripheral vascular disease, aneurysm, vasculitis, venous thrombosis, diabetes mellitus and metabolic syndrome. 155. The method of claim 155, wherein the at least one sPLA ₂ inhibitor is ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 162. The prodrug derivative according to claim 157, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl)-2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. 155. The method of claim 155, wherein the at least one compound used for the treatment of CVD comprises at least one statin. 162. The method of claim 159, wherein the one or more statins are atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe and simvastatin, and pharmaceutically acceptable Salt, solvate, stereoisomer or prodrug derivative. 155. The method of claim 155, wherein the at least one compound used for the treatment of CVD comprises at least one statin combination drug. 162. The method of claim 161, wherein the one or more statin combination drugs are atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. 155. The method of claim 155, wherein the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer proteins (MTP) inhibitor, squalene synthase inhibitor, ACE inhibitor, angiotensin II receptor antagonist, beta-adrenergic blocker, calcium channel blocker and antithrombotic agent. 155. The method of claim 155, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered simultaneously. 175. The method of claim 164, wherein said one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered in the same formulation. 155. The method of claim 155, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered sequentially. 155. The method of claim 155, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. 167. The method of claim 167, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. 155. The method of claim 155, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. 155. The method of claim 155, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD reduces the level of one or more inflammatory markers. 172. The method of claim 170, wherein the one or more inflammatory markers are selected from the group consisting of sPLA ₂ , CRP, and IL-6. A method of treating metabolic syndrome in a subject comprising administering a therapeutically effective amount of one or more sPLA ₂ inhibitors and a therapeutically effective amount of one or more statins to a subject in need thereof. 172. The method of claim 172, wherein the one or more sPLA ₂ inhibitors is ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. 172. The prodrug derivative of claim 173, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. 172. The method of claim 172, wherein the at least one compound used for the treatment of CVD comprises at least one statin. 175. The method of claim 175, wherein said at least one statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe and simvastatin, and pharmaceutically acceptable thereof Salt, solvate, stereoisomer or prodrug derivative. 172. The method of claim 172, wherein the one or more compounds used for the treatment of CVD comprises one or more statin combination drugs. 177. The method of claim 177, wherein the one or more statin combination drugs are atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. 172. The method of claim 172, wherein the one or more compounds used for the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer proteins (MTP) inhibitor, squalene synthase inhibitor, ACE inhibitor, angiotensin II receptor antagonist, beta-adrenergic blocker, calcium channel blocker and antithrombotic agent. 172. The method of claim 172, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered simultaneously. 182. The method of claim 180, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered in the same formulation. 172. The method of claim 172, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered sequentially. 172. The method of claim 172, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. 184. The method of claim 183, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. 172. The method of claim 172, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily. 172. The method of claim 172, wherein administration of the one or more sPLA ₂ inhibitors and one or more compounds used to treat CVD reduces the level of one or more inflammatory markers. 186. The method of claim 186, wherein the one or more inflammatory markers are selected from the group consisting of sPLA ₂ , CRP, and IL-6. A method of increasing the efficacy of one or more compounds used in the treatment of CVD in a subject comprising administering to the subject at least one sPLA ₂ inhibitor. 187. The method of claim 188, wherein the at least one sPLA ₂ inhibitor is ((3- (2-amino-1, _2- dioxoethyl) -2-ethyl-1- (phenylmethyl) -1 H-indol-4-yl ) Oxy) acetic acid, and pharmaceutically acceptable salts, polymorphs, cocrystals, solvates or prodrug derivatives thereof. The method of claim 189, wherein the prodrug derivative is [[3- (2-amino-1, 2-dioxoethyl) -2-ethyl-1- (phenylmethyl) -1H-indol-4-yl] oxy] Acetic acid methyl ester and ((3- (2-amino-1, 2-dioxoethyl) -2-methyl-1- (phenylmethyl) -1H-indol-4-yl) oxy) acetic acid N-morpholino ethyl The process is selected from the group consisting of esters. 187. The method of claim 188, wherein the one or more compounds used for the treatment of CVD comprises one or more statins. 192. The method of claim 191, wherein the at least one statin is atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, ezetimibe and simvastatin, and pharmaceutically acceptable Salt, solvate, stereoisomer or prodrug derivative. 185. The method of claim 188, wherein the one or more compounds used for the treatment of CVD comprises one or more statin combination drugs. 194. The method of claim 193, wherein the one or more statin combination drugs are atorvastatin and ezetimibe, atorvastatin and amlodipine, atorvastatin and CP-529414, atorvastatin and APA-01, simvastatin and ezetimibe, simvastatin and sustained release niacin, simvastatin and MK-0524A, lovastatin and sustained release niacin, rosuvastatin and fenofibrate, pravastatin and fenofibrate, and statin and TAK-457. 187. The method of claim 188, wherein the one or more compounds used in the treatment of CVD are bile acid sequestrants, fibrates, niacin or niacin derivatives, cholesterol absorption inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, microsomal triglyceride transfer proteins (MTP) inhibitor, squalene synthase inhibitor, ACE inhibitor, angiotensin II receptor antagonist, beta-adrenergic blocker, calcium channel blocker and antithrombotic agent. 186. The method of claim 188, wherein the one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered simultaneously. 197. The method of claim 196, wherein said one or more sPLA ₂ inhibitors and one or more compounds used for the treatment of CVD are administered in the same formulation. 185. The method of claim 188, wherein the one or more sPLA ₂ inhibitors and one or more compounds used in the treatment of CVD are administered sequentially. 186. The method of claim 188, wherein the administration of the one or more sPLA ₂ inhibitors is performed at least twice a day. 202. The method of claim 199, wherein the administration of the one or more sPLA ₂ inhibitors is performed twice daily. 186. The method of claim 188, wherein the administration of the one or more sPLA ₂ inhibitors is performed once daily.

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