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

Abstract

Administration of sPLA 2 inhibitors has been found to decrease cholesterol levels, atherosclerotic plaque formation and aortic aneurysm in mice, and to decrease cholesterol and triglyceride levels in humans. Interestingly, administration of sPLA 2 inhibitors was found to decrease cholesterol levels even when the inhibitors were administered only once per day. Therefore, provided herein are methods of treating dyslipidemia, CVD, and conditions associated with CVD such as atherosclerosis and metabolic syndrome, by administering one or more sPLA 2 inhibitors. Significantly, administration of sPLA 2 inhibitors and various compounds used in the treatment of CVD, such as for example statins, resulted in greater decreases in LDL and LDL particle levels in a synergistic manner. In addition, administration of sPLA 2 inhibitors and statins resulted in a synergistic decrease in plaque content. Therefore, also provided herein are compositions comprising one or more sPLA 2 inhibitors and one or more compounds used in the treatment of CVD, such as for example statins, and methods of using these compositions to treat dyslipidemia, CVD, and conditions associated with CVD such as atherosclerosis and metabolic syndrome.

1 - 38 . (canceled) 
     
     
         39 . A method of treating cardiovascular disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin. 
     
     
         40 . The method of  claim 39 , wherein said prodrug derivative is [[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester. 
     
     
         41 . The method of  claim 39 , wherein said statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug derivatives thereof. 
     
     
         42 . The method of  claim 39 , further comprising administering one or more compounds selected from the group consisting of ezetimibe, amlodipine, CP-529414, APA-01, extended release niacin, MK-0524A, fenofibrate, and TAK-457. 
     
     
         43 . The method of  claim 39 , wherein said cardiovascular disease is selected from the group consisting of atherosclerosis, coronary artery disease, coronary heart disease, conditions associated with coronary artery disease or coronary heart disease, cerebrovascular disease, conditions associated with cerebrovascular disease, peripheral vascular disease, conditions associated with peripheral vascular disease, aneurysm, vasculitis, venous thrombosis, diabetes mellitus, and metabolic syndrome. 
     
     
         44 . The method of  claim 43 , wherein said cardiovascular disease is selected from the group consisting of atherosclerosis, angina, myocardial infarction, transient ischemic attack, and stroke. 
     
     
         45 . The method of  claim 39 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin are administered simultaneously. 
     
     
         46 . The method of  claim 45 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin are administered in the same composition. 
     
     
         47 . The method of  claim 39 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin are administered sequentially. 
     
     
         48 . The method of  claim 39 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof is administered once per day. 
     
     
         49 . The method of  claim 39 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof is administered two or more times per day. 
     
     
         50 . The method of  claim 39 , wherein administration of ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof in combination with a statin results in a decrease in LDL levels. 
     
     
         51 . The method of  claim 50 , wherein the decrease in LDL levels resulting from administration of ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof in combination with a statin is greater than the expected additive effect of administering ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin separately. 
     
     
         52 . The method of  claim 50 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin reduce LDL levels in a synergistic manner. 
     
     
         53 . The method of  claim 39 , wherein administration of ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof in combination with a statin results in a decrease in small LDL particle levels. 
     
     
         54 . The method of  claim 53 , wherein the decrease in small LDL particle levels resulting from administration of ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof in combination with a statin is greater than the expected additive effect of administering ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin separately. 
     
     
         55 . The method of  claim 53 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin reduce small LDL particle levels in a synergistic manner. 
     
     
         56 . The method of  claim 39 , wherein administration of ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof in combination with a statin results in a decrease in atherosclerotic plaque formation. 
     
     
         57 . The method of  claim 56 , wherein the decrease in atherosclerotic plaque formation resulting from administration of ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof in combination with a statin is greater than the expected additive effect of administering ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin separately. 
     
     
         58 . The method of  claim 56 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and a statin reduce atherosclerotic plaque formation in a synergistic manner. 
     
     
         59 . The method of  claim 39 , wherein said subject has been diagnosed with CVD or exhibits one or more symptoms associated with CVD. 
     
     
         60 . The method of  claim 39 , wherein ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof is administered as a pharmaceutical composition comprising ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a pharmaceutically acceptable salt, polymorph, co-crystal, solvate, or prodrug derivative thereof and one or more pharmaceutically acceptable carriers. 
     
     
         61 . The method of  claim 39 , wherein the statin is administered as a pharmaceutical composition comprising a therapeutically effective amount of the statin and one or more pharmaceutically acceptable carriers. 
     
     
         62 . A method of treating cardiovascular disease in a subject in need thereof comprising administering to said subject a therapeutically effective amount of ((3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl)oxy)acetic acid or a prodrug derivative thereof and a statin, wherein said cardiovascular disease is selected from the group consisting of atherosclerosis, angina, myocardial infarction, transient ischemic attack, and stroke. 
     
     
         63 . The method of  claim 62 , wherein said prodrug derivative is [[3-(2-Amino-1,2-dioxoethyl)-2-ethyl-1-(phenylmethyl)-1H-indol-4-yl]oxy]acetic acid methyl ester. 
     
     
         64 . The method of  claim 62 , wherein said statin is selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, mevastatin, pitavastatin, pravastatin, rosuvastatin , simvastatin, and pharmaceutically acceptable salts, solvates, stereoisomers, or prodrug derivatives thereof.