Methods for treating atherosclerosis

Abstract

The invention provides compounds, pharmaceutical compositions and methods for treating atherosclerosis, inflammation, thrombosis and other conditions and for decreasing or prevention of accumulation of cholesterol in a subject by modifying LCAT polypeptide.

1 . A method for treating atherosclerosis in a subject comprising administering to the subject a therapeutically effective amount of a compound of Formula I  
       
         
           
           
               
               
           
         
         wherein X, Y and Z are independently selected from the group consisting of —N═, —S—, —CH═ and  
         
           
             
             
                 
                 
             
           
         
          provided that at least two of X, Y and Z are not —S—, and provided that no more than one of X, Y and Z is —CH═; L is —S—, —S(O)—, or —S(O) 2 —;  
         R 1  is selected from the group consisting of CN, COOR 5 ,SO 2 R 6  and halogen;  
         R 2  is selected from the group consisting of H, optionally substituted C 1 -C 12  alkyl, optionally substituted C 1 -C 12  alkenyl, optionally substituted C 1 -C 8  alkynyl, optionally substituted aryl, and optionally substituted heteroaryl, and SR 3 , wherein the substituents are selected from the group consisting of C 1 -C 4  alkyl, NH 2 , halo and CN; and wherein R 3  is selected from the group consisting of H, optionally substituted C 1 -C 12  alkyl, optionally substituted C 1 -C 8  alkenyl, optionally substituted C 1 -C 8  alkynyl, optionally substituted aryl and optionally substituted heteroaryl, wherein the substituents are selected from the group consisting of NH 2 , halo and CN;  
         R 4  is H or C 1 -C 8  alkyl;  
         R 5  and R 6  are each independently C 1 -C 4  alkyl;  
         or a pharmaceutically acceptable salt thereof.  
       
     
     
         2 . The method of  claim 1 , wherein X and Y are each —N═.  
     
     
         3 . The method of  claim 2 , wherein Z is —S—.  
     
     
         4 . The method of  claim 1 , wherein L is —S—.  
     
     
         5 . The method of  claim 1 , wherein R 1  is CN.  
     
     
         6 . The method of  claim 1 , wherein R 2  is SR 3 .  
     
     
         7 . The method of  claim 1 , wherein R 3  is C 1 -C 4  alkyl.  
     
     
         8 . The method of  claim 7 , wherein R 3  is methyl.  
     
     
         9 . The method of  claim 1 , wherein the compound is selected from the group consisting of 
 3-(5-(Methylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Ethylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Allylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Propylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Butylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Isobutylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Pentylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Dodecylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Benzylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-Mercapto-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-(Isopropylthio)-4-methyl-4H-1,2,4-triazol-3-ylthio)pyrazine-2-carbonitrile    3-(5-(Methylthio)-1,2,4-thiadiazol-3-ylthio)pyrazine-2-carbonitrile    3-(5-Methyl-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(5-Butyl-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile    3-(4-Methyl-4H-1,2,4-triazol-3-ylthio)pyrazine-2-carbonitrile    3-(1-Methyl-1H-imidazol-2-ylthio)pyrazine-2-carbonitrile, and    2-Chloro-3-(5-(methylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine 
 or a pharmaceutically acceptable salt thereof.  
   
     
     
         10 . A method for treating atherosclerosis in a subject in need thereof, comprising administering a therapeutically effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile.  
     
     
         11 . The method of  claim 10 , wherein the modified LCAT is administered intravenously.  
     
     
         12 . The method of  claim 11 , wherein the modified LCAT is administered by bolus.  
     
     
         13 . A method for treating an LCAT-mediated disease comprising administering to a subject in need thereof an effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile.  
     
     
         14 . The method of  claim 13 , wherein the LCAT-mediated disease is selected from the group consisting of atherosclerosis, thrombosis, coronary heart disease, high blood pressure, LCAT deficiency syndrome, Alzheimer's disease, corneal opacity, metabolic syndrome, dyslipidemia, myocardial infartion, stroke, critical limb ischemia, angina.  
     
     
         15 . A method for increasing HDL cholesterol in a subject comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile, and a pharmaceutically acceptable carrier or excipient.  
     
     
         16 . A method for preventing accumulation of cholesterol in a subject comprising administering to the subject a pharmaceutical composition comprising a therapeutically effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile, and a pharmaceutically acceptable carrier or excipient.  
     
     
         17 . A method for treating atherosclerosis in a subject in need thereof, comprising administering a pharmaceutical composition comprising a therapeutically effective amount of a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile and a pharmaceutically acceptable carrier or excipient.  
     
     
         18 . A pharmaceutical composition comprising a modified LCAT comprising a replacement of the amino acid residue 31 by a cysteine residue, wherein the cysteine residue is modified by replacing the thiol hydrogen with 3-pyrazinyl-2-carbonitrile, and a pharmaceutically acceptable carrier.  
     
     
         19 . The method of  claim 1 , wherein the subject is mammal.  
     
     
         20 . The method of  claim 1 , wherein the subject is human.