Compositions and methods for treating atherosclerotic cardiovascular disease

Abstract

The present invention relates to lyso-diacylglyceryltrimethylhomoserine (lyso- DGTS) or derivatives thereof for use in the treatment of atherosclerotic cardiovascular disease, and further provides particular such lyso-DGTS derivatives.

1 . A method for preventing or treating a disease in a subject in need thereof, comprising administering to said subject a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of the formula I: 
       
         
           
           
               
               
           
         
       
       wherein 
 R 1  is (C 15 -C 21 )alkyl, (C 15 -C 21 )alkenyl, or (C 15 -C 21 )alkynyl; 
 R 2  is —O—CH 2 —CHR 4 —CH 2 —O—, —NH—CH 2 —CHR 4 —CH 2 —O—, —O—, or —NH—; 
 R 3  is —(CH 2 ) n —CH(N + (R 5 ) 3 )—(CH 2 )n and optionally further substituted with one or more —OH groups; 
 each n is between 0 and 7; 
 R 4  is —OH, —O—C(O)—R 6 , or —NH—C(O)—R 6 ; 
 R 5  each independently is (C 1- C 8 )alkyl; and 
 R 6  is (C 15 -C 21 )alkyl, (C 15 -C 21 )alkenyl, or (C 15 -C 21 )alkynyl, 
 wherein said subject is in need of increasing HDL activity, reducing blood glucose level or both. 
 
     
     
         2 . The method of  claim 1 , wherein R 1  is CH 3 —(CH 2 ) 14 —, CH 3 —(CH 2 ) 7 —CH═CH—(CH 2 ) 7 —, CH 3 —(CH2) 4 —(CH═CH—CH 2 ) 2 —(CH 2 ) 6 —, CH 3 —(CH 2 —CH═CH) 3 —(CH 2 ) 7 —, CH 3 —(CH2) 4 —(CH═CH—CH 2 ) 4 —(CH 2 ) 2 —, CH 3 —(CH 2 —CH═CH) 5 —(CH 2 ) 3 —, or CH 3 —(CH 2 —CH═CH)6—(CH 2 ) 2 —. 
     
     
         3 . The method of  claim 1 , wherein R 3  is —(CH 2 ) 1 — 7 —CH(N + (R 5 ) 3 )—, optionally further substituted with one or more —OH groups and wherein n is 1-7. 
     
     
         4 . The method of  claim 1 , wherein R 6  is (C 15 -C 21 )alkyl, or (C 15 -C 21 )alkenyl having one or more double bonds. 
     
     
         5 . The method of  claim 1 , wherein:
 R 1  is optionally a linear (C 15 )alkyl, (C 17) alkenyl, (C 19 )alkenyl, or (C 21 )alkenyl;   R 2  is —O—CH 2 —CHR 4 —CH 2- O—, —NH—CH 2 —CHOH—CH 2 —O—, —O—, or —NH—;   R 3  is —(CH 2 ) 1 — 7 —CH(N + (R 5 ) 3 )—, optionally further substituted with one or more —OH groups;   R 4  is —OH, or —NH—C(O)—R 6 ;   R 5  each independently is (C 1 -C 4 )alkyl; and   R 6  is (C 15 -C 21 )alkyl, or (C 15 -C 21 )alkenyl, including any pharmaceutically acceptable salt or solvate thereof.   
     
     
         6 . The method of  claim 1 , wherein said pharmaceutical composition is formulated for oral, rectal, nasal, intravenous, intraarterial, intramuscular, intraperitoneal, intrathecal, intrapleural, intratracheal, subcutaneous, transdermal, intradermal, vaginal, or topical administration, or for inhalation. 
     
     
         7 . The method of  claim 1 , wherein said HDL activity comprises increasing cholesterol efflux, increasing HDL to LDL ratio, inducing atheroprotective effect, increasing NO release, increasing PON1 lactonase activity, increasing PON1 arylesterase activity, or a combination thereof. 
     
     
         8 . The method of  claim 1 , wherein said disease is atherosclerotic cardiovascular disease. 
     
     
         9 . The method of  claim 1 , wherein said disease is a PON1 related atherosclerotic cardiovascular disease. 
     
     
         10 . The method of  claim 8 , wherein said atherosclerotic cardiovascular disease is selected from the group consisting of cardiovascular disease, coronary artery disease, ischemic heart disease, carotid artery disease, peripheral vascular disease and diabetes, or any combination thereof.