Aromatic aldehydes with sustained and enhanced in vitro and in vivo pharmacologic activity to treat sickle cell disease

Abstract

Compounds and methods for preventing and/or treating one or more symptoms of sickle cell diseases (SCD) by administering at least one of the compounds are provided. The compounds are based on vanillin which is chemically modified to increase bioavailability and activity, e.g. so that the compounds bind to the F helix of hemoglobin (Hb) and prevent adhesion of red blood cells (RBCs).

1 . A vanillin-derived compound having Formula I: 
       
         
           
           
               
               
           
         
       
       where
 R1 and R2 are the same or different and are hydrogen, hydroxyl, halogen, or a substituted or unsubstituted alkyl, alkoxy, aryl, O-aryl, cycloalkane or heterocycle; 
 R3 is alkyl ester, aryl ester, alkylamide, arylamide, phosphate or sulfate; 
 M and Q are the same or different and are O or (CH 2 )n where n=0-6; 
 X, Y, Z, W and V are the same or different and are independently H, C, N, S or O; 
 m=0-6, and 
 P=CHO or a promoiety; 
 or a pharmaceutically acceptable salt thereof. 
 
     
     
         2 . The vanillin-derived compound of  claim 1 , wherein the vanillin-derived compound is designed to bind to the F helix of hemoglobin (Hb). 
     
     
         3 . The vanillin-derived compound of  claim 1  wherein P is CHO. 
     
     
         4 . The vanillin-derived compound of  claim 1  where P is a protected aldehyde group or promoiety. 
     
     
         5 . The vanillin-derived compound of  claim 4 , wherein the promoiety is 
       
         
           
           
               
               
           
         
       
       where R4 is H or a linear or branched C1-C5 alkyl; and where the bond marked with * bonds directly to a carbon of the benzene ring. 
     
     
         6 . The vanillin-derived compound of  claim 1 , which is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The vanillin-derived compound of  claim 6 , wherein the vanillin-derived compound is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The vanillin-derived compound of  claim 7 , wherein the vanillin-derived compound is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The vanillin derived compound of  claim 1 , wherein the pharmaceutically acceptable salt is an HCl salt. 
     
     
         10 . A composition comprising,
 at least one vanillin-derived compound of  claim 1 .   
     
     
         11 . The composition of  claim 10 , which is in a form for oral administration. 
     
     
         12 . A method of preventing or treating one or more symptoms or conditions of sickle cell disease (SCD) in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of at least one vanillin-derived compound of  claim 1 . 
     
     
         13 . The method of  claim 12 , wherein the one or more symptoms or conditions of SCD are selected from the group consisting of HbS polymerization, red blood cell (RBC) sickling, adhesion of RBCs to tissue endothelium, oxidative stress and/or damage, hemolysis of RBCs, inflammation, vaso-occlusion, impaired microvascular blood flow, a decrease in vascular nitric oxide bioavailability, pain, and death. 
     
     
         14 . The method of  claim 12 , wherein the step of administering is performed orally. 
     
     
         15 . A method of preventing or treating one or more symptoms of hypoxia in a subject in need thereof, comprising
 administering to the subject a therapeutically effective amount of at least one vanillin-derived compound of  claim 1 .   
     
     
         16 . The method of  claim 15 , wherein the step of administering is performed orally.