Heparanase inhibitors for treatment of diabetes

Abstract

Anti-heparanase compounds for the treatment of diabetes are described. The anti-heparanase compounds are high affinity, synthetic glycopolymers that result in minimal anticoagulant activity. Stereoselective fluorinated forms of these compounds are also provided.

What is claimed is: 
     
         1 . A method of treating diabetes in a subject in need thereof comprising administering a therapeutically effective amount of an anti-heparanase compound or a salt thereof to the subject, wherein the anti-heparanase compound or a salt thereof comprises 2 to 100 repeating units, and wherein the repeating unit comprises a disaccharide or a salt thereof having the structure of 
       
         
           
           
               
               
           
         
         wherein: 
         W is OH or OSO 3   − ; 
         Z 1 , is OH or F; 
         Z 2  is OH, OSO 3   − , or F; 
         Q is NHSO 3   − , NHC(O)CH 3 , NH 3 , or F; and 
         positioning of the carboxyl group, or salt thereof, can either be axial or equatorial. 
       
     
     
         2 . The method of  claim 1 , wherein the repeating unit of the anti-heparanase compound or salt thereof comprises the disaccharide or a salt thereof linked to the structure of 
       
         
           
           
               
               
           
         
         wherein: 
         X is O or 
       
       
         
           
           
               
               
           
         
         Y is O or CH 2 ; 
         R 1  is OH or N(H)-L-R a ; 
         L is a linking group,
 optionally L is (—CH 2 CH 2 O—)n 1 , wherein n 1  is 1 to 5; —CH 2 CH 2 OCH 2 CH 2 —; 
 —(CH 2 CH 2 O) 4 CH 2 CH 2 C(O)—; —NHCH 2 CH 2 OCH 2 CH 2 —; or 
 —NH(CH 2 CH 2 O) 4 CH 2 CH 2 C(O)—; 
 
         R a  is a saccharide, disaccharide, or a salt thereof, the saccharide or disaccharide comprising one or more OSO 3   −  groups and/or one or more F; 
         n is an integer of 2 to 100 repeating units; and 
         * indicates that the bond is independently single or double bonds. 
       
     
     
         3 . The method of  claim 1 , wherein the anti-heparanase compound or salt thereof has the structure of 
       
         
           
           
               
               
           
         
       
     
     
         4 . The method of  claim 3 , wherein the salt of the anti-heparanase compound is a sodium salt, a calcium salt, a magnesium salt, a lithium salt, a potassium salt, a cesium salt, or a triethylammonium salt, and optionally wherein the salt of the anti-heparanase compound is a sodium salt. 
     
     
         5 . The method of  claim 3 , wherein n is 2 to 50, 2 to 25, 2 to 20, 2 to 15, 5 to 15, 10 to 1, 5, 9, 10, 11, or 12. 
     
     
         6 . The method of  claim 3 , wherein the anti-heparanase compound or salt thereof has the structure of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         7 . The method of  claim 3 , wherein the anti-heparanase compound has the structure of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 7 , wherein the sodium salt of the anti-heparanase compound has the structure of 
       
         
           
           
               
               
           
         
         wherein R a  is 
       
       
         
           
           
               
               
           
         
       
     
     
         9 . The method of  claim 8 , wherein the anti-heparanase compound has the structure of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 3 , wherein the anti-heparanase compound or salt thereof has the structure of 
       
         
           
           
               
               
           
         
         wherein n is 12, and optionally wherein the salt of the anti-heparanase compound comprises a sodium salt. 
       
     
     
         11 . An anti-diabetes composition comprising: (i) the anti-heparanase compound or a salt thereof of  claim 1  and (ii) a pharmaceutically acceptable carrier, wherein the pharmaceutically acceptable carrier is aqueous or alcoholic and comprises a viscous base. 
     
     
         12 . The anti-diabetes composition of  claim 11 , wherein the binding affinity of the anti-heparanase compound to FGF-1 is more than the binding affinity of heparin to FGF-1. 
     
     
         13 . The anti-diabetes composition of  claim 11 , wherein the binding affinity of the anti-heparanase compound to FGF-2 is more than the binding affinity of heparin to FGF-2. 
     
     
         14 . The anti-diabetes composition of  claim 11 , wherein the binding affinity of the anti-heparanase compound to VEGF is more than the binding affinity of heparin to VEGF. 
     
     
         15 . The anti-diabetes composition of  claim 11 , wherein the binding affinity of the anti-heparanase compound to PF4 is more than the binding affinity of heparin to PF4. 
     
     
         16 . The anti-diabetes composition of  claim 11 , wherein the binding affinity of the anti-heparanase compound to P-Selectin is more than or equal to the binding affinity of heparin to P-Selectin. 
     
     
         17 . The anti-diabetes composition of  claim 11 , wherein the anti-heparanase compound has lower binding affinity to antithrombin Ill than heparin's binding affinity to antithrombin Ill.