Inhibitors of pcsk9 for treatment of lipoprotein metabolism disorders

Abstract

The present disclosure relates to inhibitors of proprotein convertase subtilisin-like/kexin type 9 (PCSK9) for the treatment of lipoprotein metabolism disorders.

1 - 95 . (canceled) 
     
     
         96 . A method of treatment of a disorder of lipoprotein metabolism in a subject in need thereof, said method comprising administering to said subject a compound selected from heparin, a heparin mimetic and a heparin analogue. 
     
     
         97 . The method according to  claim 96 , wherein the compound is capable of inhibiting binding of heparan sulfate proteoglycans (HSPGs) to PCSK9. 
     
     
         98 . The method according to  claim 96 , wherein the compound is capable of binding to one or more amino acids selected from the group consisting of R93, R96, R97, R104, R105, K136, H139, R165 and R167 of PCSK9 (SEQ ID NO: 1). 
     
     
         99 . The method according to  claim 96 , wherein the compound comprises a general structure of formula (III): 
       
         
           
           
               
               
           
         
         wherein R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19  are independently selected from the group consisting of COOH,  − O 3 SO, O, OH, H sulfate and sulfamate, and n is an integer equal to or greater than 1, and wherein R 14  optionally can act as linkers linking monomer units. 
       
     
     
         100 . The method according to  claim 96 , wherein the compound comprises a general structure of formula (I): 
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of COOH and  − O 3 SO, 
 R 2 , R 3 , R 5  and R 7  are selected from the group consisting of O and OH, 
 R 4  is a sulfate group, 
 R 6  is selected from the group consisting of a sulphamate group, OH and O, 
 R 8  is a sulfate group, 
 n is an integer equal or greater than 1. 
 
       
     
     
         101 . The method according to  claim 96 , wherein the compound is fondaparinux and has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         102 . The method according to  claim 96 , wherein the compound is a low molecular weight heparin. 
     
     
         103 . The method according to  claim 102 , wherein the low molecular weight heparin is dalteparin sodium or tinzaparin sodium. 
     
     
         104 . The method according to  claim 96 , wherein the compound comprises a general structure of formula (II): 
       
         
           
           
               
               
           
         
         wherein R 9  and R 10  are independently selected from the group consisting of H, COOH,  − O 3 SO, O, OH, sulfate and sulfamate, wherein n is an integer equal to or greater than 1. 
       
     
     
         105 . The method according to  claim 104 , wherein the compound comprising a general structure of formula (II) is pentosan and comprises the formula: 
       
         
           
           
               
               
           
         
         where n is an integer equal to or greater than 1. 
       
     
     
         106 . The method according to  claim 99 , wherein the compound comprising a general structure of formula (III) is dextran sulphate and comprises the formula: 
       
         
           
           
               
               
           
         
         wherein n is an integer equal to or greater than 1. 
       
     
     
         107 . The method according to  claim 96 , wherein the compound is suramin and has the formula: 
       
         
           
           
               
               
           
         
       
     
     
         108 . The method according to  claim 96 , wherein the compound is a phosphorothioate oligonucleotide S-dNn, where n is the number of phosphorothioate linkages in said phosphorothioate oligonucleotide, and n is between 12 and 60. 
     
     
         109 . The method according to  claim 96 , wherein the disorder of lipoprotein metabolism is dyslipidemia. 
     
     
         110 . The method according to  claim 109 , wherein the dyslipidemia is hypercholesterolemia, hyperlipidemia or hypertriglyceridemia. 
     
     
         111 . The method according to  claim 96 , wherein the disorder of lipoprotein metabolism is selected from the group consisting of sitosterolemia, metabolic syndrome, xanthoma, obesity and diabetes. 
     
     
         112 . The method according to  claim 96 , wherein the disorder of lipoprotein metabolism is coronary heart disease. 
     
     
         113 . The method according to  claim 96 , wherein the disorder of lipoprotein metabolism is selected from the group consisting of atherosclerosis, arteriosclerosis, acute coronary syndrome, hypertension, angina, and vascular inflammation. 
     
     
         114 . A method for reducing plasma LDL-C levels in a subject in need thereof, said method comprising the step of administering to said subject a compound selected from heparin, a heparin mimetic and a heparin analogue. 
     
     
         115 . The method according to  claim 114 , wherein the compound is selected from the group consisting of:
 a. a compound comprising a general structure of formula (III):   
       
         
           
           
               
               
           
         
         wherein R 11 , R 12 , R 13 , R 14 , R 15 , R 16 , R 17 , R 18 , and R 19  are independently selected from the group consisting of COOH,  − O 3 SO, O, OH, H sulfate and sulfamate, and n is an integer equal to or greater than 1, and wherein R 14  optionally can act as linkers linking monomer units; 
         b. a compound comprising a general structure of formula (I): 
       
       
         
           
           
               
               
           
         
         wherein:
 R 1  is selected from the group consisting of COOH and  − O 3 SO, 
 R 2 , R 3 , R 5  and R 7  are selected from the group consisting of O and OH, 
 R 4  is a sulfate group, 
 R 6  is selected from the group consisting of a sulphamate group, OH and 0, 
 R 8  is a sulfate group, 
 n is an integer equal or greater than 1; 
 
         c. fondaparinux, having the formula: 
       
       
         
           
           
               
               
           
         
       
       d. a low molecular weight heparin;
 e. a compound comprising a general structure of formula (II): 
 
       
         
           
           
               
               
           
         
         wherein R 9  and R 10  are independently selected from the group consisting of H, COOH,  − O 3 SO, O, OH, sulfate and sulfamate, wherein n is an integer equal to or greater than 1; 
         f. pentosane, having the formula: 
       
       
         
           
           
               
               
           
         
         where n is an integer equal to or greater than 1. 
         g. dextran sulphate, comprising the formula: 
       
       
         
           
           
               
               
           
         
         wherein n is an integer equal to or greater than 1; 
         h. suramin, having the formula: 
       
       
         
           
           
               
               
           
         
         and 
         i. a phosphorothioate oligonucleotide S-dNn, where n is the number of phosphorothioate linkages in said phosphorothioate oligonucleotide, and n is between 12 and 60.