Mic-1 compounds and uses thereof

Abstract

The invention relates to MIC-1 compounds. More specifically it relates to compounds comprising a MIC-1 polypeptide with an N-terminal amino acid extension and a protractor wherein the amino acid extension comprises 3 to 36 amino acid residues and where the MIC-1 polypeptide and the N-terminal amino acid extension together have a calculated pI lower than 6.5. The compounds of the invention have MIC-1 activity. The invention also relates to pharmaceutical compositions comprising such compounds and pharmaceutically acceptable excipients, as well as the medical use of the compounds.

1 . A MIC-1 compound comprising a MIC-1 polypeptide with an N-terminal amino acid extension and a protractor attached to the amino acid extension, wherein the amino acid extension comprises 3 to 36 amino acid residues, and wherein the MIC-1 polypeptide with the amino acid extension has a calculated pI lower than 6.5. 
     
     
         2 . The MIC-1 compound according to  claim 1 , wherein the N-terminal amino acid extension comprises one Cysteine residue, and wherein the protractor is attached to the amino acid extension at the Cysteine residue. 
     
     
         3 . The MIC-1 compound according to  claim 2 , wherein the protractor comprises Chem. 1, Chem. 2, Chem. 3 and Chem. 4;
 wherein Chem. 1 is selected from the group consisting of:
   HOOC—(CH 2 ) x —CO—*,  Chem. 1A:
 
   HO—S(═O) 2 —(CH 2 ) x —CO—*,  Chem. 1B:
 
   HOOC-benzene-O—(CH 2 ) y —CO—*, and  Chem. 1C:
 
   (1H-tetrazol-5-yl)-(CH 2 ) x —CO—*,  Chem. 1D:
 
   wherein x is an integer in the range of 12-20,   wherein y is an integer in the range of 5-15;   wherein Chem. 2 is selected from the group consisting of:
   *—(NH—CH(COOH)—(CH 2 ) m —CO) k *,  Chem. 2A:
 
   *—(NH—S(═O) 2 —(CH 2 ) m —CO) k *, and  Chem. 2B:
 
   *—(NH—(CH 2 ) m -cyclohexane-CO) k —*,  Chem. 2C:
 
   wherein m of Chem. 2 is an integer in the range of 1-5, and   k of Chem. 2 is an integer in the range of 0-4;   wherein Chem. 3 is
   *(NH—(CH 2 ) 2 —[O—(CH 2 ) 2 ] k —O—[CH 2 ] n —CO—*) l ,
 
   wherein k of Chem. 3 is an integer in the range of 1-10,   n is an integer in the range of 1-5, and   l is an integer in the range of 0-5;   wherein Chem. 4 is selected from
   *—NH—(CH 2 ) m —NH—CO—CH 2 —*, and  Chem. 4A:
 
   *—NH—CH(COOH)—(CH 2 ) m —NH—CO—CH 2 —*,  Chem. 4B:
 
   wherein m of Chem. 4 is an integer in the range of 1-5; and   wherein Chem. 1, Chem. 2, Chem. 3, and Chem. 4 are interconnected via amide bonds, connecting the *—NH end of a Chem. to the CO—* end of another Chem., and wherein the CH 2 —* end of Chem. 4 is connected to a sulphur atom of the Cysteine residue of the amino acid extension.   
     
     
         4 . The MIC-1 compound according to  claim 3 , wherein Chem. 1 is selected from the group consisting of:
   HOOC—(CH 2 ) 16 —CO—*,  Chem. 1a:
     HO—S(═O) 2 —(CH 2 ) 15 —CO—* and  Chem. 1b:
     HOOC-benzene-O—(CH 2 ) 9 —CO—*.  Chem. 1c:
   
     
     
         5 . The MIC-1 compound according to  claim 3 , wherein Chem. 2 is selected from the group consisting of:
   *—NH—CH(COOH)—(CH 2 ) 2 —CO—*,  Chem. 2a:
     *—NH—S(═O) 2 —(CH 2 ) 3 —CO—* and  Chem. 2b:
     *—NH—CH 2 -cyclohexane-CO—*.  Chem. 2c:
   
     
     
         6 . The MIC-1 compound according to  claim 3 , wherein Chem. 4 is selected from the group consisting of:
   *—NH—(CH 2 ) 2 —NH—CO—CH 2 —* and  Chem. 4a:
     *—NH—CH(COOH)—(CH 2 ) 4 —NH—CO—CH 2 —*.  Chem. 4b:
   
     
     
         7 . The MIC-1 compound according to  claim 1 , wherein the protractor is selected from the group consisting of Formula IX, Formula X, Formula XI, Formula XII and Formula XIII: 
       
         
           
           
               
               
           
         
       
     
     
         8 . The MIC-1 compound according to  claim 1 , wherein the N-terminal amino acid extension has surplus of acidic amino acid residues (such as Aspartic acid and/or Glutamic acid) of at least 3, 4, 5 or 6 compared to the number of basic amino acid residues (such as Lysine, Arginine and/or Histidine). 
     
     
         9 . The MIC-1 compound according to  claim 8 , wherein the N-terminal amino acid extension is composed of amino acid residues selected among the group consisting of A, C, E, G, P, S and T. 
     
     
         10 . The MIC-1 compound according to  claim 2 , wherein the distance between the Cysteine residue of the amino acid extension and N-terminal amino acid of the MIC-1 polypeptide is at least 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 or 32 amino acids. 
     
     
         11 . The MIC-1 compound according to  claim 1 , wherein the N-terminal amino acid extension comprises one or more of the following sequences: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 223) 
                 
                     
                   SEPATCGSETPGTSESATPESGPGTSTEPS, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 224) 
                 
                     
                   SEPATSGCETPGTSESATPESGPGTSTEPS, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 225) 
                 
                     
                   SEPCTSGSETPGTSESATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 226) 
                 
                     
                   SEPATCGSETPGTSESATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 227) 
                 
                     
                   SEPATSCSETPGTSESATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 229) 
                 
                     
                   SEPACSGSETPGTSESATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 230) 
                 
                     
                   SEPATSGCETPGTSESATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 231) 
                 
                     
                   SEPATSGSECPGTSESATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 232) 
                 
                     
                   SEPATSGSETPCTSESATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 233) 
                 
                     
                   SEPATSGSETPGTCESATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 234) 
                 
                     
                   SEPATSGSETPGTSECATPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 235) 
                 
                     
                   SEPATSGSETPGTSESACPESGPGTSTEPSEG, 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 236) 
                 
                     
                   SEPATSGSETPGTSESATPECGPGTSTEPSEG, 
                 
                     
                   and 
                 
                     
                     
                 
                     
                   (SEQ ID NO: 237) 
                 
                     
                   SEPATSGSETPGTSESATPESCPGTSTEPSEG. 
                 
             
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
     
     
         12 . The MIC-1 compound according to  claim 1 , wherein the MIC-1 polypeptide comprises at least one substitution of M57L and/or M86L, compared to MIC-1 of SEQ ID NO: 1, and/or comprises a deletion of the first three residues or a deletion of N3 compared to MIC-1 of SEQ ID NO:1. 
     
     
         13 . The MIC-1 compound according to  claim 1 , wherein the MIC-1 polypeptide with the N-terminal amino acid extension comprises an amino acid sequence according to SEQ ID NO: 100, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 164, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291 or SEQ ID NO: 292. 
     
     
         14 . The MIC-1 compound according to  claim 1 , where the compound is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The MIC-1 compound according to  claim 1  for use in the prevention and/or treatment of a metabolic disorder, wherein the metabolic disorder is obesity, diabetes, cardiovascular like dyslipidaemia, arteriosclerosis, steatohepatitis, or diabetic nephropathy.