Glp-1 compounds

Abstract

GLP-1 compounds comprising GLP-1 analogs and methods of using the GLP-1 compounds for treating metabolic disorders, enhancing insulin expression, and promoting insulin secretion in a patient are provided.

What is claimed is: 
     
         1 . A GLP-1 compound comprising a GLP-1 analog that comprises the amino acid sequence of Formula IV (SEQ ID NO: 29) 
       
         
           
                 
                 
               
                     
                   (Formula IV, SEQ ID NO: 29) 
                 
                     
                   Xaa 7 -Xaa 8 -Xaa 9 -Xaa 10 -Xaa 11 -Xaa 12 -Xaa 13 -Xaa 14 - 
                 
                     
                     
                 
                     
                   Xaa 15 -Xaa 16 -Xaa 17 -Xaa 18 -Xaa 19 -Xaa 20 -Xaa 21 -Xaa 22 - 
                 
                     
                     
                 
                     
                   Xaa 23 -Xaa 24 -Xaa 25 -Xaa 26 -Xaa 27 -Xaa 28 -Xaa 29 -Xaa 30 - 
                 
                     
                     
                 
                     
                   Xaa 31 -Xaa 32 -Xaa 33 -Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 - 
                 
                     
                     
                 
                     
                   Xaa 39 -Xaa 40 -Xaa 41 C(O)-R 1   
                 
             
                
                
                
                
                
                
                
                
                
                
               
            
           
         
       
       wherein,
 R 1  is OR 2  or NR 2 R 3 ; 
 R 2  and R 3  are independently hydrogen or (C 1 -C 8 )alkyl; 
 Xaa at position 7 is: L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, 3-hydroxy-histidine, homohistidine, α-fluoromethyl-histidine or α-methyl-histidine; 
 Xaa at position 8 is Gly, bAla (2-aminopropionic acid), 1-amino-cylcopentanecarboxylic acid, 2-aminoisobutryic acid or an alpha-alpha-disubstituted amino acid; 
 Xaa at position 9 is Glu, Asp, or Lys; 
 Xaa at position 10 is Gly or His; 
 Xaa at position 11 is Thr, Ala, Gly, Ser, Leu, Ile, Val, Glu, Asp, or Lys; 
 Xaa at position 12 is: His, Trp, Phe, or Tyr; 
 Xaa at position 13 is Thr or Gly; 
 Xaa at position 14 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys; 
 Xaa at position 15 is Asp or Glu; 
 Xaa at position 16 is Val, Ala, Gly, Ser, Thr, Leu, Ile, Tyr, Glu, Asp, Trp, or Lys; 
 Xaa at position 17 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, or Lys; 
 Xaa at position 18 is Ser, Ala, Gly, Thr, Leu, Ile, Val, Glu, Asp, Trp, Tyr, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 19 is Tyr, Phe, Trp, Glu, Asp, Gln, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 20 is Leu, Ala, Gly, Ser, Thr, Ile, Val, Glu, Asp, Met, Trp, Tyr, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 21 is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 22 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 23 is Gln, Asn, Arg, Glu, Asp, Lys, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 24 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Arg, Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, or alpha, gamma-diaminobutyric acid, homoglutamic acid; 
 Xaa at position 25 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, or alpha, gamma-diaminobutyric acid, homoglutamic acid; 
 Xaa at position 26 is Lys, Homolysine, Arg, Gln, Glu, Asp, His, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 27 is Leu, Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 28 is Phe, Trp, Asp, Glu, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 29 is Ile, Leu, Val, Ala, Phe, Asp, Glu, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 30 is Ala, Gly, Ser, Thr, Leu, Ile, Val, Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid; 
 Xaa at position 31 is Trp, Phe, Tyr, Glu, Asp, or Lys; 
 Xaa at position 32 is Leu, Gly, Ala, Ser, Thr, Ile, Val, Glu, Asp, or Lys; 
 Xaa at position 33 is Val, Gly, Ala, Ser, Thr, Leu, Ile, Glu, Asp, or Lys; 
 Xaa at position 34 is Asn, Lys, Arg, Glu, Asp, or His; 
 Xaa at position 35 is Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys; 
 Xaa at position 36 is Gly, Arg, Lys, Glu, Asp, or His; 
 Xaa at position 37 is Pro, Gly, Ala, Ser, Thr, Leu, Ile, Val, Glu, Asp, or Lys; 
 Xaa at position 38 is Gly, Ser, Lys, Cys, or is omitted; 
 Xaa at position 39 is Gly, Ala, Ser, Thr, Ile, Val, Leu, Phe, Pro, Cys or is omitted; 
 Xaa at position 40 is Gly, Cys, or is omitted; 
 Xaa at position 41 is Gly or is omitted; 
 
       wherein two amino acids selected from Xaa 18 , Xaa 19 , Xaa 20 , Xaa 21 , Xaa 22 , Xaa 23 , Xaa 24 , Xaa 25 , Xaa 26 , Xaa 27 , Xaa 28 , Xaa 29 , and Xaa 30  are joined to form a ring and the two amino acids forming the ring are separated by 3, 4 or 5 amino acids, and wherein the compound has a GLP-1 activity. 
     
     
         2 . The GLP-1 compound of  claim 1 , wherein the two amino acids forming the ring are separated by 3 amino acids. 
     
     
         3 . The GLP-1 compound of  claim 1 , wherein the two amino acids forming the ring are separated by 4 amino acids. 
     
     
         4 . The GLP-1 compound of  claim 1 , wherein the two amino acids forming the ring are separated by 5 amino acids. 
     
     
         5 . The GLP-1 compound of  claim 1 , wherein
 Xaa 18  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 22  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid, and   amino acids Xaa 18  and Xaa 22  are joined to form the ring.   
     
     
         6 . The GLP-1 compound of  claim 1 , wherein
 Xaa 19  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 23  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid, and   amino acids Xaa 19  and Xaa 23  are joined to form the ring.   
     
     
         7 . The GLP-1 compound of  claim 1 , wherein
 Xaa 20  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 24  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, or alpha, gamma-diaminobutyric acid, homoglutamic acid, and   amino acids Xaa 20  and Xaa 24  are joined to form the ring.   
     
     
         8 . The GLP-1 compound of  claim 1 , wherein
 Xaa 21  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 25  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid, and   amino acids Xaa 21  and Xaa 25  are joined to form the ring.   
     
     
         9 . The GLP-1 compound of  claim 1 , wherein
 Xaa 22  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 26  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid, and   amino acids Xaa 22  and Xaa 26  are joined to form the ring.   
     
     
         10 . The GLP-1 compound of  claim 1 , wherein
 Xaa 23  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 27  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid, and   amino acids Xaa 23  and Xaa 27  are joined to form the ring.   
     
     
         11 . The GLP-1 compound of  claim 1 , wherein
 Xaa 24  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 28  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid, and   amino acids Xaa 24  and Xaa 28  are joined to form the ring.   
     
     
         12 . The GLP-1 compound of  claim 1 , wherein
 Xaa 25  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 29  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid, and   amino acids Xaa 25  and Xaa 29  are joined to form the ring.   
     
     
         13 . The GLP-1 compound of  claim 1 , wherein
 Xaa 26  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid,   Xaa 30  is Glu, Asp, Lys, Homolysine, Ornithine, 4-carboxy-phenylalanine, beta-glutamic acid, beta-Homoglutamic acid, alpha, gamma-diaminobutyric acid, or homoglutamic acid, and   amino acids Xaa 26  and Xaa 30  are joined to form the ring.   
     
     
         14 . The GLP-1 compound of  claim 1 , wherein the GLP-1 analog has the amino acid sequence of any of SEQ ID NO: 30 to 246 with no more than 5 conservative amino acid substitutions. 
     
     
         15 . The GLP-1 compound of  claim 1 , wherein the GLP-1 analog has the amino acid sequence of any of SEQ ID NO: 30 to 246. 
     
     
         16 . The GLP-1 compound of  claim 1 , wherein R 1  is a carboxyl group, amine, ester, or substitute amine. 
     
     
         17 . A method for treating a subject with a metabolic disorder, comprising administering to the subject an effective amount of a GLP-1 compound of  claim 1  wherein the metabolic disorder is selected from the group of diabetes, obesity and metabolic syndrome. 
     
     
         18 . A method for enhancing insulin expression in a subject, comprising administering to the subject an effective amount of a GLP-1 compound of  claim 1 . 
     
     
         19 . A method for promoting insulin secretion in a subject, comprising administering to the subject an effective amount of the GLP-1 compound of  claim 1 . 
     
     
         20 . The GLP-1 compound of  claim 1 , which is covalently modified with a water-soluble polymer. 
     
     
         21 . The polypeptide of  claim 20 , wherein the water-soluble polymer is selected from the group consisting of polyethylene glycol, monomethoxy-polyethylene glycol, dextran, cellulose, poly-(N-vinyl pyrrolidone) polyethylene glycol, propylene glycol homopolymers, polypropylene oxide/ethylene oxide co-polymers, polyoxyethylated polyols, and polyvinyl alcohol. 
     
     
         22 . The polypeptide of  claim 20 , wherein the water-soluble polymer is selected from the group consisting of polyethylene glycol and dextran. 
     
     
         23 . The GLP-1 compound of  claim 1 , wherein the GLP-1 analog is pegylated. 
     
     
         24 . A pharmaceutical composition comprising a pharmaceutically acceptable carrier and an effective amount of the GLP-1 compound of  claim 1 . 
     
     
         25 . A method for treating a subject with a metabolic disorder, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 24 , wherein the metabolic disorder is selected from the group of diabetes, obesity and metabolic syndrome. 
     
     
         26 . A method for enhancing insulin expression in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 24 . 
     
     
         27 . A method for promoting insulin secretion in a subject, comprising administering to the subject an effective amount of the pharmaceutical composition of  claim 24 .