Human glucagon-like peptide-1 mimics and their use in the treatment of diabetes and related conditions

Abstract

The present invention provides novel human glucagon-like peptide-1 (GLP-1) peptide mimics that mimic the biological activity of the native GLP-1 peptide and thus are useful for the treatment or prevention of diseases or disorders associated with GLP activity. Further, the present invention provides novel, chemically modified peptides that not only stimulate insulin secretion in type II diabetics, but also produce other beneficial insulinotropic responses. These synthetic peptide GLP-1 mimics exhibit increased stability to proteolytic cleavage making them ideal therapeutic candidates for oral or parenteral administration.

1 . An isolated polypeptide having a sequence of Formula I
   A-X aa1 -X aa2 -X aa3 -X aa4 -X aa5 -X aa6 -X aa7 -X aa8 -X aa9 -Y-Z-B  I   
       wherein,
 X aa1-9  is a naturally or nonnaturally occurring amino acid residue; 
 Y and Z are amino acid residues; 
 wherein one of the substitutions at the alpha-carbon atoms of Y and Z may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, heterocyclylalkyl said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group; any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocyclooxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidine acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary or secondary substituents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other; 
 wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; 
 wherein, the other substitution at the alpha-carbon of Z may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; 
 A and B are optionally present; 
 wherein A is present and A is hydrogen, an amino acid or peptide containing from about 1 to about 15 amino acid residues, an R group, an R—C(O) (amide) group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2 , or a R 4 R 5 N—SO 2 ; 
 wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; 
 wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; 
 wherein the alpha-amino group of X aa1  is substituted with a hydrogen or an alkyl group, said alkyl group may optionally form a ring with A; 
 wherein B is present and B is OR 1 , NR 1 R 2 , or an amino acid or peptide containing from 1 to 15 amino acid residues, terminating at the C-terminus as a carboxamide, substituted carboxamide, an ester, a free carboxylic acid or an amino-alcohol; 
 wherein R 1  and R 2  are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl. 
 
     
     
         2 . The isolated polypeptide of  claim 1  wherein the substitutions upon the alpha-carbon atoms of Y and Z are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocyclooxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl and phosphonic group. 
     
     
         3 . The isolated polypeptide of  claim 1  wherein B is an amino acid or peptide containing 1 to about 10 amino acid residues. 
     
     
         4 . An isolated polypeptide having a sequence of Formula I
   A-X aa1 -X aa2 -X aa3 -X aa4 -X aa5 -X aa6 -X aa7 -X aa8 -X aa9 -Y-Z-B  I   
       wherein,
 X aa1-9  is a naturally or nonnaturally occurring amino acid residue; 
 Y and Z are amino acid residues; 
 wherein one of the substitutions at the alpha-carbon atoms of Y and Z may each independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group; any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocycle, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidine, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocyclooxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary or secondary substituents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other; 
 wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; 
 wherein, the other substitution at the alpha-carbon of Z may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; 
 A and B are optionally present; 
 wherein A is not present, and X aa1  is an R group, an R—C(O) (amide) group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2 , or a R 4 R 5 N—SO 2 ; 
 wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl and heteroarylalkoxyalkyl; 
 wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; 
 wherein B is present and B is OR 1 , NR 1 R 2 , or an amino acid or peptide containing from 1 to 15 amino acid residues, terminating at the C-terminus as a carboxamide, substituted carboxamide, an ester, a free carboxylic acid or an amino-alcohol; 
 wherein R 1  and R 2  are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl. 
 
     
     
         5 . The isolated polypeptide of  claim 4  wherein 13 is an amino acid or peptide containing 1 to about 10 amino acid residues. 
     
     
         6 . An isolated polypeptide having a sequence of Formula I
   A-X aa1 -X aa2 -X aa3 -X aa4 -X aa5 -X aa6 -X aa7 -X aa8 -X aa9 -Y-Z-B  I   
       wherein,
 X aa1-9  is a naturally or nonnaturally occurring amino acid residue; 
 Y is an amino acid residue; 
 wherein one of the substitutions at the alpha-carbon atom of Y may independently be substituted with a primary substituent group selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclylalkyl, arylalkyl and heteroarylalkyl, said primary substituent optionally being substituted with a secondary substituent selected from a cycloalkyl, heterocyclyl, aryl or heteroaryl group; any of said primary or secondary substituents may further be substituted with one or more of, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocyclyloxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamido, alkyl sulfonyl, aryl sulfonyl or phosphonic group; wherein, the primary or secondary substituents may optionally be bridged by covalent bonds to form one or more fused cyclic or heterocyclic systems with each other; 
 wherein, the other substitution at the alpha-carbon of Y may be substituted with hydrogen, alkyl, aminoalkyl, hydroxyalkyl or carboxyalkyl; 
 A and B are optionally present; 
 wherein A is present and A is hydrogen, an amino acid or peptide containing from about 1 to about 15 amino acid residues, an R group, an R—C(O) (amide) group, a carbamate group RO—C(O), a urea R 4 R 5 N—C(O), a sulfonamido R—SO 2  or a R 4 R 5 N—SO 2 ; 
 wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; 
 wherein R 4  and R 5  are each independently selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky; 
 wherein the alpha-amino group of X aa1  is substituted with a hydrogen or an alkyl group, said alkyl group may optionally form a ring with A; 
 wherein B is not present and Z is OR 1 , NR 1 R 2  or an amino-alcohol; and 
 wherein R 1  and R 2  are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl. 
 
     
     
         7 . The isolated polypeptide of  claim 6  wherein the substitutions upon the alpha-carbon atoms of Y are selected from the group consisting of heteroarylarylmethyl, arylheteroarylmethyl or biphenylmethyl forming biphenylalanine residues, any of which is also optionally substituted with one or more, hydrogen, alkyl, cycloalkyl, arylalkyl, aryl, heterocyclyl, heteroaryl, alkenyl, alkynyl, halo, hydroxy, mercapto, nitro, cyano, amino, acylamino, azido, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocyclooxy, acyloxy, mercapto, mercapto alkyl, mercaptoaryl, mercapto acyl, halo, cyano, nitro, azido, amino, guanidino alkyl, guanidino acyl, sulfonic, sulfonamide, alkyl sulfonyl, aryl sulfonyl and phosphonic group. 
     
     
         8 . A pharmaceutical composition comprising a compound as defined in  claim 1  and a pharmaceutically acceptable carrier therefor. 
     
     
         9 . A pharmaceutical combination comprising a compound as defined in  claim 1  and at least one therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent. 
     
     
         10 . A method for treating or delaying the progression or onset of diabetes, diabetic retinopathy, diabetic neuropathy, diabetic nephropathy, wound healing, insulin resistance, hyperglycemia, hyperinsulinemia, Syndrome X, diabetic complications, elevated blood levels of free fatty acids or glycerol, hyperlipidemia, obesity, hypertriglyceridemia, atherosclerosis or hypertension, which comprises administering to a mammalian species in need of treatment a therapeutically effective amount of a compound as defined in  claim 1 . 
     
     
         11 . A method according to  claim 10  further comprising administering, concurrently or sequentially, a therapeutically effective amount of at least one additional therapeutic agent selected from the group consisting of an antidiabetic agent, an anti-obesity agent, a anti-hypertensive agent, an anti-atherosclerotic agent and a lipid-lowering agent.