HUMAN GLUCAGON-LIKE PEPTIDE-1 MIMICS AND THEIR USE IN THE TREATMENT OF DIABETES AND RELATED CONDITIONS
First Claim
1. An isolated polypeptide having a sequence of Formula I
A-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Y-Z-B
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Iwherein,Xaa1-9 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 R4R5N—
C(O), a sulfonamido R—
SO2, or a R4R5N—
SO2;
wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl;
wherein R4 and R5 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 Xaa1 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 OR1, NR1R2, 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 R1 and R2 are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl.
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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.
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Citations
11 Claims
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1. An isolated polypeptide having a sequence of Formula I
A-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Y-Z-B-
Iwherein, Xaa1-9 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 R4R5N—
C(O), a sulfonamido R—
SO2, or a R4R5N—
SO2;wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; wherein R4 and R5 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 Xaa1 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 OR1, NR1R2, 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 R1 and R2 are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl. - View Dependent Claims (2, 3, 8, 9, 10, 11)
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4. An isolated polypeptide having a sequence of Formula I
A-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Y-Z-B-
Iwherein, Xaa1-9 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 Xaa1 is an R group, an R—
C(O) (amide) group, a carbamate group RO—
C(O), a urea R4R5N—
C(O), a sulfonamido R—
SO2, or a R4R5N—
SO2;wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl, heteroaryloxyalkyl and heteroarylalkoxyalkyl; wherein R4 and R5 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 OR1, NR1R2, 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 R1 and R2 are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocyclyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl. - View Dependent Claims (5)
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6. An isolated polypeptide having a sequence of Formula I
A-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Xaa9-Y-Z-B-
Iwherein, Xaa1-9 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 R4R5N—
C(O), a sulfonamido R—
SO2 or a R4R5N—
SO2;wherein R is selected from the group consisting of hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalkyl; wherein R4 and R5 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 Xaa1 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 OR1, NR1R2 or an amino-alcohol; and wherein R1 and R2 are independently chosen from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl or heteroaryloxyalkyl. - View Dependent Claims (7)
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Specification