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

An isolated polypeptide having a sequence of Formula I

• A—Xaa1—Xaa2—Xaa3—Xaa4—Xaa5—Xaa6—Xaa7—Xaa8—Xaa9—Y—Z—B I
• wherein,
• 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, guanidino, amidino, carboxyl, carboxamido, carboxamido alkyl, formyl, acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycleoxy, 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 substitutents 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.

An isolated polypeptide having a sequence of Formula I

• A—Xaa1—Xaa2—Xaa3—Xaa4—Xaa5—Xaa6—Xaa7—Xaa8—Xaa9—Y—Z—B I
• wherein,
• 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 substitutents 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.

An isolated polypeptide having a sequence of Formula I

• A—Xaa1—Xaa2—Xaa3—Xaa4—Xaa5—Xaa6—Xaa7—Xaa8—Xaa9—Y—Z—B I
• wherein,
• Xaa1-9 is a naturally or nonnaturally occur acid residue;
• Y is an amino acid residue;
• wherein one of the substitutions at the atom of Y may each independently be with a primary substituent group select group consisting of hydrogen, alkyl, cyck cycloalkylalkyl, heterocyclylalkyl, aryll heteroarylalkyl, said primary substitu optionally being substituted with a pri secondary substituent selected from a heterocycle, aryl or heteroaryl group;
• secondary substituents may further be sit with one or more of, hydrogen, alkyl, arylalkyl, aryl, heterocycle, heteroarylk, alkynyl, halo, hydroxy, mercapto, nitrotn amino, acylamino, azido, guanidino, ami carboxyl, carboxamido, carboxamido alkyl acyl, carboxyl alkyl, alkoxy, aryloxy, arylalkyloxy, heteroaryloxy, heterocycl acyloxy, mercapto, mercapto alkyl, mercar mercapto acyl, halo, cyano, nitro, azidai guanidino alkyl, guanidino acyl, sulfon sulfonamido, alkyl sulfonyl, aryl sulforr phosphonic group;
• wherein, the primary secondary substitutents may optionally by covalent bonds to form one or more or heterocyclic systems with each other;
• wherein, the other substitution at the carbon of Y may be substituted with bg 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, heterocycle, 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, heterocycle, heterocycloalkyl, aryl, heteroaryl, arylalkyl, aryloxyalkyl, heteroarylalkyl and heteroaryloxyalky;
• 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.

A method of making a polypeptide recognized by the family of B G-protein coupled receptors wherein the polypeptide mimics the activity of a polypeptide receptor agonist, said polypeptide having the formula

• 52
• the method comprising replacing an address sequence of the polypeptide receptor agonist with Y and Z,
• wherein Y and Z are 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, heterocyclyl 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, heterocycleoxy, 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 substitutents 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;
• and
• wherein Xaa1-Xaan is a message sequence capable of inducing receptor mediated signal transduction.