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US 8,697,632 B2Granted
Amide based insulin prodrugs
AssigneeIndiana University Research and Technology Corporation
InventorsRichard D. DiMarchi, Binbin Kou, Shujiang Cheng
Life of this patent
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Abstract
Prodrug formulations of insulin and insulin analogs are provided wherein the insulin peptide has been modified by an amide bond linkage of a dipeptide prodrug element. The prodrugs disclosed herein have extended half lives of at least 10 hours, and more typically greater than 2 hours, 20 hours and less than 70 hours, and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.
Claims27
An insulin prodrug analog comprising
- an A chain comprising SEQ ID NO:
- 1, or a modified derivative of SEQ ID NO:
- 1 comprising modification of the amino acid at position A19 to a 4-amino phenylalanine and optionally one or more amino acid substitutions at positions selected from A5, A8, A9, A10, A14, A15, A17, A18, A19 and A21;
- a B chain comprising SEQ ID NO:
- 2, or a modified derivative of SEQ ID NO:
- 2 comprising modification of the amino acid at position B16 or B25 to a 4-amino phenylalanine and optionally one or more amino acid substitutions at positions selected from B1, B2, B3, B4, B5, B9, B10, B13, B14, B17, B20, B22, B23, B26, B27, B28, B29 and B30 or deletions of any or all of positions B1-4 and B26-30;
- and
- a dipeptide element linked via an amide bond to the N-terminal amino group of the A chain or B chain, or the side chain amino group of an aromatic amine of a 4-amino-phenylalanine residue present at position A19, wherein said dipeptide element comprises an N-terminal C-alkylated amino acid followed by an N-alkylated amino acid, wherein the N-alkylated group of said N-alkylated amino acid is a C1-C6 alkyl.
5 more elements
An insulin analog comprising an A chain and B chain, wherein said A chain has the general structure of Z-peptide A, wherein peptide A comprises the sequence of GIVEQCCX1SICSLYQLENX2CX3 (SEQ ID NO:
- 3), or an analog thereof comprising a sequence that differs from SEQ ID NO:
- 3 by 1 to 3 amino acid modifications, selected from positions A5, A8, A9, A10, A14, A15, A17, A18;
- and said B chain has the general structure of J-X14-peptide B, wherein peptide B comprises the sequence of X4LCGX5X6LVEALX7LVCGERGFX8 (SEQ ID NO:
- 14), or an analog thereof comprising a sequence that differs from SEQ ID NO:
- 14 sequence by 1 to 3 amino acid modifications, selected from positions B5, B13, B14, B17, B20, B22, and B23 said B chain being linked to said A chain through intermolecular disulfide linkages and optionally through an amide bond linkage between the carboxy terminus of the B chain and the amino terminus of the A chain to form a single chain polypeptide wherein
- Z and J are independently H or a dipeptide element of the structure U-O, wherein U-O is linked to SEQ ID NO:
- 3 or SEQ ID NO:
- 14 through an amide bond, further wherein U-O is a compound having the general structure of Formula I:
- wherein
- R1, R2, R4 and R8 are independently selected from the group consisting of H, C1-C18 alkyl, C2-C18 alkenyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+)NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, (C1-C4 alkyl)(C3-C9 heteroaryl), and C1-C12 alkyl(W1)C1-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R1 and R2 together with the atoms to which they are attached form a C3-C12 cycloalkyl;
- or R4 and R8 together with the atoms to which they are attached form a C3-C6 cycloalkyl;
- R3 is selected from the group consisting of C1-C18 alkyl, (C1-C18 alkyl)OH, (C1-C18 alkyl)NH2, (C1-C18 alkyl)SH, (C0-C4 alkyl)(C3-C6)cycloalkyl, (C0-C4 alkyl)(C2-C5 heterocyclic), (C0-C4 alkyl)(C6-C10 aryl)R7, and (C1-C4 alkyl)(C3-C9 heteroaryl) or R4 and R3 together with the atoms to which they are attached form a pyrrolidine ring;
- R5 is NHR6 or OH;
- R6 is H, C1-C8 alkyl or R6 and R1 together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring;
- and
- R7 is selected from the group consisting of hydrogen, C1-C18 alkyl, C2-C18 alkenyl, (C0-C4 alkyl)CONH2, (C0-C4 alkyl)COOH, (C0-C4 alkyl)NH2, (C0-C4 alkyl)OH, and halo;
- X1 is selected from the group consisting of threonine, histidine and lysine;
- X2 is an amino acid of the general structure
- wherein m is an integer selected from the group consisting of 0-3;
- X is selected from the group consisting of OH, OCH3, NH2 and NHR10, wherein R10 is a dipeptide element comprising the general structure:
- U-O;
- X3 is selected from the group consisting of asparagine, glycine and alanine;
- X4 is selected from the group consisting of histidine and threonine;
- X5 is selected from the group consisting of alanine, glycine and serine;
- X6 is selected from the group consisting of histidine, aspartic acid, glutamic acid, homocysteic acid and cysteic acid;
- X7 is an amino acid of the general structure
- wherein m is an integer selected from 0-3 and X12 is selected from the group consisting of OH, NH2, NHR11 and OCH3, wherein R11 is a dipeptide element comprising the general structure:
- U-O;
- X8 is an amino acid of the general structure
- wherein m is an integer selected from 0-3 and X13 is selected from the group consisting of H, OH, NH2, NHR12 and OCH3, wherein R12 is a dipeptide element comprising the general structure:
- U-O;
- X14 is selected from the group consisting of a bond, X9VNQ (SEQ ID NO:
- 21), VNQ, NQ and Q, wherein X9 is selected from the group consisting of phenylalanine and desamino-phenylalanine;
- with the proviso that one or more of X, X12, X13, J and Z is a dipeptide element comprising the general structure:
- U-O, and R1 and R2 are not both H.
32 more elements
An insulin analog comprising an A chain and a B chain wherein said A chain has the general structure Z-peptide A, wherein peptide A comprises the sequence of GIVEQCCX1SICSLYQLENX2CX3 (SEQ ID NO:
- 3), or an analog thereof comprising a sequence that differs from SEQ ID NO:
- 3 by 1 to 3 amino acid modifications, selected from positions A5, A8, A9, A10, A14, A15, A17, A18;
- and said B chain has the general structure J-X14-peptide B, wherein peptide B comprises the sequence of X4LCGX5X6LVEALX7LVCGERGFX8 (SEQ ID NO:
- 14) or a sequence that differs from SEQ ID NO:
- 14 by 1 to 3 amino acid modifications, selected from positions B5, B13, B14, B17, B20, B22, and B23, said B chain being linked to said A chain through intermolecular disulfide linkages and optionally through an amide bond linkage between the carboxy terminus of the B chain and the amino terminus of the A chain to form a single chain polypeptide, wherein
- Z and J are independently H or a dipeptide element comprising the general structure:
- X14 is selected from the group consisting of a bond, X9VNQ (SEQ ID NO:
- 21), VNQ, NQ and Q;
- X1 is selected from the group consisting of threonine and histidine;
- X2 is an amino acid of the general structure
- wherein X is selected from the group consisting of OH, NHR10 and OCH3, wherein R10 is H or a dipeptide element comprising the general structure:
- X3 is selected from the group consisting of asparagine, glycine and alanine;
- X4 is selected from the group consisting of histidine and threonine and serine;
- X5 is selected from the group consisting of alanine, glycine and serine;
- X6 is selected from the group consisting of histidine, aspartic acid, glutamic acid, homocysteic acid and cysteic acid;
- X7 is an amino acid of the general structure
- wherein X12 is selected from the group consisting of OH, OCH3 and NHR11, wherein R11 is H or a dipeptide element comprising the general structure:
- X8 is an amino acid of the general structure
- wherein X13 is selected from the group consisting of H, OH, OCH3 and NHR12, wherein R12 is H or a dipeptide element comprising the general structure:
- X9 is selected from the group consisting of phenylalanine and desamino-phenylalanine;
- wherein R1 is selected from the group consisting of H and C1-C8 alkyl;
- and
- R2 and R4 are independently selected from the group consisting of H, C1-C8 alkyl, C2-C8 alkenyl, (C1-C4 alkyl)OH, (C1-C4 alkyl)SH, (C2-C3 alkyl)SCH3, (C1-C4 alkyl)CONH2, (C1-C4 alkyl)COOH, (C1-C4 alkyl)NH2, (C1-C4 alkyl)NHC(NH2+) NH2, (C0-C4 alkyl)(C3-C6 cycloalkyl), (C0-C4 alkyl)(C6-C10 aryl)R7, and CH2(C5-C9 heteroaryl);
- R3 is selected from the group consisting of C1-C8 alkyl, (C1-C4 alkyl)OH, (C1-C4 alkyl)SH, (C1-C4 alkyl)NH2, (C3-C6)cycloalkyl;
- R5 is NHR6 or OH;
- R6 is H, or R6 and R2 together with the atoms to which they are attached form a 5 or 6 member heterocyclic ring;
- and
- R7 is selected from the group consisting of H and OH, with the proviso that one and only one of R10, R11, R12, J and Z comprises a dipeptide element of the general structure:
25 more elements
An insulin analog comprising an A chain and B chain, wherein said A chain has the general structure Z-peptide A, wherein peptide A comprises the sequence of GIVEQCCX1SICSLYQLENX2CX3 (SEQ ID NO:
- 3), or an analog thereof comprising a sequence that differs from SEQ ID NO:
- 3 by 1 to 3 amino acid modifications, selected from positions A5, A8, A9, A10, A14, A15, A17, A18;
- and said B chain has the general structure J-X14-peptide B, wherein peptide B comprises the sequence of X4LCGX5X6LVEALX7LVCGERGFX8 (SEQ ID NO:
- 14), or an analog thereof comprising a sequence that differs from SEQ ID NO:
- 14 sequence by 1 to 3 amino acid modifications, selected from positions B5, B13, B14, B17, B20, B22, and B23 said B chain being linked to said A chain through intermolecular disulfide linkages and optionally through an amide bond linkage between the carboxy terminus of the B chain and the amino terminus of the A chain to form a single chain polypeptide wherein
- Z and J are independently H or a dipeptide element of the structure U-O, wherein U is aminoisobutyric acid, hydroxyl aminoisobutyric acid, an amino acid in the D-stereochemical configuration or a hydroxyl acid in the D-stereochemical configuration, and O is an N-alkylated amino acid, and O is linked to SEQ ID NO:
- 3 or SEQ ID NO:
- 14 through an amide bond linkage;
- X1 is selected from the group consisting of threonine, histidine and lysine;
- X2 is an amino acid of the general structure
- wherein m is an integer selected from the group consisting of 0-3;
- X is selected from the group consisting of OH, OCH3, NH2 and NHR10, wherein R10 is a dipeptide element comprising the general structure:
- U-O;
- X3 is selected from the group consisting of asparagine, glycine and alanine;
- X4 is selected from the group consisting of histidine and threonine;
- X5 is selected from the group consisting of alanine, glycine and serine;
- X6 is selected from the group consisting of histidine, aspartic acid, glutamic acid, homocysteic acid and cysteic acid;
- X7 is an amino acid of the general structure
- wherein m is an integer selected from 0-3 and X12 is selected from the group consisting of OH, NH2, NHR11 and OCH3, wherein R11 is a dipeptide element comprising the general structure:
- U-O;
- X8 is an amino acid of the general structure
- wherein m is an integer selected from 0-3 and X13 is selected from the group consisting of H, OH, NH2, NHR12 and OCH3, wherein R12 is a dipeptide element comprising the general structure:
- U-O;
- X14 is selected from the group consisting of a bond, X9VNQ (SEQ ID NO:
- 21), VNQ, NQ and Q, wherein X9 is selected from the group consisting of phenylalanine and desamino-phenylalanine;
- with the proviso that one or more of X, X12, X13, J and Z is a dipeptide element comprising the general structure:
- U-O, and R1 and R2 are not both H.
24 more elements
Dependencies are inferred from the claim text.