Back to results
US 8,946,147 B2Granted
Amide-based insulin prodrugs
AssigneeIndiana University Research and Technology Corporation
InventorsRichard D. DiMarchi, Binbin Kou, Shujiang Cheng
Life of this patent
Estimating the term…
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.
Claims23
An insulin analog comprising the structure:
- X—Y—Z;
- wherein Z is an insulin peptide comprising an A chain and a B chain wherein the A chain comprises the sequence 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 the B chain comprises the sequence of X14-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;
- and
- X—Y is a dipeptide linked via an amide bond to the N-terminal amino group of the A chain or B chain or to an amino group on a side chain of an amino acid of said A chain or B chain
- wherein
- X14 is a bond, or a 1 to 4 amino acid sequence selected from the group consisting of a FVNQ (SEQ ID NO:
- 11), 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, NH2, NHR10 and OCH3, wherein R10 is a dipeptide of the general structure X—Y;
- X3 is selected from the group consisting of asparagine, ornithine, glycine, alanine, threonine, and serine;
- 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 X12 is selected from the group consisting of OH, NH2, NHR11 and OCH3, wherein R11 is a dipeptide of the general structure X—Y;
- X8 is histidine, asparagine or an amino acid of the general structure
- wherein X13 is selected from the group consisting of H, OH, NH2, NHR12 and OCH3, wherein R12 is a dipeptide of the general structure X—Y;
- wherein X—Y comprises a dipeptide structure:
- wherein
- R1 and R2 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;
- R3 is C1-C18 alkyl;
- R4 is selected from the group consisting of CH3, CH2(C1-C10 alkyl), CH2(C2-C10 alkenyl), CH2(C0-C10 alkyl)OH, CH2(C0-C10 alkyl)SH, CH2(C0-C3 alkyl)SCH3, CH2(C0-C3 alkyl)CONH2, CH2(C0-C3 alkyl)COOH, CH2(C0-C3 alkyl)NH2, CH2(C0-C3 alkyl)NHC(NH2+)NH2, CH2(C0-C3 alkyl)(C3-C6 cycloalkyl), CH2(C0-C3 alkyl)(C2-C5 heterocyclic), CH2(C0-C3 alkyl)(C6-C10 aryl)R7, CH2(C1-C3 alkyl)(C3-C9 heteroaryl), and CH2(C0-C12 alkyl)(W1)C1-C12 alkyl, wherein W1 is a heteroatom selected from the group consisting of N, S and O, or R4 and R3 together with the atoms to which they are attached form a pyrrolidine ring;
- R8 is H;
- R5 is NHR6, or OH;
- R6 is H or C1-C4 alkyl;
- and,
- R7 is selected from the group consisting of H, OH, halo, (C1-C7 alkyl), (C2-C7 alkenyl), OCF3, NO2, CN, NC, O(C1-C7 alkyl), CO2H, CO2(C1-C7 alkyl), NHR6, aryl, and heteroaryl,
- wherein chemical cleavage half-life (t1/2) of X—Y from Z is at least about 1 hour to about 1 week in PBS under physiological conditions.
30 more elements
An insulin analog comprising
- an A chain, wherein said A chain comprises the sequence GIVEQCCX1SICSLYQLENX2CX3 (SEQ ID NO:
- 3);
- a B chain, wherein said B chain comprises the sequence X9VNQX4LCGX5X6LVEALX7LVCGERGFX8YTPKT (SEQ ID NO:
- 15) or X9VNQX4LCGX5X6LVEALX7LVCGERGFX8YTKPT (SEQ ID NO:
- 16);
- and
- a dipeptide comprising the general structure of X—Y linked to an amino group on a side chain of an amino acid of said A chain or B chain via an amide bond, wherein
- X1 is selected from the group consisting of threonine, histidine, arginine and lysine;
- X2 is an amino acid of the general structure
- wherein X is selected from the group consisting of OH, NH2, NHR10 and OCH3, wherein R10 is a dipeptide of the general structure X—Y;
- X3 is asparagine, glycine, alanine, threonine, or serine;
- 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 X12 is selected from the group consisting of OH, NH2, NHR1 1 and OCH3, wherein R11 is a dipeptide of the general structure X—Y;
- X8 is an amino acid of the general structure
- wherein X13 is selected from the group consisting of H, OH, NH2, NHR12 and OCH3, wherein R12 is a dipeptide of the general structure X—Y;
- X9 is selected from the group consisting of phenylalanine and desamino-phenylalanine;
- X—Y has 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.
25 more elements
An insulin analog comprising the structure:
- X—Y—Z:
- wherein Z is an insulin peptide comprising an A chain and a B chain wherein the A chain comprises the sequence 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 the B chain comprises the sequence of X14-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
- X—Y is a dipeptide linked to an amino group on a side chain of an amino acid of said A chain or B chain via an amide bond, said X—Y dipeptide comprising the general structure:
- wherein
- R2 comprises (C1-C4 alkyl)NH2 that is acylated at the amino group of R2 with an acyl group of sufficient size to bind serum albumin;
- R1 and R4 are each hydrogen;
- R3 is CH3;
- and
- R5 is NH2.
11 more elements
Dependencies are inferred from the claim text.