Ester-based insulin prodrugs
AssigneeIndiana University Research and Technology Corporation
InventorsRichard D. DiMARCHI, Arnab DE
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Abstract
Prodrug formulations of bioactive polypeptides are provided wherein the bioactive polypeptide has been modified by the linkage of a dipeptide to the bioactive polypeptide through an ester linkage. The prodrugs disclosed herein in some embodiments have extended half lives of at least 1.5 hours (e.g., at least 10 hours), and more typically greater than 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.
Claims19
1-85. (canceled)
A method of treating diabetes, said method comprising administering an effective amount of a pharmaceutical composition comprising an insulin polypeptide, said polypeptide comprising an A chain and a B chain, wherein a hydroxyl group of said insulin polypeptide is modified by the covalent linkage of the group:
- and one of said A or B chain comprises an amino acid residue of the general structure of Formula I:
- wherein
- said amino acid residue is an amino acid present in either the A or B chain of said insulin polypeptide, optionally as an internal amino acid with flanking N-terminal and C-terminal insulin amino acid sequences;
- R3 is selected from the group consisting of NH2, said N-terminal insulin amino acid sequence, and
- R4 is —OH, NH2 or said C-terminal insulin amino acid sequence,
- R10 is selected from the group consisting of H, C1-C4 alkyl, and (CH2)n(C6-C10 aryl);
- W is C6-C10 aryl or a bond;
- n is an integer from 0 to 3;
- R12 is —OH, H or
- R1 and R2 are independently selected from the group consisting of H, C1-C4 alkyl, (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, (C4-C6)cycloalkyl, (C0-C4 alkyl)(C6-C10 aryl)R9, and CH2(C5-C9 heteroaryl),
- R5 is OH or NH2;
- R9 is C1-C4 alkyl, NH2 or OH;
- and
- R7 is —O— said N-terminal insulin amino acid sequence or O,
- with the proviso that one of R3 or R12 comprises an ester linked dipeptide of the general structure:
A method of treating diabetes, said method comprising administering an effective amount of a pharmaceutical composition comprising an insulin polypeptide, said polypeptide comprising
- an A chain;
- a B chain;
- and
- a dipeptide of the formula
- wherein said A chain comprises a sequence of X5IVX6QCCX7SICSLYQLENYCX8 (SEQ ID NO:
- 626), and said B chain comprises a sequence of X13LCGX9X10LVEALX11LVCGERGFX12 (SEQ ID NO:
- 628), and said dipeptide is linked via an ester bond to the N-terminus, or a side chain of an amino acid located at position 1, 4 or 21 of SEQ ID NO:
- 626 or at the N-terminus, or a side chain of an amino acid at position 1, 5, 12 or 21 of SEQ ID NO:
- 628;
- further wherein
- X5 is HO-glycine, glycine or desamino-glycine;
- X6 is glutamic acid, serine or threonine;
- X7 is threonine, histidine, arginine or lysine;
- X8 is asparagine, serine, threonine or glycine;
- X9 is serine or threonine;
- X10 is aspartic acid, glutamic acid, homocysteic acid or cysteic acid
- X11 and X12 are independently selected from the group consisting of tyrosine, phenylalanine and 4-hydroxymethyl Phe;
- X13 is selected from the group consisting of FVNQX50 (SEQ ID NO:
- 1119), VNQX50 (SEQ ID NO:
- 1120), NQX50, QX50, and X50, wherein X50 is histidine, serine or threonine, further wherein the first amino acid of X13 is an O-amino acid;
- R1 and R2 are independently selected from the group consisting of H, C1-C4 alkyl, (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, (C4-C6)cycloalkyl, (C0-C4 alkyl)(C6-C10 aryl)R9, and CH2(C5-C9 heteroaryl),
- R5 is OH or NH2 and R9=C1-C4 alkyl, NH2 or OH.
Dependencies are inferred from the claim text.