Amide based glucagon superfamily peptide prodrugs

• US 8,778,872 B2
• Filed: 06/14/2011
• Issued: 07/15/2014
• Est. Priority Date: 06/24/2010
• Status: Active Grant

• Current Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Original Assignee: Indiana University Research & Technology Corporation (Indiana University)
• Inventors: DiMarchi, Richard D., Kou, Binbin
• Primary Examiner(s): Skowronek, Karlheinz R
• Assistant Examiner(s): Mader, Catherine
• Application Number:
  US13/697,021
• Publication Number:
  US 20130123462A1
• Time in Patent Office: 1,127 Days
• US Class Current: 514/1.3
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/08 for glucose homeostasis pancreatic hormones A61P5/48
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 5/00 Drugs for disorders of the endocrine system
• CPC Class Codes: C07K 14/605 Glucagons

Abstract

Prodrug formulations of glucagon superfamily peptides are provided wherein the glucagon superfamily peptide has been modified by the linkage of a dipeptide to the glucagon superfamily through an amide bond linkage. The prodrugs disclosed herein have extended half lives and are converted to the active form at physiological conditions through a non-enzymatic reaction driven by chemical instability.

Claims

1. A prodrug comprising the structure:

A-B-Q;

wherein Q is a glucagon superfamily peptide;

wherein A-B comprises the structure;

2. The prodrug of claim 1, wherein for structure (I), B is selected from the group consisting of glycine(N-methyl), glycine(N-ethyl), glycine(N-propyl), glycine(N-butyl), glycine(N-pentyl), glycine(N-hexyl), glycine(N-heptyl), and glycine(N-octyl).

3. The prodrug of claim 1, wherein for structure (II), R₄ is selected from the group consisting of CH₃, CH₂(C₁-C₄ alkyl), CH₂(C₁-C₄) alkenyl, CH₂(C₀-C₄ alkyl)OH, CH₂(C₀-C₄ alkyl)SH, CH₂(C₀-C₃ alkyl)SCH₃, CH₂(C₀-C₃ alkyl)CONH₂, CH₂(C₀-C₃ alkyl)COOH, CH₂(C₀-C₄ alkyl)NH₂, and CH₂(C₀-C₃ alkyl)NHC(NH₂⁺)NH₂.

4. The prodrug of claim 3, wherein B is selected from the group consisting of alanine(N—

C₁-C₁₀alkyl), leucine(N—

C₁-C₁₀alkyl), methionine(N—

C₁-C₁₀alkyl), asparagine(N—

C₁-C₁₀alkyl), glutamic acid(N—

C₁-C₁₀alkyl), aspartic acid(N—

C₁-C₁₀alkyl), glutamine(N—

C₁-C₁₀alkyl), histidine(N—

C₁-C₁₀alkyl), lysine(N—

C₁-C₁₀alkyl), arginine(N—

C₁-C₁₀alkyl), serine(N—

C₁-C₁₀alkyl), cysteine(N—

C₁-C₁₀alkyl), alanine(N—

C₁-C₆alkyl), leucine(N—

C₁-C₆alkyl), methionine(N—

C₁-C₆alkyl), asparagine(N—

C₁-C₆alkyl), glutamic acid(N—

C₁-C₆alkyl), aspartic acid(N—

C₁-C₆alkyl), glutamine(N—

C₁-C₆alkyl), histidine(N—

C₁-C₆alkyl), lysine(N—

C₁-C₆alkyl), arginine(N—

C₁-C₆alkyl), serine(N—

C₁-C₆alkyl), cysteine(N—

C₁-C₆alkyl), alanine(N-methyl), leucine(N-methyl), methionine(N-methyl), asparagine(N-methyl), glutamic acid(N-methyl), aspartic acid(N-methyl), glutamine(N-methyl), histidine(N-methyl), lysine(N-methyl), arginine(N-methyl), serine(N-methyl), and cysteine(N-methyl).

5. The prodrug of claim 1, wherein for structure (II), R₄ is selected from the group consisting of 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), CH₂(C₀-C₁₂ alkyl)(W₁)C₁-C₁₂ alkyl, wherein W₁ is a heteroatom selected from the group consisting of N, S and O, and wherein R₇ is selected from the group consisting of H and OH.

6. The prodrug of claim 5 wherein B is selected from the group consisting of phenylalanine(N—

C₁-C₁₀alkyl), tyrosine(N—

C₁-C₁₀alkyl), tryptophan (N—

C₁-C₁₀alkyl), phenylalanine(N—

C₁-C₆alkyl), tyrosine(N—

C₁-C₆alkyl), and tryptophan(N—

C₁-C₆alkyl), phenylalanine(N-methyl), tyrosine(N-methyl), and tryptophan(N-methyl).

7. The prodrug of claim 1, wherein for structure (III), R₄ is CH(C₁-C₈ alkyl)₂ or CH(C₁-C₈ alkyl)OH.

8. The prodrug of claim 7, wherein B is selected from the group consisting of isoleucine(N—

C₁-C₁₀alkyl), valine(N—

C₁-C₁₀alkyl), threonine(N—

C₁-C₁₀alkyl), isoleucine(N—

C₁-C₆alkyl), valine(N—

C₁-C₆alkyl), threonine(N—

C₁-C₆alkyl), isoleucine(N-methyl), valine(N-methyl), and threonine(N-methyl).

9. The prodrug of claim 1, wherein the aliphatic amino group is the alpha amino group on the N-terminal amino acid of Q or an aliphatic amino group on a side chain of Q.

10. The prodrug of claim 1, wherein for structure (IV), B is selected from the group consisting of glycine(N-methyl), glycine(N-ethyl), glycine(N-propyl), glycine(N-butyl), glycine(N-pentyl), glycine(N-hexyl), glycine(N-heptyl), and glycine(N-octyl).

11. The prodrug of claim 1, wherein for structure (V), R₄ is selected from the group consisting of CH₃, CH₂(C₁-C₄ alkyl), CH₂(C₁-C₄) alkenyl, CH₂(C₀-C₄ alkyl)OH, CH₂(C₀-C₄ alkyl)SH, CH₂(C₀-C₃ alkyl)SCH₃, CH₂(C₀-C₃ alkyl)CONH₂, CH₂(C₀-C₃ alkyl)COOH, CH₂(C₀-C₄ alkyl)NH₂, CH₂(C₀-C₃ alkyl)NHC(NH₂⁺)NH₂.

12. The prodrug of claim 11, wherein B is selected from the group consisting of alanine(N—

C₁-C₁₀alkyl), leucine(N—

C₁-C₁₀alkyl), methionine(N—

C₁-C₁₀alkyl), asparagine(N—

C₁-C₁₀alkyl), glutamic acid(N—

C₁-C₁₀alkyl), aspartic acid(N—

C₁-C₁₀alkyl), glutamine(N—

C₁-C₁₀alkyl), histidine(N—

C₁-C₁₀alkyl), lysine(N—

C₁-C₁₀alkyl), arginine(N—

C₁-C₁₀alkyl), serine(N—

C₁-C₁₀alkyl), and cysteine(N—

C₁-C₁₀alkyl), -alanine(N—

C₁-C₆alkyl), leucine(N—

C₁-C₆alkyl), methionine(N—

C₁-C₆alkyl), asparagine(N—

C₁-C₆alkyl), glutamic acid(N—

C₁-C₆alkyl), aspartic acid(N—

C₁-C₆alkyl), glutamine(N—

C₁-C₆alkyl), histidine(N—

C₁-C₆alkyl), lysine(N—

C₁-C₆alkyl), arginine(N—

C₁-C₆alkyl), serine(N—

C₁-C₆alkyl), cysteine(N—

C₁-C₆alkyl), alanine(N-methyl), leucine(N-methyl), methionine(N-methyl), asparagine(N-methyl), glutamic acid(N-methyl), aspartic acid(N-methyl), glutamine(N-methyl), histidine(N-methyl), lysine(N-methyl), arginine(N-methyl), serine(N-methyl), and cysteine(N-methyl).

15. The prodrug of claim 1, wherein for structure (VI), R₄ is CH(C₁-C₈ alkyl)₂ or CH(C₁-C₈ alkyl)OH.

16. The prodrug of claim 15, wherein B is selected from the group consisting of isoleucine(N—

C₁-C₁₀alkyl), valine(N—

C₁-C₁₀alkyl), and threonine(N—

C₁-C₁₀alkyl), isoleucine(N—

C₁-C₆alkyl), valine(N—

C₁-C₆alkyl), threonine(N—

C₁-C₆alkyl), isoleucine(N-methyl), valine(N-methyl), and threonine(N-methyl).

17. The prodrug of claim 1, wherein R₁ and R₂ are independently selected from the group consisting of C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, (C₁-C₁₀ alkyl)OH, (C₁-C₁₀ 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, and wherein R₇ is selected from the group consisting of H and OH.

18. The prodrug of claim 17, wherein A is aminoisobutyric acid.

19. The prodrug of claim 1, wherein R₁ is H and R₂ is selected from the group consisting of H, C₁-C₁₀ alkyl, C₂-C₁₀ alkenyl, (C₁-C₁₀ alkyl)OH, (C₁-C₁₀ 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 R₇ is selected from the group consisting of H and OH, 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 R₂ and R₅ together with the atoms to which they are attached form a 4, 5 or 6 member heterocyclic ring.

20. The prodrug of claim 19, wherein A is selected from the group consisting of lysine, cysteine, and alanine.

21. The prodrug of claim 19, wherein A has d-stereochemistry.

22. The prodrug of claim 1, wherein A-B is selected from the group consisting of Aib-Gly(N-Hexyl), dLys-Gly(N-Hexyl), dCys-Gly(N-Hexyl), dAla-Gly(N-Hexyl), Aib-Gly(N-Methyl), dLys-Gly(N-Methyl), dCys-Gly(N-Methyl), dAla-Gly(N-Hexyl), Aib-Phe(N-Methyl), dLys-Phe(N-Methyl), dCys-Phe(N-Methyl), or dAla-Phe(N-Methyl).

23. The prodrug of claim 1 wherein Q is selected from the group consisting of SEQ ID NOs:

1-564, 566-570, 573-575, 577, 579-580, 585-612, 616, 618-632, 634-642, 647, 657-684, 701-732, 742-768, 801-878, 883-919, 1001-1262, 1301-1371, 1401-1518, 1701-1708, 1710, 1711, 1731-1734, 1738, 1740, 1741, 1745, and 1747-1776.

24. The prodrug of claim 1, further comprising a hydrophilic moiety covalently linked to the prodrug.

25. The prodrug of claim 1, further comprising an acyl group or alkyl group covalently linked to the prodrug.

13. The prodrug of 1, wherein for structure (V), R₄ is selected from the group consisting of 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, and wherein R₇ is selected from the group consisting of H and OH.

14. The prodrug of claim 13 wherein B is selected from the group consisting of phenylalanine(N—

C₁-C₁₀alkyl), tyrosine(N—

C₁-C₁₀alkyl), tryptophan(N—

C₁-C₁₀alkyl), phenylalanine(N—

C₁-C₆alkyl), tyrosine(N—

C₁-C₆alkyl), tryptophan(N—

C₁-C₆alkyl)phenylalanine(N-methyl), tyrosine(N-methyl), and tryptophan(N-methyl).