Search

US-12616739-B2 - GLP-1 prodrugs and uses thereof

US12616739B2US 12616739 B2US12616739 B2US 12616739B2US-12616739-B2

Abstract

The invention relates to DKP-based prodrugs. The invention also relates to the use of DKP-based prodrugs.

Inventors

  • Jesper F. Lau
  • Lennart Lykke
  • Bhavesh Premdjee
  • Cecilie Mia Joergensen

Assignees

  • NOVO NORDISK A/S

Dates

Publication Date
20260505
Application Date
20211105
Priority Date
20201106

Claims (20)

  1. 1 . A compound comprising A-Z (Formula I), wherein Z comprises a GLP-1 polypeptide; wherein A is of Formula II: wherein X is of Formula III: (Formula III); wherein p is 1-5; and wherein Y comprises a lipophilic moiety comprising a distal carboxylic acid; or a pharmaceutical acceptable salt, ester or amide thereof.
  2. 2 . The compound according to claim 1 , wherein the N-terminal amino group of the GLP-1 polypeptide is linked to A via an amide bond.
  3. 3 . The compound according to claim 1 , wherein the N-terminal residue of the GLP-1 polypeptide is His.
  4. 4 . The compound according to claim 1 , wherein the GLP-1 polypeptide is a GLP-1 analogue comprising maximum of 2 amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 1).
  5. 5 . The compound according to claim 1 , wherein Z is semaglutide.
  6. 6 . The compound according to claim 1 , wherein the lipophilic moiety comprising a distal carboxylic acid is a moiety selected from the group consisting of wherein n is 12, 14, 16 or 18; and wherein m is 9 or 10.
  7. 7 . The compound according to claim 6 , wherein Y is
  8. 8 . The compound according to claim 1 , wherein Y is A 5 -A 4 -A 3 -A 2 -A 1 - (Formula IV); wherein A 1 , A 2 and A 3 are each absent or individually selected from the group consisting of and wherein A 5 is wherein n is 12, 14, 16 or 18; or wherein m is 9 or 10.
  9. 9 . The compound according to claim 8 , wherein the residues A 5 , A 4 , A 3 , A 2 , and A 1 are interconnected via amide bonds.
  10. 10 . The compound according to claim 1 , wherein the compound is a prodrug and Z is a parent drug, and wherein the prodrug to drug conversion half-life, determined in vitro at 37° C. and pH 7.4, is at least 3.0 days.
  11. 11 . The compound according to claim 1 , wherein the compound is a prodrug and Z is a parent drug, and wherein the observed terminal half-life of the parent drug, determined upon administration of the prodrug in mini-pigs, is >80 hours.
  12. 12 . The compound according to claim 1 , wherein the compound is selected from the group consisting of or a pharmaceutical acceptable salt, ester or amide thereof.
  13. 13 . A method for treating type 2 diabetes, comprising administering the compound according to claim 1 to a subject in need thereof.
  14. 14 . A method for treating type 2 diabetes, comprising administering the compound according to claim 12 to a subject in need thereof.
  15. 15 . A method for reducing body weight, comprising administering the compound according to claim 1 to a subject in need thereof.
  16. 16 . The method according to claim 15 , wherein the subject is suffering from obesity.
  17. 17 . A method for reducing body weight, comprising administering the compound according to claim 12 to a subject in need thereof.
  18. 18 . The method according to claim 17 , wherein the subject is suffering from obesity.
  19. 19 . A method for treating a disease of the liver, comprising administering the compound according to claim 1 to a subject in need thereof, wherein the disease of the liver is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).
  20. 20 . A method for treating a disease of the liver, comprising administering the compound according to claim 12 to a subject in need thereof, wherein the disease of the liver is non-alcoholic fatty liver disease (NAFLD) or non-alcoholic steatohepatitis (NASH).

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a 35 U.S.C. § 371 National Stage application of International Application PCT/EP2021/080747 (WO2022/096636), filed Nov. 5, 2021, which claims priority to European Patent Application 20206198.2, filed Nov. 6, 2020 and European Patent Application 21182351.3, filed Jun. 29, 2021; the contents of which are incorporated herein by reference. INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING A computer-readable form of the sequence listing was indicated on the PCT Request as part of the International Application No. PCT/EP2021/080747 and the sequence listing was published as part of the International application. Thus, in accordance with PCT Rule 13ter.3 and 37 CFR 1.821-1.825, the sequence listing is not submitted herewith. TECHNICAL FIELD The invention relates to DKP-based prodrugs as well as the therapeutic use thereof. SEQUENCE LISTING The present application is filed with a Sequence Listing in electronic form. The entire content of the sequence listing is hereby incorporated by reference. BACKGROUND Prodrug technology may be used to generate compounds with properties suitable for a specific dosing frequency. Diketopiperazine (DKP) based prodrugs has previously been described (e.g. Arnab De, Richard D. DiMarchi, Investigation of the Feasibility of an Amide-based Prodrug Under Physiological Conditions, International Journal of Peptide Research and Therapeutics, 2008, Vol 14, 3, pp 255-262). This technology is based on a chemical conversion where a moiety consisting of two amino acids cyclize to form a six membered ring whereupon the active drug is liberated. WO2010/071807 allegedly discloses prodrug formulations of glucagon superfamily peptides wherein the peptide has been modified by linkage of a dipeptide through an amide bond linkage.WO2010/080605 allegedly discloses a non-enzymatically self-cleaving dipeptide element linked to known medical agents via an amide bondWO2011/163012 allegedly discloses prodrug formulations of glucagon superfamily peptides wherein the peptide has been modified by linkage of a dipeptide through an amide bond linkage.WO2013/127779 allegedly discloses ester prodrugs of insulinotropic peptides.WO2014/152460 allegedly discloses peptide-based prodrugs having significantly extended half-lives.WO2016/049174 allegedly discloses prodrug formulations of insulin and insulin analogues wherein the insulin peptide has been modified by an amide bond linkage of a dipeptide prodrug element.WO2011/089216 allegedly discloses dipeptide-based prodrugs for aliphatic amine-containing drugs. SUMMARY GLP-1 receptor agonists are widely used for treatment of chronic disease. Currently available oral GLP-1 receptor agonist medicaments must be administered once daily. A treatment regimen with less frequent dosing than once daily may lead to improved patient convenience and improved patient compliance, and consequently the development of oral GLP-1 receptor agonists suitable for dosing less frequently than once daily would constitute a significant improvement to the available treatment options. Prodrug technology may be employed to optimise the properties of a drug in a manner that makes it suitable for a specific dosing regimen, e.g. for once weekly dosing. The present invention relates to prodrugs with desirable properties, e.g. for once weekly oral dosing. In a first aspect the invention relates to a compound comprising Formula I: A-Z; wherein Z comprises a GLP-1 polypeptide, and wherein A is of Formula II: wherein X is of Formula III: wherein p=1-5 (Formula III); wherein Y comprises a lipophilic moiety with a distal carboxylic acid; or a pharmaceutical acceptable salt, ester or amide thereof. In a second aspect the invention relates to the prodrug of the invention for use as a medicament. In one functional aspect the invention provides for a prodrug that has a conversion half-life suitable for once-weekly dosing. Also or alternatively, in a another functional aspect the invention provides for a prodrug that has an observed terminal half-life suitable for once-weekly dosing. Also or alternatively, in another functional aspect the invention provides for a prodrug that has a surprisingly high oral bioavailability. The invention may also solve further problems that will be apparent from the disclosure of the exemplary embodiments. BRIEF DESCRIPTION OF DRAWINGS FIG. 1: Dose normalised plasma concentration (vs time) profiles of test compound following oral administration in Beagle dogs. DESCRIPTION In what follows, Greek letters may be represented by their symbol or the corresponding written name, e.g.: α=alpha; β=beta; ε=epsilon; γ=gamma; ω=omega; etc. Also, the Greek letter of μ may be represented by “u”, e.g. in μl=ul, or in μM=uM. The symbol * in a chemical formula or in a chemical drawing designates a point of attachment to a neighbouring moiety. In what follows, unless otherwise indicated in the specification, terms presented in singular form als