# US 10,308,700 B2 · GLP-1 derivatives

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- Number: US 10,308,700 B2
- Document ID: US10308700B2
- Status: Granted
- Kind: B2
- Application number: 15/404,808
- Filed: 2017-01-12
- Published: 2017-05-25
- Granted: 2019-06-04
- Earliest claimed: 2011-09-06
- Assignees: Novo Nordisk A/S
- Applicants: Novo Nordisk A/S
- Inventors: Jesper Lau; Paw Bloch; Jacob Kofoed; Patrick William Garibay
- Web page: https://patentgrep.com/patent/US10308700B2

## CPC

- C07K 14/605: Glucagons
- A61K 38/26: Glucagons
- A61P 1/04: for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
- A61P 1/14: Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
- A61P 3/06: Antihyperlipidemics
- A61P 3/10: for hyperglycaemia, e.g. antidiabetics
- A61P 5/48: of the pancreatic hormones
- A61P 7/00: Drugs for disorders of the blood or the extracellular fluid
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 15/08: for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
- 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)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The invention relates to a derivative of a GLP-1 peptide, which peptide has two Lys residues, namely a first and a second Lys residue, and a maximum of eight amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3), which derivative comprises two protracting moieties attached to the epsilon amino group of said first and second Lys residue, respectively, via a linker, wherein the protracting moiety is selected from Chem. 15: HOOC—(CH2)x—CO—*, and Chem. 16: HOOC—C6H4—O—(CH2)y—CO—*, in which x is an integer in the range of 10-16, and y is an integer in the range of 8-12; and the linker comprises a first linker element *—NH—CH(CH2OH)—CO—*. A preferred linker is gGlu-Ser-Ser-Gly-Ser-Ser-Gly (SEQ ID NO: 2). The derivative of the invention has a very good potency, and a very good binding to the GLP-1 receptor. The invention also relates to the pharmaceutical use of the derivative, for example in the treatment and/or prevention of all forms of diabetes and related diseases.

## Claims

### Claim 1

A derivative of a GLP-1 peptide, wherein the GLP-1 peptide has a sequence according to Formula I:
Xaa7-Xaa8-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa20-Glu-Xaa22-Xaa23-Ala-Xaa25-Xaa26-Xaa27-Phe-Ile-Xaa30-Xaa31-Leu-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38, wherein
Xaa7 is L-histidine, imidazopropionyl, α-hydroxy-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, Nα-acetyl-histidine, Nα-formyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine;
Xaa8 is Ala, Gly, Val, Leu, Ile, Thr, Ser, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid;
Xaa16 is Val or Leu;
Xaa18 is Ser or Lys;
Xaa19 is Tyr or Gln;
Xaa20 is Leu or Met;
Xaa22 is Gly, Glu, Lys, or Aib;
Xaa23 is Gln, Glu, or Arg;
Xaa25 is Ala or Val;
Xaa26 is Val, His, Lys, or Arg;
Xaa27 is Glu, Leu, or Lys;
Xaa30 is Ala, Glu, Lys, or Arg;
Xaa31 is Trp, Lys, or His;
Xaa33 is Val or Lys;
Xaa34 is Lys, Glu, Asn, Gly, Gln, His, Arg, or absent;
Xaa35 is Gly, Aib, or absent;
Xaa36 is Arg, Gly, Lys, or absent;
Xaa37 is Gly, Ala, Glu, Pro, Lys, Arg, or absent; and
Xaa38 is Ser, Gly, Ala, Glu, Pro, Lys, Arg, or absent;
which peptide has only two Lys residues designated a first and a second Lys residue, and a maximum of eight amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3),
which derivative comprises two protracting moieties where one protracting group is attached to the epsilon amino group of said first Lys residue, respectively, via a linker, and the other protracting group is attached to the epsilon amino group of said second Lys residue, respectively, via a linker, wherein
the protracting moiety is selected from Chem. 15, and Chem. 16:
HOOC—(CH2)x—CO—* Chem. 15:
HOOC—C6H4—O—(CH2)y—CO—*, Chem. 16:
in which x is an integer in the range of 10-16, and y is an integer in the range of 8-12; and
the linker comprises gGlu-Ser, wherein gGlu has the structure of Chem. 5:
and Ser has the structure of Chem. 1:
wherein the gamma carboxy group of gGlu is connected to the N-terminus of Ser in the first linker element;
or a pharmaceutically acceptable salt, amide, or ester of said derivative.

### Claim 2 (depends on 1)

The derivative of claim 1, wherein the linker further comprises Chem. 2:
or Chem. 7:

### Claim 3 (depends on 2)

The derivative of claim 2, wherein the linker comprises Chem. 3:

### Claim 4 (depends on 2)

The derivative of claim 2, wherein the linker comprises a Chem. 4:

### Claim 5 (depends on 1)

The derivative of claim 1, wherein the linker comprises Chem. 6:

### Claim 6 (depends on 5)

The derivative of claim 5, wherein the linker further comprises Chem. 12:
*—NH—(CH2)4—CH(NH2)—CO—*.

### Claim 7 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1 and a pharmaceutically acceptable excipient.

### Claim 8 (depends on 7)

A method for treating diabetes, obesity, binge eating, bulimia nervosa, cardiovascular diseases, gastrointestinal diseases, diabetic complications, critical illness poly-nephropathy (CIPNP), systemic inflammatory response syndrome (SIRS), bacteraemia, septicaemia, septic shock and/or polycystic ovary syndrome; and/or for improving lipid parameters, improving β-cell function, and/or for delaying or preventing diabetic disease progression in a subject in need of such treatment, said method comprising administering to said subject a pharmaceutically active amount of a compound according to claim 7.

### Claim 9 (depends on 1)

The derivative according to claim 1, wherein in the sequence of Formula I, Xaa18 and Xaa26 are each Lys.

### Claim 10 (depends on 9)

The derivative according to claim 9, wherein the GLP-1 peptide of Formula I has a maximum of four amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3).

### Claim 11 (depends on 10)

The derivative according to claim 10, wherein in the sequence of Formula I, Xaa34 is selected from Gln or Arg.

### Claim 12 (depends on 11)

The derivative according to claim 11, wherein in the sequence of Formula I, Xaa8 is Aib.

### Claim 13 (depends on 1)

The derivative according to claim 1, wherein in the sequence of Formula I, Xaa26 and Xaa37 are each Lys.

### Claim 14 (depends on 13)

The derivative according to claim 13, wherein the GLP-1 peptide of Formula I has a maximum of four amino acid changes as compared to GLP-1(7-37) (SEQ ID NO: 3).

### Claim 15 (depends on 14)

The derivative according to claim 14, wherein in the sequence of Formula I, Xaa34 is selected from Gln or Arg.

### Claim 16 (depends on 15)

The derivative according to claim 15, wherein in the sequence of Formula I, Xaa8 is Aib.