Peptide conjugates of GLP-1 receptor agonists and gastrin and their use

Patent metadata

Field	Value
Publication number	US-9649362-B2
Application number	US-201514735738-A
Country	US
Kind code	B2
Filing date	Jun 10, 2015
Priority date	Apr 27, 2010
Publication date	May 16, 2017
Grant date	May 16, 2017

Abstract

The present invention relates, inter alia, to certain peptide conjugates, and to the use of the conjugates in the treatment of a variety of diseases or disorders, including diabetes (type 1 and/or type 2) and diabetes-related diseases or disorders.

First claim

The invention claimed is:

1. A peptide conjugate or pharmaceutically acceptable salt thereof having the formula
R 1 —Z a -L-Y a —R 2

wherein
R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;
R 2 is OH or NH 2 ;
Z a is a peptide sequence having the formula IIIa

(IIIa)

His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Z9-Leu-Ser-Z12-

Z13-Z14-Glu-Z16-Glu-Ala-Val-Z20-Leu-Phe-Ile-Z24-

Z25-Leu-Z27-Z28 

wherein
Z9 is selected from Asp and Glu;
Z12 is selected from Lys, Arg and Orn;
Z13 is selected from Gln and Tyr;
Z14 is selected from Met and Leu;
Z16 is selected from Glu, Cys and Lys;
Z20 is selected from Arg, Lys and Orn;
Z24 is selected from Lys and Glu;
Z25 is selected from Trp, Lys, Cys and Phe;
Z27 is selected from Lys, Arg and Orn;
Z28 is selected from Asn and Asp or is absent;
L is a peptide sequence having the formula IIIb

(IIIb)

L1-L2-L3-L4 

wherein
L1 is selected from Peg3, Gln, Cys, Lys and Orn or is absent;
L2 is selected from Peg3, Gln, Cys, Lys and Orn or is absent;
L3 is selected from Peg3, Gln, Cys, Lys and Orn or is absent;
L4 is selected from Peg3, Gln, Cys, Lys and Orn or is absent;
Y a is a peptide sequence having the formula IIIc

(IIIc)

Y12-Y13-Y14-Y15-Asp-Y17 

wherein
Y12 is selected from Tyr and Ala or is absent;
Y13 is selected from Gly and Ala or is absent;
Y14 is selected from Trp, 1Nal and Phe;
Y15 is selected from Leu, Nle, Thr and Phe; and
Y17 is selected from Phe and 3-(3-Pyridyl)-alanine.

2. A peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 wherein Z12 is Lys and Z16 is Glu and said pair of residues form an intramolecular bridge.

3. A peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 , wherein the peptide of formula I is selected from the group consisting of:
Exendin-4(1-28)-[Leu4]Gastrin6  (SEQ ID NO: 28),

Exendin-4(1-28)-K-[Leu4]Gastrin6  (SEQ ID NO: 29),

Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 33),

Exendin-4(1-28)-Peg3-Peg3-[Leu3]Gastrin5  (SEQ ID NO: 55),

Exendin-4(1-28)-Peg3-Peg3-[Ala1,Leu4]Gastrin6  (SEQ ID NO: 56),

Exendin-4(1-28)-Peg3-Peg3-[Ala2,Leu4]Gastrin6  (SEQ ID NO: 57),

Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 58),

Exendin-4(1-28)-Peg3-Peg3-[Leu2]Gastrin4  (SEQ ID NO: 59),

[Leu14]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 60),

[Orn12]Exendin-4(1-28)-Peg3-Peg34Leu4Gastrin6  (SEQ ID NO: 61),

[Orn27]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 62),

[Phe25]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 63),

[Asp28]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 64),

[Tyr13]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 65),

[Orn20]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 66),

Exendin-4(1-28)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 67),

Exendin-4(1-28)-[Leu4]Gastrin6  (SEQ ID NO: 68),

Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 70),

Exendin-4(1-27)-Peg3-[Leu3]Gastrin5  (SEQ ID NO: 71),

Exendin-4(1-26)-Peg3-[Leu3]Gastrin5  (SEQ ID NO: 72),

Exendin-4(1-27)-Peg3-[Leu2]Gastrin4  (SEQ ID NO: 73),

[Tyr13,Leu14]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 74),

[Tyr13,Phe25]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 75),

[Leu14,Phe25]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 76),

[Tyr13,Leu14,Phe25]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 77),

Side chain-cyclo([Lys12,Glu16]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 78),

Side chain-cyclo([Glu16,Lys20]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 79),

Side chain-cyclo([Lys20,Glu24]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 80),

[Lys16]Exendin-4(1-28)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 81),

Exendin-4(1-28)-Peg3-K-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 82),

Exendin-4(1-28)-[Thr4]Gastrin6  (SEQ ID NO: 83),

Exendin-4(1-28)-[Phe4]Gastrin6  (SEQ ID NO: 84),

[Leu14]Exendin-4(1-28)-[1Nal3,Leu4]Gastrin6  (SEQ ID NO: 85),

[Leu14]Exendin-4(1-28)-[Nle4]Gastrin6  (SEQ ID NO: 86),

[Leu14]Exendin-4(1-28)-[Leu4,[3-(3-Pyridyl)-Ala]6]Gastrin6  (SEQ ID NO: 87),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 88),

[Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Peg3-[Leu4,Phe3]Gastrin6  (SEQ ID NO: 89),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Peg3-[Leu4,Phe3]Gastrin6  (SEQ ID NO: 90),

[Arg27,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 91),

[Arg12,27,Leu14,Lys16,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 92),

[Arg12,27,Leu14,Lys20,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 93),

[Arg12,27,Leu14,Lys24,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 94),

[Arg12,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 95),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-[Leu2]Gastrin4  (SEQ ID NO: 96),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu2]Gastrin4  (SEQ ID NO: 97),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Orn-Peg3-[Leu2]Gastrin4  (SEQ ID NO: 98),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Orn-[Leu2]Gastrin4  (SEQ ID NO: 99),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Orn-Orn-[Leu2]Gastrin4  (SEQ ID NO: 100),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-[Leu4]Gastrin6  (SEQ ID NO: 101),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 102),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Orn-Peg3-[Leu4]Gastrin6  (SEQ ID NO: 103),

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Peg3-Orn-[Leu4]Gastrin6  (SEQ ID NO: 104), and

[Glu9,Leu14,Phe25,Tyr13]Exendin-4(1-27)-Orn-Orn-[Leu4]Gastrin6  (SEQ ID NO: 105).

4. A method for treatment, in a subject in need thereof, of a disease or disorder selected from the group consisting of:
type 1 diabetes, type 2 diabetes, pre-diabetes, Insulin resistance syndrome, impaired glucose tolerance (IGT), disease states associated with elevated blood glucose levels, hyperglycemia, and metabolic syndrome,
the method comprising administering to said subject a therapeutically effective amount of a peptide conjugate or pharmaceutically acceptable salt thereof according to claim 1 .

5. A method according to claim 4 , wherein said subject is a human.

6. A pharmaceutical composition comprising a peptide conjugate, or pharmaceutically acceptable salt thereof, according to claim 1 , together with a pharmaceutically acceptable carrier, excipient or vehicle.

7. A method for preventing weight gain or promoting weight loss in an individual in n

Assignees

• Zealand Pharma As

Inventors

• Neerup Trine Skovlund Ryge
• Østerlund Torben
• Tolborg Jakob Lind
• Fosgerau Keld
• Martensson Ulrika
• Brorson Marianne
• Rolsted Kamilla

Classifications

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P9/14

  Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title