US 2017/0320927 A1Published application

GLP-1 Derivatives and Uses Thereof

AssigneeNovo Nordisk A/S

InventorsPer SAUERBERG, Jacob KOFOED

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Abstract

The invention relates to a derivative of a GLP-1 analogue of a general Formula I, which derivative comprises a side chain attached to a Lys residue at position 34, 35, 36, 37, or 38 of the GLP-1 analogue, which side chain comprises a Branched linker, a 1st and a 2nd Protractor selected from C18 diacid, C20 diacid, and sulfonic acid C16, and at least one Linker element-1 incorporating ethylene glycol units. Linker element-1 may be incorporated in an optional Pre-linker, and/or in a 1st or 2nd Post-linker. The invention also relates to novel GLP-1 analogues, novel side chain intermediate products and their manufacture and use to prepare derivatives of biologically active peptides and proteins, as well as pharmaceutical compositions and medical uses of the analogues and derivatives. The derivatives have very long half-lives while maintaining a satisfactory potency, which makes them potentially suitable for once-monthly administration.

A derivative of a GLP-1 analogue, where the GLP-1 analogue has the general Formula I:

Xaa7-Xaa8-Glu-Gly-Thr-Xaa12-Thr-Ser-Asp-Xaa16-Ser-Xaa18-Xaa19-Xaa28-Glu-Xaa22-Xaa23-Ala-Xaa25-Xaa26-Xaa27-Phe-Ile-Xaa30-Xaa31-Leu-Xaa33-Xaa34-Xaa35-Xaa36-Xaa37-Xaa38(SEQ ID NO:9), wherein
Xaa7 is L-histidine, (S)-2-Hydroxy-3-(1H-imidazol-4-yl)-propionic acid, D-histidine, deamino-histidine, homohistidine, Nα-acetyl-histidine, Nα-formyl-histidine, Nα-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine, or 4-pyridylalanine;
Xaa8 is Ala, Gly, Ser, Aib, (1-aminocyclopropyl) carboxylic acid, or (1-aminocyclobutyl) carboxylic acid;
Xaa12 is Phe or Leu;
Xaa16 is Val or Leu;
Xaa18 is Ser, Val, Arg, or Leu;
Xaa19 is Tyr or Gln;
Xaa20 is Leu or Met;
Xaa22 is Gly or Glu;
Xaa23 is Gln, Glu, or Arg;
Xaa25 is Ala or Val;
Xaa26 is Arg;
Xaa27 is Glu or Leu;
Xaa38 is Ala, Glu, or Arg;
Xaa31 is Trp or His;
Xaa33 is Val;
Xaa34 is Arg, His, Asn, Gln, or Lys;
Xaa35 is Gly, Ala, or Lys;
Xaa36 is Arg, Gly, or Lys;
Xaa37 is Gly, Pro, or Lys;
Xaa38 is Lys, or absent;
wherein at least one of Xaa34, Xaa35, Xaa36, Xaa37, and Xaa38 is Lys;
which derivative comprises a side chain that is attached to the Lys residue of Xaa34, Xaa35, Xaa36, Xaa37, or Xaa38;
which side chain comprises:
(i) a Branched linker of formula Chem. 11
wherein w is an integer in the range of 0-2;
(ii) a 1st and a 2nd Protractor selected from Chem. 12, Chem. 12a, and Chem. 13:
and
(iii) at least one Linker element-1 of Chem. 1:
wherein k is an integer in the range of 1-23, and n is an integer in the range of 1-5;
wherein the Branched linker is connected
a) at its —CO end to the epsilon amino group of the Lys residue of Xaa34, Xaa35, Xaa36, Xaa37, or Xaa38, via an optional Pre-linker, and
b) at each of its two —NH ends to the —CO end of each of the 1st and 2nd Protractor, respectively, via a 1st and a 2nd Post-linker, respectively;
and
wherein
if the Pre-linker is present it comprises the Linker element-1, or
if the Pre-linker is absent, each of the 1st Post-linker and the 2nd Post-linker comprises the Linker element-1;
or a pharmaceutically acceptable salt, amide, or ester thereof.

35 more elements

Facts

Application

15/531,105Filed 26 Nov 2015

Priority

EP 14195172.327 Nov 2014

Published

9 Nov 2017

Term ends

Not estimatedThe source records don’t support an estimate.

Classification36 codes

C07K 14/605
Hormones: glucagons
A61K 47/542
The modifying agent being an organic compound: carboxylic acids, e.g. a fatty acid or an amino acid
A61K 47/59
The modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule: obtained otherwise than by…
A61P 1/00
Drugs for disorders of the alimentary tract or the digestive system

Abstract

Claims15