Truncated glp-1 derivaties and their therapeutical use
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a technology of truncated glucagon and derivate, which is applied in the field of new truncated glucagonlike peptide1 (glp1) analogues, can solve the problems that the fear of injection may become a serious obstacle to the widespread use of clinically very promising compounds
Inactive Publication Date: 2010-11-18
NOVO NORDISK AS
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Problems solved by technology
In the type 2 diabetes segment most patients are treated with oral hypoglycaemic agents, and since GLP-1 compounds are expected to be an injectable pharmaceutical
Method used
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example 1
[Glu22,Arg26]GLP-1(7-33)amide
[0782]
H—H A E G T F T S D V S S Y L E E Q A A R E F I A W L V—NH2
[0783]Preparation method: B
[0784]The peptide was eluted at 64% acetonitrile.
[0785]Structure confirmed by MALDI-MS
[0786]Calculated MW=3056.4
example 2
N epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Val25,Arg26,Leu27,Glu30,Lys33)GLP-1(7-33)amide
[0787]
[0788]Preparation method: Method C except that the peptide was prepared on an Apex396 from Advanced Chemtech using a molar excess of 8-10 fold amino acid, DIC and HOAt / HOBt (1:1) and the Mtt group was deprotected with hexaflouroisopropanol. The final product was characterized by analytical HPLC and MALDI-MS.
[0789]HPLC (METHOD 02_B6—1):
[0790]RT=32 min
[0791]MALDI-MS=3901
[0792]Calculated MW=3900.5
example 3
N epsilon20 {2-(2-{2-[2-(2-{2-[4-Carboxy-4-(17-carboxy-heptadecanoylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl}-(Aib8,Lys20,Glu22,Arg26,Glu30)GLP-1(7-33)amide
[0793]
[0794]Preparation method: Method C except that the peptide was prepared on an Apex396 from Advanced Chemtech using a molar excess of 8-10 fold amino acid, DIC and HOAt / HOBt (1:1) and the Mtt group was deprotected with hexaflouroisopropanol. The final product was characterized by analytical HPLC and MALDI-MS.
[0795]HPLC (METHOD 02_B6—1):
[0796]RT=32.9 min
[0797]MALDI-MS=3858.7
[0798]Calculated MW=3859.3
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Abstract
The invention relates to truncated GLP-1 analogues, in particular a GLP-1 analogue which is a modified GLP-1(7-35) (SEQ ID No 1) having: i) a total of 2, 3, 4, 5 6, 7, 8, or 9 amino acid substitutions as compared to GLP-1(7-35), including a) a Glu residue at a position equivalent to position 22 of GLP-1(7-35), and b) an Arg residue at a position equivalent to position 26 of GLP-1(7-35); as well as derivatives thereof, and therapeutic uses and compositions. These analogues and derivatives are highly potent, have a good binding affinity to the GLP-1 receptor, also to the extracellular domain of the GLP-1 receptor, which is of potential relevance achieving long-acting, stable GLP-1 compounds with a potential for once weekly administration.
Description
FIELD OF THE INVENTION[0001]This invention relates to the field of therapeutic peptides, i.e. to new truncated Glucagon-Like Peptide-1 (GLP-1) analogues and derivatives thereof.BACKGROUND OF THE INVENTION[0002]A range of different approaches have been used for modifying the structure of glucagon-like peptide 1 (GLP-1) compounds in order to provide a longer duration of action in vivo.[0003]WO 2006 / 097538, WO 2006 / 097536, WO 2006 / 037810, WO2006005667, WO 2005 / 027978. WO 98 / 08871 and US 2001 / 0011071 describes various GLP-1 analogues and derivatives thereof.[0004]Runge et al (Journal of Biological Chemistry, vol. 283, no. 17, pp. 11340-11347), which was published after the priority dates of the present invention, discloses the crystal structure of the extracellular domain of the ligand-bound GLP-1 receptor.[0005]Many diabetes patients particularly in the type 2 diabetes segment are subject to so-called “needle-phobia”, i.e. a substantial fear of injecting themselves. In the type 2 diabe...
Claims
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