GLP-1 and FGF21 combinations for treatment of diabetes type 2

A GLP-1, FGF21 technology, applied in the field of type 2 diabetes drugs, can solve problems such as unsupported

Inactive Publication Date: 2012-11-28
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

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  • GLP-1 and FGF21 combinations for treatment of diabetes type 2
  • GLP-1 and FGF21 combinations for treatment of diabetes type 2
  • GLP-1 and FGF21 combinations for treatment of diabetes type 2

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0217] Embodiment 1: Preparation of GLP-1 derivatives

[0218] The following GLP-1 compounds (both derivatives of analogs of GLP-1(7-37) (SEQ ID NO: 3)) were prepared:

[0219] Compound G1 :

[0220] N-ε26-((S)-4-carboxy-4-hexadecanoylaminobutyryl)[Arg34]GLP-1-(7-37), which can also be named Arg 34 Lys 26 (Nε-(γ-glutamyl (Nα-hexadecanoyl)))-GLP-1(7-37)-OH

[0221]

[0222] Compound G2 :

[0223] N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-({trans-4-[(19-carboxynonadecanoylamino) -methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][deaminoHis7, Glu22, Arg26, Arg34, Lys37] GLP-1-(7-37):

[0224]

[0225] Compound G3 :

[0226] N-ε26-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy} Ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8, Arg34]GLP-1-(7-37):

[0227]

[0228] Compound G4 :

[0229] N-ε37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-(15-carboxypentadecylamino)butyrylamino]ethoxy} Et...

Embodiment 2

[0243] Embodiment 2: Preparation of FGF21 compound

[0244] The following FGF21 compounds were prepared:

[0245] Compound F1 :

[0246] Native human FGF21 (SEQ ID NO: 1 ), but with an N-terminal Met due to expression in E. coli, Met-FGF21_human.

[0247] Compound F2 :

[0248] The S71C analog of compound F1 is modified at position 71 with the following reagents:

[0249]

[0250]Compound S-71-({2-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(19-carboxynonadecanoylamino)butanoyl) Amino]ethoxy}ethoxy)acetamido]ethoxy}ethoxy)acetamido]ethylcarbamoyl}methyl)[Cys71]Met-FGF21.

[0251] Compound F3 :

[0252] The K56R, K59R, K69R, K122R analogs of compound F1 were modified at the N-terminal Met residue with the following reagents:

[0253]

[0254] Compound N-α1-[2-(2-{2-[2-(2-{2-[(S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyrylamino]ethoxy Base}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Arg56, Arg59, Arg69, Arg122]-Met-FGF21.

[0255] Compounds F1, F2 and F3 were prepa...

Embodiment 3

[0305] Example 3: Ex vivo repair of glucose-stimulated insulin release

[0306] This ex vivo example investigates the ability of islets of diabetic db / db mice to restore the ability to release insulin in response to glucose stimulation in response to treatment with FGF21 and GLP-1 compounds.

[0307] Islets from 25 15-week-old db / db mice (Charles River) were isolated according to the following procedure:

[0308] Animals were sacrificed by cervical dislocation and pinned to Styrofoam plates. The pancreas was removed and transferred to a Packard vial containing 5 ml of collagenase (Life Science, Class II, Cat# 100502) (300 units / ml (one pancreas / vial)), which was kept on ice until all the pancreas was removed. The pancreas was then shaken in a Grant / Edmund S25 thermoshaker at 200 strokes / min for 5 minutes at 37°C. The tissue was transferred to a fresh vial containing 5 ml of 150 units / ml collagenase (supernatant discarded) and shaken again for 5 minutes on a thermostatic shak...

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Abstract

The invention relates to the use of a Fibroblast Growth Factor 21 (FGF21 ) compound and a Glucagon-Like Peptide 1 (GLP-1 ) compound in combination for the preparation of a medicament for the treatment of diabetes, more in particular type 2 diabetes, as well as pharmaceutical compositions comprising certain FGF21 and GLP-1 compounds in combination, together with a pharmaceutically acceptable carrier. The combination has a significant effect on parameters of relevance for diabetes type 2, viz. on the viability of [beta] cells ex vivo in the presence of free fatty acids, on caspase activity of [beta] cells ex vivo (a measure of cell apoptosis), and a blood glucose lowering effect on db / db mice in vivo.

Description

field of invention [0001] The present invention relates to the use of a fibroblast growth factor 21 (FGF21) compound and a glucagon-like peptide 1 (GLP-1) compound in combination for preparing a medicament for treating diabetes, more particularly type 2 diabetes. [0002] The present invention also relates to pharmaceutical compositions comprising certain combinations of FGF21 compounds and GLP-1 compounds and a pharmaceutically acceptable carrier. Background of the invention [0003] Fibroblast growth factors are polypeptides expressed in developing and mature tissues. It is involved in several physiological mechanisms including, for example, metabolic regulation and cell differentiation. There are more than twenty fibroblast growth factors in the entire family (FGF family). Three members of the FGF family including FGF19, FGF21 and FGF23 form a subfamily that functions as endocrine factors involved in metabolic regulation. [0004] FGF21 is preferentially expressed in t...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/18A61K38/26A61P3/10A61K47/48
CPCA61K38/26C07K14/50A61K38/1825A61K47/48046A61K47/543A61K2300/00A61P3/10
Inventor B·安德森A·M·K·汉森B·C·罗林
Owner NOVO NORDISK AS
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