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Novel GLP-1 compounds

a technology of insulionotropic peptides and compounds, applied in the field of new glp1 compounds, can solve the problems of insufficient bioavailability of analogs and derivatives of insulionotropic peptides when administered by pulmonary rou

Inactive Publication Date: 2007-02-22
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, these analogues and derivatives of insulionotropic peptides lack a satisfactory bioavailability when administered by the pulmonary route, i.e. when administered to the lower respirary tract such as through the bronchioles or alveoli.
Patients and to some extent also doctors are often not keen on initiating insulin treatment before this is absolutely necessary, presumably because of the fear of hypoglycaemic events or the fear of injections / needles.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

Preparation of Nε37-(3-(mPEGyl)propionyl)[Aib8,22,35,Lys37]GLP-1(7-37) amide wherein mPEGyl is Polydisperse and has a Molecular Weight of Approximately 2 kDa

[0781]

1.a Synthesis of the Protected Peptidyl Resin.

[0782] Boc-His(Boc)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)-Asp(OtBu)-Val-Ser(tBu)Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Aib-Gln(Trt)-Ala-Ala-Lys(Boc)-Glu(OtBu)-Phe-Ile-Ala-Trp(Boc)-Leu-Val-Lys(Boc)-Aib-Arg(Pmc)-Lys(Dde)-Rink amide resin was prepared according to the Fmoc strategy on an Applied Biosystems 433A peptide synthesizer in 0.25 mmol scale using the manufacturer supplied FastMoc UV protocols which employ HBTU mediated couplings in NMP, and UV monitoring of the deprotection of the Fmoc protection group. To improve the coupling efficiency, Aib residues and residues following Aib, these residues were coupled using HATU instead of HBTU as the coupling reagent. The starting resin (438 mg) used for the synthesis was 4-(2′,4′-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxy res...

example 2

Nε37-(3-(mPEGyl)propionyl)[Aib8,22,35,Lys37]GLP-1(7-37) wherein mPEGyl is Polydisperse and has a Molecular Weight of Approximately 5 kDa

[0791]

2.a Synthesis of the Protected Peptidyl Resin

[0792] The protected peptidyl resin Boc-His(Boc)-Aib-Glu(OtBu)-Gly-Thr(tBu)-Phe-Thr(tBu)-Ser(tBu)Asp(OtBu)-Val-Ser(tBu)-Ser(tBu)-Tyr(tBu)-Leu-Glu(OtBu)-Aib-Gln(Trt)-Ala-Ala-Lys(Boc)Glu(OtBu)-Phe-Ile-Ala-Trp(Boc)-Leu-Val-Lys(Boc)-Aib-Arg(Pmc)-Lys(Dde)-2-Chlorotrityl resin was synthesized using the procedures in example 1.a. with the exception that the starting resin was 337 mg of (2S)-6-[1-(4,4-Dimethyl-2,6-dioxocyclohexylidene)ethylamino]-2-(((9H-fluoren-9-yl)methoxycarbonyl)amino)hexanoyl 2-Chlorotrityl resin (Fmoc-Lys(Dde)-2-ClTrt resin). This Fmoc-Lys(Dde)-2-ClTrt resin was prepared by suspending 1 g of 2-Chlorotrityl chloride resin (Bachem, Switzerland. cat. #: D-1965), having a substitution capacity of 1.15 mmol / g in a mixture of 10 ml DCM and 100 μl DMF. To this was added 533 mg Fmoc-Lys(Dd...

example 3

Nε37-(3-(mPEGyl)propionyl)[Aib8,22,35,Lys37]GLP-1(7-37) wherein mPEGyl is Polydisperse and has a Molecular Weight of Approximately 20 kDa

[0798]

[0799] This compound was prepared from 100 mg of crude protected peptide from 2.b using procedures similar to those in example 2.c and 2.b with the major exception that 400 mg 100 mg mPEG-20000-SPA (mPEG-SPA m.w. 20.000 Lot PT-05C-11, Shearwater, Ala., USA) was used for the pegylation.

[0800] The final product obtained was characterized as follows:

Analytical methodResultHPLC A1r.t.: 47.62 min.HPLC B6r.t.: 34.47 min.Maldi TOF MSThe mass spectrum displays a cluster of peaks withan average mass 25304 Da. This is in agreementwith the expected structure of the target compound.

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Abstract

Novel GLP-1 compounds and their therapeutic use.

Description

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS [0001] This application is a continuation International Patent Application No. PCT / DK2004 / 00886 filed Dec. 17, 2004 and claims priority of U.S. Patent Application Nos. 60 / 531,053, filed Dec. 19, 2003, and 60 / 587,181, filed Jul. 12, 2004 and Danish Patent Application Nos. PA 2003 01885, filed Dec. 18, 2003 and PA 2004 01090, filed Jul. 9, 2004.FIELD OF THE INVENTION [0002] The present invention relates to novel GLP-1 compounds, to pharmaceutical compositions comprising these compounds and to the use of the compounds for the treatment of diseases related to diabetes. BACKGROUND OF THE INVENTION [0003] Diabetes mellitus is a metabolic disorder in which the ability to utilize glucose is partly or completely lost. About 5% of all people suffer from diabetes and the disorder approaches epidemic proportions. Since the introduction of insulin in the 1920's, continuous efforts have been made to improve the treatment of diabetes mellitus. [0004] ...

Claims

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Application Information

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IPC IPC(8): A61K38/22C07K14/575A61K38/00A61K38/26C07K14/605
CPCA61K38/00C07K14/605C07K14/57563A61P1/00A61P1/04A61P1/14A61P25/00A61P25/28A61P3/00A61P3/10A61P3/04A61P3/06A61P5/48A61P9/00A61P9/10A61P9/12
Inventor JOHANSEN, NILS LANGELANDLAU, JESPERMADSEN, KJELDHANSEN, THOMAS KRUSESTURIS, JEPPE
Owner NOVO NORDISK AS
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