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Novel glp-1 derivatives

A technology for albumin and compounds, applied in the field of albumin-binding derivatives of therapeutic peptides

Active Publication Date: 2006-11-22
NOVO NORDISK AS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this high variability in the plasma half-life of peptides, proteins, or other compounds is not fully understood

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0564] N ε37 -(2-(2-(2-(Dodecylamino)ethoxy)ethoxy)acetyl)-[Aib 8，22，35 Lys 37 ]GLP-1(7-37)amide

[0565]

[0566] The initial sequence was generated using the resin (Rink amide, 0.68 mmol / g, Novabiochem, 0.25 mmole) on an ABI433A machine following the manufacturer's instructions. All protecting groups are acid labile with the exception of the residue used at position 37 (Fmoc-Lys(ivDde)-OH, Novabiochem), allowing specificity for this lysine but not any other lysine. off protection.

[0567] process

[0568] The resin (0.25 mmole) containing the GLP-1 analog amino acid sequence prepared above was placed in a manual shaker / filter device, and was treated with 2% hydrazine dissolved in N-methylpyrrolidone (2×20ml, 2×12min ) to remove the DDE group, followed by washing with N-methylpyrrolidone (4×20 ml). Fmoc-8-amino-3,6-dioxoctanoic acid (Neosystem FA03202) (4 molar equivalents relative to the resin) was dissolved in N-methylpyrrolidone / dichloromethane (1:1, 20 ml). Hyd...

Embodiment 2

[0573] N ε37 -(2-(2-(2-(17-Sulfohexadecanoylamino)ethoxy)ethoxy)acetyl)-[Aib 8，22，35 , Lys 37 ]GLP-1(7-37)amide

[0574]

[0575] Compounds were prepared according to the methods in Example 1 and "General Synthetic Methods".

[0576] HPLC: (Method A1): RT=45.5min

[0577] LCMS: m / z=792.9 (M+5H) 5+ ,990.9(M+4H) 4+ , 1320.9(M+3H) 3+ , Calculated (M+H) + =3959.9

Embodiment 3

[0579] N ε37 -{2-[2-(2-(15-Carboxypentadecanoylamino)ethoxy)ethoxy]acetyl}-[Aib 8，22，35 , Lys 37 ]GLP-1(7-37)amide

[0580]

[0581] Compounds were prepared according to the methods in Example 1 and "General Synthetic Methods".

[0582] HPLC: (Method B1): RT=43.8min

[0583] HPLC: (Method A1): RT=42.0min

[0584] LCMS: m / z=978.3 (M+4H) 4+ , 1303.8(M+3H) 3+ , Calculated (M+H) + =3909.6

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Abstract

Novel polypeptide derivatives having protracted profile of action. The present invention relates to a compound which comprises a therapeutic polypeptide linked to an albumin binding residue via a hydrophilic spacer. The present invention also relates to a compound which comprises a therapeutic polypeptide linked to an albumin binding residue via a hydrophilic spacer that separates the polypeptide and the albumin binding residue with a chemical moiety comprising at least 5 non-hydrogen atoms where 30-50% of these atoms are either N or O. In one embodiment of this invention the spacer is defined as -(CH2)lD[(CH2)nE]m(CH2)pQq-, wherein l, m and n independently are 1-20 and p is 0-10, Q is -Z-(CH2)lD[(CH2)nG]m(CH2)p-, q is an integer in the range from 0 to 5, each D, E and G independently are selected from -O-, NR<3>-, -N(COR<4>)-, -PR<5>(O)-, and -P(OR<6>)(O)-, wherein R<3>, R<4>, R<5>, and R<6> independently represent hydrogen or C1-6-alky, Z is selected from -C(O)NH-, -C(O)NHCH2-, -OC(O)NH-, -C(O)NHCH2CH2-, -C(O)CH2-, -C(O)CH=CH-, -(CH2)s-, -C(O)-, -C(O)O- or -NHC(O)-, wherein s is 0 or 1.

Description

field of invention [0001] The present invention relates to novel derivatives of glucagon-like polypeptide-1 (GLP-1) and fragments thereof, analogs of these fragments having protracted action properties, and methods of producing and using them. The present invention also relates to novel derivatives of exendin and uses thereof. Background of the invention [0002] Peptides are widely used in medical practice, and since they can be produced by recombinant DNA techniques, their importance is expected to increase in the coming years. When natural peptides or their analogs are used therapeutically, they are generally found to have higher clearance. In cases where it is desired to maintain high blood levels of a therapeutic agent for an extended period of time, high clearance is inconvenient because of the need for repeated administrations. Examples of peptides with high clearance are ACTH, corticotropin releasing factor, angiotensin, calcitonin, insulin, g...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K47/62
Inventor J·劳T·K·汉森K·马德森P·布罗奇F·Z·迪尔沃德N·L·乔安森
Owner NOVO NORDISK AS
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