IP Library › Granted Patent US 9,067,977

Granted Patent B2

US 9,067,977 · App. 13/930,079 · Granted Jun 30, 2015

Peptides derivatized with A-B-C-D- and their therapeutical use

Inventors: Jane Spetzler (Broenshoej, DK); Lauge Schaeffer (Lyngby, DK); Jesper Lau (Farum, DK); Thomas Kruse (Herlev, DK); Patrick William Garibay (Holte, DK); Soeren Oestergaard (Broenshoej, DK); Steffen Reedtz-Runge (Frederiksberg, DK); Henning Thoegersen (Farum, DK)

Assignee: Novo Nordisk A/S

C07K14/001 C07K14/00 C07K14/575 A61K38/16 A61K38/17 A61K38/22 A61K38/26 A61K47/48 A61K47/48007 A61K47/48023 A61K47/48169 A61K38/00 A61K47/48038 A61K47/48046 A61K47/48061 A61K47/48215 C07K14/57563 C07K14/605

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Quick Facts

Patent No.: US 9,067,977
App. No.: 13/930,079
Granted: Jun 30, 2015
Kind: B2

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Abstract

The invention relates to protracted peptide derivatives such as Glucagon-Like Peptide-1 (GLP-1), exendin-4, and analogs thereof, as well as therapeutic uses thereof. The peptide derivative of the invention comprises a peptide wherein at least one amino acid residue is derivatized with A-B-C-, or A-B-C-D-. These compounds are useful in the treatment or prevention of diabetes type 2 and related diseases. The compounds are potent, have a low ratio of binding affinity to the GLP-1 receptor in the presence of high/low albumin concentrations, have long half-lives, and have a high affinity of binding to albumin, all of which is of potential relevance for the overall aim of achieving long-acting, stable and active GLP-1 derivatives with a potential for once weekly administration.

Claims (201)

1. A peptide derivative comprising a peptide wherein at least one amino acid residue is derivatized with A-B-C-D-

wherein (i) A- is

wherein R is lower linear or branched alkyl, p is selected from the group consisting of 10, 11, 12, 13 and 14, and d is selected from the group consisting of 0, 1, 2, 3, 4 and 5, and

B- is selected from the group consisting of

wherein x is selected from the group consisting of 0, 1, 2, 3 and 4, and y is selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12,

or (ii) A is

wherein n is selected from the group consisting of 14, 15, 16 17, 18 and 19, and B is selected from the group consisting of

wherein x is selected from the group consisting of 0, 1, 2, 3 and 4, and together with either (i) or (ii)

-C- is selected from the group consisting of

wherein b and e are each independently selected from the group consisting of 0, 1 and 2, and c and f are each independently selected from the group consisting of 0, 1 and 2 with the proviso that b is 1 or 2 when c is 0, or b is 0 when c is 1 or 2, and e is 1 or 2 when f is 0, or e is 0 when f is 1 or 2, and

-D- is attached to said amino acid residue and is a linker, represents a bond, or is absent.

2. The derivative according to claim 1 , wherein at least one amino acid residue is derivatized with A-B-C-.

3. The derivative according to claim 1 , wherein said peptide is a GLP-1 peptide selected from GLP-1(7-37) and an analogue of GLP-1(7-37), wherein, in said peptide, at least one amino acid residue is derivatised with A-B-C-, or A-B-C-D-.

4. The derivative according to claim 3 , wherein the derivatised amino acid residue comprises an amino group.

5. The derivative according to claim 4 , wherein the derivatised amino acid residue is lysine.

6. The derivative according to claim 5 , wherein the linker comprises at least 5 non-hydrogen atoms, 30-50% of which are either N or O.

7. The derivative according to claim 6 , wherein D is selected from the group consisting of

wherein k is selected from the group consisting of 0, 1, 2, 3, 4, 5, 11 and 27, and m is selected from the group consisting of 0, 1, 2, 3, 4, 5 and 6, and D is attached to the amino acid residue in the end depicted with *.

8. The derivative according to claim 1 , wherein said GLP-1 analogue comprises an amino acid sequence according to formula (I):

Formula (I) (SEQ ID No: 2)

Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa 16 -

Ser-Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Ala-

Xaa 25 -Xaa 26 -Xaa 27 -Phe-Ile-Xaa 30 -Trp-Leu-

Xaa 33 -Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -

Xaa 40 -Xaa 41 -Xaa 42 -Xaa 43 -Xaa 44 -Xaa 45 -Xaa 46

wherein

Xaa 7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, Nα-acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 2(3H-imidazol-4-yl)acetyl, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;

Xaa 8 is Ala, Gly, Val, Leu, Ile, Lys, Aib, (1-aminocyclopropyl) carboxylic acid, (1-aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1-aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid;

Xaa 16 is Val, or Leu;

Xaa 18 is Ser, Lys, or Arg;

Xaa 19 is Tyr, or Gln;

Xaa 20 is Leu, Met, or Lys;

Xaa 22 is Gly, Glu, or Aib;

Xaa 23 is Gln, Glu, Lys, or Arg;

Xaa 25 is Ala, or Val;

Xaa 26 is Lys, Glu, or Arg;

Xaa 27 is Glu, or Leu;

Xaa 30 is Ala, Glu, Lys, or Arg;

Xaa 33 is Val, Thr(O-benzyl), or Lys;

Xaa 34 is Lys, Glu, Gln, Asn, or Arg;

Xaa 35 is Gly, Aib, or absent;

Xaa 36 is Arg, Gly, Lys, or absent;

Xaa 37 is Gly, Ala, Glu, Pro, Lys, epsilon-amino-Lys, amide or is absent;

Xaa 38 is Lys, Ser, amide, or is absent;

Xaa 39 is Ser, Lys, amide, or is absent;

Xaa 40 is Gly, amide, or is absent;

Xaa 41 is Ala, amide, or is absent;

Xaa 42 is Pro, amide, or is absent;

Xaa 43 is Pro, amide, or is absent;

Xaa 44 is Pro, amide, or is absent;

Xaa 45 is Ser, amide, or is absent;

Xaa 46 is amide, or is absent;

provided that if Xaa 38 , Xaa 39 , Xaa 40 , Xaa 41 , Xaa 42 , Xaa 43 , Xaa 44 , Xaa 45 or Xaa 46 is absent then each amino acid residue downstream is also absent.

9. The derivative according to claim 1 , wherein said GLP-1 analogue comprises an amino acid sequence according to formula (II):

Formula (II) (SEQ ID No: 3)

Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-

Xaa 18 -Tyr-Leu-Glu-Xaa 22 -Xaa 23 -Ala-Ala-Xaa 26 -

Glu-Phe-Ile-Xaa 30 -Trp-Leu-Val-Xaa 34 -Xaa 35 -

Xaa 36 -Xaa 37 -Xaa 38

wherein

Xaa 7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 2(3H-imidazol-4-yl)acetyl, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;

Xaa 18 is Ser, Lys, or Arg;

Xaa 22 is Gly, Glu, or Aib;

Xaa 23 is Gln, Glu, Lys, or Arg;

Xaa 26 is Lys, Glu, or Arg;

Xaa 30 is Ala, Glu, Lys, or Arg;

Xaa 34 is Lys, Glu, Gln, or Arg;

Xaa 35 is Gly, Aib, or absent;

Xaa 36 is Arg, Lys, or absent;

Xaa 37 is Gly, Ala, Glu, Pro, Lys, or epsilon-amino-Lys;

Xaa 38 is Lys, amide, or is absent.

10. The derivative according to claim 1 , wherein said GLP-1 analogue comprises an amino acid sequence according to formula (III) which is derivatised in position 18, 23, 26, 30, 31, 34, 36, 37 or 38:

Formula (III) (SEQ ID No: 6)

Xaa 7 -Xaa 8 -Xaa 9 -Gly-Thr-Phe-Thr-Ser-Asp-Xaa 16 -

Ser-Xaa 18 -Tyr-Leu-Glu-Glu-Xaa 23 -Ala-Xaa 25 -

Arg-Xaa 27 -Phe-Ile-Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -

Xaa 35 -Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39

wherein

Xaa 7 - Xaa 8 is 2(3H-imidazol-4-yl)acetyl-alanine, L-histidine-Aib, desamino-histidine-alanine, or desamino-histidine-Aib;

Xaa 9 is Glu or a Glu derivative such as alpha, alpha dimethyl-Glu;

Xaa 16 is Val, or Leu;

Xaa 18 is Ser, Lys, or Arg;

Xaa 19 is Tyr, or Gln;

Xaa 23 is Gln, Glu, Lys, or Arg;

Xaa 25 is Ala, or Val;

Xaa 27 is Glu, or Leu;

Xaa 30 is Ala, Glu, Lys, Arg, or absent;

Xaa 33 is Val, Thr(O-benzyl), or Lys;

Xaa 34 is Lys, Glu, Gln, Asn, or Arg;

Xaa 35 is Gly, Aib, or absent;

Xaa 36 is Arg, Lys, or absent;

Xaa 37 is Gly, Aib, Pro, epsilon-amino-Lys, or absent

Xaa 38 is Lys, Glu, or absent

Xaa 39 is amide, or is absent;

provided that if Xaa 37 is absent then Xaa 38 is also absent.

11. The derivative according to claim 1 , wherein the GLP-1 peptide comprises an amino acid sequence according to formula (IV) which is derivatised with an albumin binding residue in position 18, 23, 26, 30, 31, 34, 36, 37, or 38:

Formula (IV) (SEQ ID No: 7)

Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-

Xaa 18 -Tyr-Leu-Glu-Glu-Gln-Ala-Ala-Arg-Glu-Phe-

Ile-Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 -

Xaa 38 -Xaa 39

wherein

Xaa 7 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 2(3H-imidazol-4-yl)acetyl, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;

Xaa 18 is Ser, Lys or Arg;

Xaa 30 is Ala, Glu, Lys or Arg;

Xaa 33 is Val or Lys;

Xaa 34 is Lys, Glu, Gln, or Arg;

Xaa 35 is Gly, Aib, or absent;

Xaa 36 is Arg, Lys, or absent;

Xaa 37 is Gly, Aib, Pro, epsilon-amino-Lys, or absent;

Xaa 38 is Lys, or absent; and

Xaa 39 is amide or is absent.

12. The derivative according to claim 11 , wherein Xaa 38 is absent.

13. The derivative according to claim 11 , wherein Xaa 37 and Xaa 38 are both absent.

14. The derivative according to claim 11 , wherein Xaa 7 is desamino-histidine.

15. The derivative according to claim 11 , wherein Xaa 8 is Aib.

16. The derivative according to claim 1 , which is selected from the following:

N-ε 37{ 2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbon yl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [desaminoHis 7 ,Glu 22 ,Arg 26 ,Arg 34 ,Lys 37 ]GLP-1(7-37)amide;

N-ε 20 -{2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib 2 ,Leu 14 ,Lys 20 ,Gln 28 ,Ser(O-benzyl) 39 ] exendin-4 (1-39)amide;

N-ε 26 {2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [desaminoHis 7 ,Arg 34 ]GLP-1-(7-37);

N-epsilon37{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

N-epsilon23-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-Carboxyheptadecanoylamino)piperidin-4-ylcarbonylamino]-3-(carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8,Arg26,Arg 34]GLP-1-(7-37);

N-epsilon37-[2-(2-[2-(2-[2-(2-((R)-3-[1-(17-Carboxyheptadecanoyl)piperidin-4-ylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][DesaminoHis7, Glu22 Arg26, Arg 34, Phe(m-CF3)28]GLP-1-(7-37)amide;

[DesaminoHis7,Glu22,Arg26,Arg34]GLP-1-(7-37)-Lys(2-{2-[2-(2-{2-[2-((S)-4-Carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl);

N-ε 20 ({2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(17-carboxyheptadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [Aib 8 ,Lys 20 ,Arg 26 ,Glu 30 ,Thr(O-benzyl) 33 ]GLP-1-(7-37)amide;

N-epsilon30{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8,Glu22,Arg26,Lys30]GLP-1-(7-37);

N-epsilon31{2-[2-(2-{2-[2-((S)-3-carboxy-3-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl [Aib8, Glu22, Arg26,Lys 31]GLP-1-(7-37);

N-ε 20 ({2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(17-carboxyheptadecanoyl)piperidine-4-carbon yl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [Aib 8 ,Lys 20 ,Arg 26 ,2-Naphtylalanine 28 , Glu 30 ]GLP-1 (7-37)amide;

[Aib8, Glu22, Arg26, Arg34]GLP-1-(7-37)Lys[2-(2-[2-(2-[2-(2-((S)-4-[1-[19-Carboxynonadecanoyl]piperidine-4-carbonylamino]-4-carboxybutyrylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]amide;

N-ε 20 ({2-[2-(2-{2-[2-((R)-3-carboxy-3-{[1-(17-carboxyheptadecanoyl)piperidine-4-carbon yl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [Aib 8 ,Lys 20 ,Arg 26 , 2-Naphtylalanine 12 , Glu 30 ]GLP-1-(7-37)amide;

[DesaminoHis7,Glu22,Arg26,Arg34]GLP-1-(7-37)Lys[2-(2-[2-(2-[2-(2-((S)-4-[1-[19-Carboxynonadecanoyl]piperidine-4-carbonylamino]-4-carboxybutyrylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]amide

N-epsilon31-(2-{2-[2-(2-{2-[2-((S)-3-Carboxy-3-{[1-(19-carboxy-nonadecanoyl)piperidine-4-carbonyl]amino}propionylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl)[Aib8,Glu22,Arg26,Lys31,Arg34]GLP-1-(7-37);

N-epsilon26-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyryl][Aib8,Arg34]GLP-1-(7-37);

N-epsilon26-{4-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]butyryl}[Aib 8,Arg34]GLP-1-(7-37);

N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy) acetyl][Aib8,Arg34]GLP-1-(7-37);

N-epsilon26-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37)-amide;

N-epsilon18-{2-(2-(2-(2-[2-(2-[(S)-4-Carboxy-4-({4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butanoylamino]ethoxy)ethoxy]acetyl)ethoxy)ethoxy)acetyl}[Aib8,Lys18,Arg26,Arg34]GLP-1(7-37)

N-ε 20 -[2-(2-[2-(2-[2-(2-((S)-4-[trans-4-([19-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][desaminoHis 1 , Lys 20 , Ser(O-benzyl) 33 , Ser(O-benzyl) 39 ] exendin (1-39);

[Aib8,Glu22,Arg26,Arg34]GLP-1-(7-37)Lys[2-(2-[2-(2-[2-(2-((S)-3-[4-([19-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]-3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({4-[(trans-19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

[DesaminoHis7,Glu22,Arg26,Arg34]GLP-1-(7-37)Lys[2-(2-{2-[2-(2-{2-[4-Carboxy-4-({trans-4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl]-amide;

[desaminoHis 7 ,Arg 26 ,Arg 34 ]GLP-1-(7-37)Lys[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl]amide;

N-epsilon26[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({4-[(19-carboxy-nonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl[Aib8, Lys 26] GLP-1 (7-37)amide;

N-epsilon26 [2-(2-[2-(2-[2-(2-((S)-2-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]-4-carboxybutanoylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Lys26] GLP-1 (7-37)amide;

N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)-hexadecanoylsulfamoyl)butyrylamino]-butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);

N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);

N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{6-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]hexanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-37);

N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{4-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);

N-epsilon26-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]-dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Arg34]GLP-1-(7-34);

N-epsilon26-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Lys26,Arg34]GLP-1-(7-36)amide;

[Aib8,Glu22,Arg26,Arg34]GLP-1-(7-37)Lys[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}-butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl]amide;

N-epsilon20-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Lys20,Glu22,Arg26,Glu30,Pro37]GLP-1-(7-37)amide;

N-epsilon37-[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

N-epsilon37-[[2-(2-{2-[(S)-4-Carboxy-4-((S)-4-carboxy-4-{12-[4-(16-(1H-tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37)amide;

[Aib8,Glu22,Arg26,Glu30,Pro37]GLP-1-(7-37)Lys [2-(2-{2-[4-Carboxy-4-(4-carboxy-4-{4-[4-(16-1H-tetrazol-5-yl-hexadecanoylsulfamoyl)butyrylamino]butyrylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl];

[Aib8,Glu22,Arg26,Glu30,Pro37]GLP-1-((7-37)Lys (2-(2-(3-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-(2-[4-(S)-carboxy-4-(4-(S)-carboxy-4-(4-{4-[16-(Tetrazol-5-yl)hexadecanoylsulfamoyl]butanoylamino}butanoylamino) butyrylamino)butyrylamino];

ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy)ethoxy) propionylamino)ethoxy)ethoxy) peptide;

N-alpha37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][DesaminoHis7,Glu22,Arg26,Arg34,epsilon-Lys37]GLP-1-(7-37);

N-alpha8-[2-(4-imidazolyl)acetyl] N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Glu22,Arg26,Arg34,Lys37]GLP-1-(8-37);

[DesaminoHis7,Glu22,Arg26,34]-GLP-1 (7-37)-Lys-(2-{2-[2-((S)-4-carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetyl) peptide;

[DesaminoHis7,Glu22,Arg26,34]-GLP-1 (7-37)-Lys-[2-(2-{2-[2-(2-{2-[4-Carboxy-4-({4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl] peptide;

[DesaminoHis7,Glu22,Arg26,34]-GLP-1 (7-37)-Lys((S)-4-carboxy-4-(2-{2-[2-((S)-4-carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)butyryl) peptide;

[DesaminoHis7,Glu22,Arg26,34]-GLP-1 (7-37)-Lys-(2-(2-{2-[(S)-4-carboxy-4-(2-{2-[2-((S)-4-carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)butyrylamino]ethoxy}ethoxy)acetyl) peptide;

[DesaminoHis7,Arg26,34]-GLP-1 (7-37)-Lys(2-{2-[2-(2-{2-[2-((S)-4-Carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) peptide;

N-epsilon37-(2-{2-[2-(2-{2-[2-((S)-4-Carboxy-4-{[1-(19-carboxynonadecanoyl)piperidine-4-carbonyl]amino}butyrylamino)ethoxy]ethoxy}acetylamino)ethoxy]ethoxy}acetyl) [DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);

N-epsilon37-((S)-4-Carboxy-4-{[1-(19-carboxy-nonadecanoyl)-piperidine-4-carbonyl]-amino}-butyryl) [DesaminoHis7,Arg26,Arg34,Lys37]GLP-1-(7-37);

[DesaminoHis7,Glu22,Arg26,34]-GLP-1 (7-37)-Lys-((S)-4-Carboxy-4-{[1-(19-carboxy-nonadecanoyl)-piperidine-4-carbonyl]-amino}-butyryl) peptide;

N-epsilon26-[2-(2-{2-[(R)-4-Carboxy-4-((R)-4-carboxy-4-{12-[4-(16-1H-tetrazol-5-yl-hexadecanoylsulfamoyl)butyrylamino]dodecanoylamino}butyrylamino)butyrylamino]ethoxy}ethoxy)acetyl]-[Aib8,Arg34]GLP-1 (7-37);

N-epsilon37-{2-[2-(2-{(S)-4-[(S)-4-(12-{4-[16-(2-tert-Butyl-2H-tetrazol-5-yl)-hexadecanoylsulfamoyl]butyrylamino}dodecanoylamino)-4-carboxybutyrylamino]-4-carboxybutyrylamino}ethoxy)ethoxy]acetyl}[DesaminoHis7,Glu22,Arg26,Arg34,Lys37] GLP-1 (7-37);

N-epsilon37-[2-(2-{2-[2-(2-{2-[(S)-4-Carboxy-4-({trans-4-[(19-carboxynonadecanoylamino)methyl]cyclohexanecarbonyl}amino)butyrylamino]ethoxy}ethoxy)acetylamino]ethoxy}ethoxy)acetyl][Aib8,Glu22,Arg26,Arg34,Lys37]GLP-1-(7-37);

[ImPr 7 ,Arg 26,34 ,Glu 22 ]GLP-1-(7-37)Lys[2-(2-[2-((S)-4-((S)-4-(12-[4-(16-1H-tetrazol-5-ylhexadecanoylsulfamoyl)butyrylamino]dodecanoylamino)-4-carboxybutyrylamino)-4-carboxybutyrylamino)ethoxy]ethoxy)acetyl]-amid;

N-epsilon36-[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Glu22, Gln34]GLP-1-(7-37);

N-epsilon26-[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, Glu22, Gln34]GLP-1-(7-37);

N-epsilon18-[2-(2-[2-(2-[2-(2-((R)-3-[trans-4-((9-Carboxynonadecanoylamino]methyl)cyclohexylcarbonylamino]3-carboxypropionylamino)ethoxy)ethoxy]acetylamino)ethoxy]ethoxy)acetyl][Aib8, 22,35, Lys18, Arg26,34]GLP-1-(7-37); and

17. A pharmaceutical composition comprising a derivative according to claim 1 or a pharmaceutically acceptable salt, amide, alkyl, or ester thereof, and a pharmaceutically acceptable excipient.

18. A method of treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia and gastric ulcers in a subject in need of such treatment, the method comprising administering to the subject a therapeutically effective amount of a pharmaceutical composition according to claim 17 .

19. The derivative according to claim 3 , wherein A is

wherein n is selected from the group consisting of 14, 15, 16 17, 18 and 19, and B is selected from the group consisting of

wherein x is selected from the group consisting of 0, 1, 2, 3 and 4.

20. The derivative according to claim 8 , wherein A is

wherein n is selected from the group consisting of 14, 15, 16, 17, 18 and 19, and B is selected from the group consisting of

wherein x is selected from the group consisting of 0, 1, 2, 3 and 4.

21. The derivative according to claim 19 , wherein A-B-C-D- is selected and combined from

22. The derivative according to claim 20 , wherein A-B-C-D- is selected and combined from

Priority Claims (2)

EP 07115741 · Sep 5, 2007 · regional

EP 08101011 · Jan 28, 2008 · regional

Continuity (4)

Continuation 12676310

Provisional Application 60971931 · Sep 13, 2007

Provisional Application 61024622 · Jan 30, 2008

Related Publication 20140011732A1 · Jan 9, 2014