Novel GLP-1 compounds

Abstract

Novel GLP-1 compounds and their therapeutic use.

1 . A compound having a structure of formula (I)  
         Insulinotropic agent(—Y—C*) f -Q  (I)  wherein    Insulinotropic agent is a radical derived from an insulinotropic peptide which binds to the human glucagon-like peptide 1 (GLP-1) receptor, or a radical derived from a peptide in which 22 positions out of the first 30 are identical to those found in corresponding positions in GLP-1 or found in corresponding positions in Exendin-4, and    Y is a bivalent connecting chemical group connecting C* with the Insulinotropic agent, and    C* is a bivalent polar separating chemical group where 50-20% of the heavy atoms are either O or N, and    f is 0 or 1 and    Q is selected from                          wherein 
 A is a polar chemical group of a single molecular size (monodisperse) or of several molecular sizes (polydisperse) where  
 50-20% of the heavy atoms are independently oxygen or nitrogen, and  
 W is a bivalent chemical group whereby A is connected, and  
 X is a bivalent connecting chemical group whereby B is connected, and  
 B is a connecting or branching chemical group.  
   
     
     
         2 . The compound according to  claim 1 , wherein the C-terminal amino acid residue of said insulinotropic agent is not cysteine.  
     
     
         3 . The compound according to  claim 1 , wherein A is a monodisperse or polydisperse chemical group having the structure —(CH 2 ) l O[(CH 2 ) n O] m (CH 2 ) p —H, where l, n and p independently are an integer in the range from 1 to 10, m is an integer in the range from 1 to 5000, and where m multiplied by n+1 is less than 10000.  
     
     
         4 . The compound according to  claim 1 , wherein A is a monodisperse or polydisperse chemical group having the structure —(CH 2 ) l C(═O)O[(CH 2 ) n O] m (CH 2 ) p —H, where l, n and p independently are an integer in the range from 1 to 10, m is an integer in the range from 1 to 5000, and where m multiplied by n+1 is less than 10000.  
     
     
         5 . The compound according to  claim 3 , wherein n is 2 or 3.  
     
     
         6 . The compound according to  claim 3 , wherein m is in the range from 10-1000, or in the range from 20-250.  
     
     
         7 . The compound according to  claim 1 , wherein A is a monodisperse or polydisperse chemical group having the structure -(Z 1 (CH 2 ) l O[(CH 2 ) 2 O] m (CH 2 ) p —NR 1 ) q -Z 2 , where Z 1  is —CO— or —CO—(CH 2 ) n —CO—NH—, and Z 2  is —R 1 , —CO—(CH 2 ) n —R 1 , —(CH 2 ) l O[(CH 2 ) 2 O] m (CH 2 ) P —R 1  wherein l and n and p independently are integers in the range from 1 to 10, and R 1  is —OH, —NH 2 , —NH—R 2 , —NH(—R 2 )—R 2 , —COOH, C 1-6 -alkyl, or —NH—CH(R 2 )—COOH, and where m and q are independently integers in the range from 1 to 20, and where l, n and p are independently integers in the range from 1 to 6, and R 2  is hydrogen or C 1-6 alkyl.  
     
     
         8 . The compound according to  claim 1 , wherein A is mPEGyl.  
     
     
         9 . The compound according to  claim 1 , wherein A is mPEGyl-C(═O)—(CH 2 ) r —, wherein r is an integer in the range from 1-10.  
     
     
         10 . The compound according to  claim 1 , wherein A is monodisperse.  
     
     
         11 . The compound according to  claim 1 , wherein A is polydisperse.  
     
     
         12 . The compound according to  claim 1 , wherein the branching chemical group B is selected from  
       
         
           
           
               
               
           
         
       
       wherein a, b, c, d, e, f, g, h, i are integers independently selected from the range from 0 to 24.  
     
     
         13 . The compound according to  claim 1 , wherein the branching group B is  
       
         
           
           
               
               
           
         
       
       wherein a, b, c are integers independently selected from the range from 0 to 24.  
     
     
         14 . The compound according to  claim 12 , wherein the branching chemical group B is selected from  
       
         
           
           
               
               
           
         
       
       wherein a, b, c, d, e, f, g, h, i are integers independently selected from the range from 0 to 24.  
     
     
         15 . The compound according to  claim 12 , wherein the insulinotropic agent is attached to B via the left hand terminal of B.  
     
     
         16 . The compound according to  claim 12 , wherein a+b is less than 6 or a+b+c is less than 14 or a+b+c+d+e+f+g+h+l is less than 16.  
     
     
         17 . The compound according to  claim 12 , wherein a is 0 or 1 and b, c, d, e, f, h and i are all in the range from 0 to 5.  
     
     
         18 . The compound according to  claim 12 , wherein a, c, d, e, g and i are all 0 and b, f and h are all in the range from 1 to 4.  
     
     
         19 . The compound according to  claim 1 , wherein a, c, d, e, g and l are all 0 and b, f and h are all in the range from 1 to 4.  
     
     
         20 . The compound according to any  claim 1 , wherein W and X are independently selected from the bivalent connecting chemical groups comprising 
 amides: —C(O)—NR—, where R is hydrogen or C 1-6 -alkyl,    amine: —NR—, where R is hydrogen or C 1-6 -alkyl,    thioethers: —S—, —S—(CH 2 ) 2 —SO 2 — or                          ethers: —O—,    urethanes: —N(R 1 )—CO—N(R 2 )—, where R 1  and R 2  independently is hydrogen or C 1-6 -alkyl,    carbamates: —O—CO—N(R)—, where R is hydrogen or C 1-6 -alkyl,    hydrazines:                          where R is hydrogen or C 1-6 -alkyl,    oximes: —O—N═C(—R)—, where R is hydrogen or C 1-6 -alkyl,    oxazolidines or thiazolidines:                          
     
     
         21 . The compound according to  claim 20 , wherein W is: —C(O)—NR—, where R is hydrogen or C 1-6 -alkyl.  
     
     
         22 . The compound according to  claim 21 , wherein the insulinotropic agent is attached to W via the left hand terminal (the carbon) of W.  
     
     
         23 . The compound according to  claim 21 , wherein the insulinotropic agent is attached to W via the right hand terminal (the nitrogen) of W.  
     
     
         24 . The compound according to  claim 1 , wherein f is 0.  
     
     
         25 . The compound according to  claim 1 , wherein C* is —(CH 2 ) n1 O[(CH 2 ) n2 O] n3 (CH 2 ) n4 —, where n1, n2 and n4 independently is an integer in the range from 1 to 10, n3 is an integer in the range from 1 to 5000, and where n3 multiplied by n2+1 is less than 10000.  
     
     
         26 . The compound according to  claim 25 , wherein n2 is 2 or 3.  
     
     
         27 . The compound according to  claim 25 , wherein n3 is in the range from 1-20.  
     
     
         28 . The compound according to  claim 1 , wherein C* is —(CH 2 ) n5 —, where n5 is an integer in the range from 1 to 10.  
     
     
         29 . The compound according to  claim 1 , wherein Y is selected from the bi-valent connecting chemical groups comprising 
 amides: —C(O)—NR—, where R is hydrogen or C 1-6 -alkyl,    amine: —NR—, where R is hydrogen or C 1-6 -alkyl,    thioethers: —S—, —S—(CH 2 ) 2 —SO 2 — or                          ethers: —O—,    urethanes: —N(R 1 )—CO—N(R 2 )—, where R 1  and R 2  independently is hydrogen or C 1-6 -alkyl,    carbamates: —O—CO—N(R)—, where R is hydrogen or C 1-6 -alkyl,    hydrazines:                          where R is hydrogen or C 1-6 -alkyl,    oximes: —O—N═C(—R)—, where R is hydrogen or C 1-6 -alkyl,    oxazolidines or thiazolidines:                          
     
     
         30 . The compound according to  claim 1 , wherein said insulinotropic agent is a DPPIV protected peptide.  
     
     
         31 . The compound according to  claim 1 , wherein said insulinotropic agent has an EC 50  of less than 1 nM as determined by the functional receptor assay disclosed herein.  
     
     
         32 . The compound according to  claim 1 , wherein said insulinotropic agent has an EC 50  of less than 300 pM, less than 200 pM or less than 100 pM as determined by the functional receptor assay disclosed herein.  
     
     
         33 . The compound according to  claim 1 , wherein said insulinotropic agent is derived from a peptide having a length between 27 and 45 amino acid residues in which 22 out of the first 28 amino acid residues are identical to those found in corresponding positions in GLP-1(7-37) (SEQ ID No. 1) or in corresponding positions in Exendin-4(1-39) (SEQ ID No. 2).  
     
     
         34 . The compound according to  claim 1 , wherein said insulinotropic agent is derived from a peptide having a length between 28 and 45 amino acid residues in which 22 out of the first 28 amino acid residues are identical to those found in corresponding positions in GLP-1(7-37) or in corresponding positions in Exendin-4(1-39).  
     
     
         35 . The compound according to  claim 1 , wherein said insulinotropic agent is selected from a peptide comprising the amino acid sequence of the formula (II):  
         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   Formula (II) (SEQ ID No: 3)  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, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;    Xaa 8  is Ala, D-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 or Met;    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 or Arg;    Xaa 33  is Val or Lys;    Xaa 34  is Lys, Glu, Asn or Arg;    Xaa 35  is Gly or Aib;    Xaa 36  is Arg, Gly or Lys;    Xaa 37  is Gly, Ala, Glu, Pro, 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.    
     
     
         36 . The compound according to  claim 1 , wherein said insulinotropic agent is a peptide comprising the amino acid sequence of formula (III):  
         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   Formula (III) (SEQ ID No: 4)  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, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;    Xaa 8  is Ala, D-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 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 or Arg;    Xaa 34  is Lys, Glu or Arg;    Xaa 35  is Gly or Aib;    Xaa 36  is Arg or Lys;    Xaa 37  is Gly, Ala, Glu or Lys;    Xaa 38  is Lys, NH 2  or is absent.    
     
     
         37 . The compound according to  claim 1 , wherein said insulinotropic agent is selected from GLP-1(7-35), GLP-1(7-36), GLP-1(7-36)-amide, GLP-1(7-37), GLP-1(7-38), GLP-1(7-39), GLP-1(7-40), GLP-1(7-41) or an analogue thereof.  
     
     
         38 . The compound according to  claim 1 , wherein said insulinotropic agent comprises no more than fifteen amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1), or no more than ten amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1).  
     
     
         39 . The compound according to  claim 38 , wherein said insulinotropic agent comprises no more than six amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1).  
     
     
         40 . The compound according to  claim 1 , wherein said insulinotropic agent comprises no more than 4 amino acid residues which are not encoded by the genetic code.  
     
     
         41 . The compound according to  claim 1 , wherein said insulinotropic agent comprises an Aib residue as the second amino acid residue from the N-terminal.  
     
     
         42 . The compound according to  claim 1 , wherein the N-terminal amino acid residue (position 7 in formulae II and III) of said insulinotropic agent is selected from the group consisting of D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine and 4-pyridylalanine.  
     
     
         43 . The compound according to  claim 1 , wherein said insulinotropic agent is selected from the group consisting of [Arg 34 ]GLP-1(7-37), [Arg 26,34 ]GLP-1(7-37)Lys, [Lys 36 Arg 26,34 ]GLP-1(7-36), [Aib 8,22,35 ]GLP-1(7-37), [Aib 8,35 ]GLP-1(7-37), [Aib 8,22 ]GLP-1(7-37), [Aib 8,22,35  Arg 26,34 ]GLP-1(7-37)Lys, [Aib 8,35 Arg 26,34 ]GLP-1(7-37)Lys, [Aib 8,22 Arg 26,34 ]GLP-1(7-37)Lys, [Aib 8,22,35 Arg 26,34 ]GLP-1(7-37) Lys, [Aib 8,35 Arg 26,34 ]GLP-1(7-37)Lys, [Aib 8,22,35 Arg 26 ]GLP-1(7-37) Lys, [Aib 8,35 Arg 26 ]GLP-1(7-37)Lys, [Aib 8,22 Arg 26 ]GLP-1(7-37)Lys, [Aib 8,22,35 Arg 34 ]GLP-1(7-37)Lys, [Aib 8,35 Arg 34 ]GLP-1(7-37)Lys, [Aib 8,22 Arg 34 ]GLP-1(7-37) Lys, [Aib 8,22,35 Ala 37 ]GLP-1(7-37)Lys, [Aib 8,35 Ala 37 ]GLP-1(7-37) Lys, [Aib 8,22 Ala 37 ]GLP-1(7-37)Lys, [Aib 8,22,35 Lys 37 ]GLP-1(7-37), [Aib 8,35 Lys 37 ]GLP-1(7-37), [Aib 8,22 Lys 37 ]GLP-1(7-37) or derivatives thereof which has been amidated on the C-terminal.  
     
     
         44 . The compound according to  claim 1 , wherein said insulinotropic agent comprises at least one Aib residue.  
     
     
         45 . The compound according to  claim 1 , wherein said insulinotropic agent contains two Aib residues.  
     
     
         46 . The compound according to  claim 1 , wherein said insulinotropic agent comprises a serine residue at position 18 relative to GLP-1(7-37) (SEQ ID. No. 1), corresponding to position 12 relative to Exendin-4(1-39).  
     
     
         47 . The compound according to any one of the previous claims, wherein said insulinotropic agent comprises a tyrosine residue at position 19 relative to GLP-1(7-37) (SEQ ID. No. 1), corresponding to position 13 relative to Exendin-4(1-39).  
     
     
         48 . The compound according to  claim 1 , wherein said insulinotropic agent comprises a glycine residue at position 22 relative to GLP-1(7-37) (SEQ ID. No. 1), corresponding to position 16 relative to Exendin-4(1-39).  
     
     
         49 . The compound according to  claim 1 , wherein said insulinotropic agent comprises a glutamine residue at position 23 relative to GLP-1(7-37) (SEQ ID. No. 1), corresponding to position 17 relative to Exendin-4(1-39).  
     
     
         50 . The compound according to  claim 1 , wherein said insulinotropic agent comprises a lysine residue at position 26 relative to GLP-1(7-37) (SEQ ID. No. 1), corresponding to position 20 relative to Exendin-4(1-39).  
     
     
         51 . The compound according to  claim 1 , wherein said insulinotropic agent comprises a glutamate residue at position 27 relative to GLP-1(7-37) (SEQ ID. No. 1), corresponding to position 21 relative to Exendin-4(1-39).  
     
     
         52 . The compound according to  claim 1 , wherein said insulinotropic agent is exendin-4(1-39).  
     
     
         53 . The compound according to  claim 1 , wherein said insulinotropic agent is [Ser 38 Lys 39 ]Exendin-4(1-39)LysLysLysLysLys-amide (SEQ ID No. 5).  
     
     
         54 . The compound according to  claim 1 , wherein said insulinotropic agent is attached to Y—C*-Q or Q via the amino acid residue in position 25 to 45 relative to the amino acid sequence SEQ ID No:1.  
     
     
         55 . The compound according to  claim 1 , wherein said insulinotropic agent is attached to Y—C*-Q or Q via an amino acid residue selected from one of the 10 C-terminal amino acid residues.  
     
     
         56 . The compound according to  claim 1 , wherein said insulinotropic agent is attached to Y—C*-Q or Q via the amino acid residue in position 23, 26, 34, 36 or 38 relative to the amino acid sequence SEQ ID No:1.  
     
     
         57 . The compound according to  claim 1 , wherein said insulinotropic agent is attached to Y—C*-Q or Q via the amino acid residue in position 17, 20, 28, 30 or 32 relative to the amino acid sequence SEQ ID No:2.  
     
     
         58 . The compound according to  claim 1 , wherein said insulinotropic agent is attached to Y—C*-Q or Q via the C-terminal amino acid residue.  
     
     
         59 . The compound according to  claim 1 , wherein said insulinotropic agent is attached to Y—C*-Q or Q via a carboxyl group, an amino group, a keto group, a hydroxyl group, a thiol group or a hydrazide group.  
     
     
         60 . The compound according to  claim 1 , wherein said insulinotropic agent is attached to Y—C*-Q or Q via a the epsilon-amino group on a lysine residue.  
     
     
         61 . The compound according to  claim 60 , wherein said insulinotropic agent comprises only one lysine residue.  
     
     
         62 . The compound according to  claim 61 , wherein said lysine residue is the C-terminal amino acid residue of said insulinotropic agent.  
     
     
         63 . The compound according to  claim 1 , wherein said compound has an EC 50  of less than 1000 pM, less than 500 pM as determined by a functional receptor assay.  
     
     
         64 . The compound according to  claim 1 , wherein said compound is selected from the group consisting of 
 N ε37 -((2S)-2,6-di-(mPEGylcarbonylamino)hexanoyl)[Aib 8,22,35 ,Lys 37 ]GLP-1(7-37) wherein mPEGyl is polydisperse and has a molecular weight of approximately 20 kDa,    N ε37 -(3-(mPEGyl)propionyl)[Aib 8,22,35 ,Lys 37 ]GLP-1(7-37) wherein mPEGyl is polydisperse and has a molecular weight of approximately 20 kDa,    N ε37 -(3-(mPEGyl)propionyl)[Aib 8,22,35 ,Lys 37 ]GLP-1(7-37) wherein mPEGyl is polydisperse and has a molecular weight of approximately 5 kDa,    N ε37 -(3-(mPEGyl)propionyl)[Aib 8,22,35 ,Lys 37 ]GLP-1(7-37) amide wherein mPEGyl is polydisperse and has a molecular weight of approximately 2 kDa,    N ε26 -(3-(mPEGyl)propionyl)[Aib 8 Glu 22,30 ,Lys 33 ,Asn 34 ,Gly 35,36 , Pro 37 ]GLP-1(7-37)ylSerSerGly AlaProProProSer amide wherein mPEGyl is polydisperse and has a molecular weight of approximately 2 kDa,    N α -[Aib 8,22,35 ]GLP-1-(7-37)yl(N ε -(3-(mPEGyl)propionyl)Lysinamide) wherein mPEGyl is polydisperse and has a molecular weight of approximately 750 Da,    N ε -[Aib 8,22,35 ]GLP-1(7-37)yl(S ε -(1-mPEGylpropyl-2,5-dioxo-pyrrolidin-3-yl)Cysteinamide wherein mPEGyl is polydisperse and has a molecular weight of approximately 5000 Da,    N α -(3(3H-imidazol-4-yl)-propionyl [Aib 22,35 ,Arg 26,34 ]GLP-1-(8-37))yl(N ε -(3-(mPEGyl)propionyl)Lysinamide) wherein mPEGyl is polydisperse and has a molecular weight of approximately 2000 Da,    N ε26 -(3-(mPEGyl)propionyl)[Arg 34 ]GLP-1-(7-37) wherein mPGyl is polydisperse and has a molecular weight of approximately 2 kDa, and    (S)—N—((S)-5-(N—((S)-5-carbamoyl-5-(mPEGylpropionylamino)pentyl)carbamoyl)-5-(mPEGylpropionylamino)pentyl)-5-(N α7 -(3-(4-imidazolyl)propionyl)[Aib 22,35 ,Arg 26,34 ]GLP-1-(8-37)yl)-2-(mPEGylpropionylamino)hexanoic amide wherein mPEGyl is polydisperse and has a molecular weight of approximately 750 Da,    
     
     
         65 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable excipient.  
     
     
         66 . The pharmaceutical composition according to  claim 65 , which is suited for pulmonary administration.  
     
     
         67 . A method for 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, said method comprising administering to a subject in need of such treatment an effective amount of a pharmaceutical composition according to  claim 65 .  
     
     
         68 . A method for delaying disease progression in type 2 diabetes in a subject, said method comprising administering to said subject an effective amount of a pharmaceutical composition according to  claim 65 .  
     
     
         69 . A method for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells in a subject, said method comprising administering to said subject an effective amount of a pharmaceutical composition according to  claim 65.