Multi-receptor agonist and medical use thereof

1 . A GLP-1 analog of formula (I) or a pharmaceutically acceptable salt form thereof:

(R1-SEQ ID NO: 84-R2) (I)

R 1 -X 1 -X 2 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-X 10 -Ser-X 12 -

Tyr-Leu-X 15 -X 16 -X 17 -X 18 -X 19 -X 20 -Glu-Phe-X 23 -X 24 -

Trp-Leu-X 27 -X 28 -X 29 -X 30 -Pro-Ser-Ser-Gly-Ala-Pro-

Pro-Pro-Ser-X 40 -R 2

wherein:

R 1 is H, alkyl, acetyl, formyl, benzoyl, trifluoroacetyl, pGlu or absent;

R 2 is —NH 2 , —OH, or absent;

X 1 is Tyr;

X 2 is Aib;

X 10 is Tyr;

X 12 is Ile;

X 15 is Glu;

X 16 is Lys;

X 17 is Ile;

X 18 is Ala;

X 19 is Ala, Aib or Gln;

X 20 is Gln, Glu, Lys or Y1;

X 23 is Ile or Val;

X 24 is Ala, Asn or Gln;

X 27 is Leu;

X 28 is Ala;

X 29 is Gly;

X 30 is Gly, Lys or Y1;

X 40 is Lys or Y1;

Y1 is Lys, Orn, Dap, Dab or Cys residue, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

2 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala, Aib or Gln;

X 20 is Gln, Lys or Y1;

X 23 is Ile or Val;

X 24 is Ala, Asn or Gln;

X 30 is Gly, Lys or Y1;

X 40 is Lys or Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

3 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala or Gln;

X 20 is Gln, Glu, Lys or Y1;

X 23 is Val;

X 24 is Ala, Asn or Gln;

X 30 is Gly, Lys or Y1;

X 40 is Lys or Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

4 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala or Gln;

X 20 is Gln, Lys, or Y1;

X 23 is Val;

X 24 is Asn or Gln;

X 30 is Gly, Lys or Y1;

X 40 is Lys or Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

5 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala;

X 20 is Gln, Lys, or Y1;

X 23 is Val;

X 24 is Asn;

X 30 is Gly, Lys or Y1;

X 40 is Lys or Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

6 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala;

X 20 is Gln, Lys, or Y1;

X 23 is Val;

X 24 is Asn;

X 30 is Gly, Lys or Y1;

X 40 is Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

7 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala;

X 20 is Gln;

X 23 is Val;

X 24 is Asn;

X 30 is Gly, Lys or Y1;

X 40 is Lys or Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

8 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala;

X 20 is Lys;

X 23 is Val;

X 24 is Asn;

X 30 is Gly, Lys or Y1;

X 40 is Lys or Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

9 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala;

X 20 is Y1;

X 23 is Val;

X 24 is Asn;

X 30 is Gly, Lys or Y1;

X 40 is Lys or Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2; and

b is 1 or 2; and

c is an integer between 16-20.

10 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that:

X 19 is Ala;

X 20 is Gln;

X 23 is Val;

X 24 is Asn;

X 30 is Gly or Y1;

X 40 is Lys or Y1;

Y1 is Lys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

11 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , wherein X 20 , X 30 and X 40 are each independently Y1;

Y1 is Lys, Orn, Dap, Dab or Cys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is an integer between 16-20.

12 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that, a is 2, b is 1 or 2, and c is 16, 18 or 20.

13 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that X 40 is Y1;

Y1 is Lys, in which a side chain of Y1 is coupled to a substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH;

a is 2;

b is 1 or 2; and

c is 16 or 18.

14 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , wherein Y1 is Lys covalently linked to the substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH via the side chain amino group of the Lys by forming an amide bond.

15 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , characterized in that Y1 is

K(-OEG-OEG-yGlu-C 18 —OH), wherein the -OEG-OEG-yGlu-C 18 —OH is

16 . The GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , wherein Y1 is Lys covalently linked to the substituent shown as formula of {[2-(2-amino-ethoxy)-ethoxy]-acetyl} a -(y-Glu) b -CO—(CH 2 ) c —COOH via the ε amino group of the C-terminal of Lys by forming an amide bond.

17 . A pharmaceutical composition comprising:

a therapeutic amount of the GLP-1 analog or the pharmaceutically acceptable salt thereof according to claim 1 , and a pharmaceutically acceptable excipient or a pharmaceutical carrier.

18 . A GLP-1 analog selected from the following compounds:

SEQ ID

NO:

sequence

13

H-YAibEGTFTSDYSIYLEKIAAKEFVNWLLAGGPSSGAPPPSK-NH 2

14

H-YAibEGTFTSDYSIYLEKIAAQEFVNWLLAGGPSSGAPPPSK-NH 2

15

H-YAibEGTFTSDYSIYLEKIAQKEFVNWLLAGGPSSGAPPPSK-NH 2

28

H-YAibEGTFTSDYSIYLEKIAAQEFVNWLLAGGPSSGAPPPSK(OEG-OEG-yGlu-

C18-OH)-NH 2

29

H-YAibEGTFTSDYSIYLEKIAAQEFVNWLLAGK(OEG-OEG-yGlu-C18-

OH)PSSGAPPPS-NH 2

30

H-YAibEGTFTSDYSIYLEKIAAK(OEG-OEG-yGlu-C18-

OH)EFVNWLLAGGPSSGAPPPS-NH 2

34

H-YAibEGTFTSDYSIYLEKIAQQEFIQWLLAGGPSSGAPPPS-NH 2

36

H-YAibEGTFTSDYSIYLEKIAAQEFIQWLLAGGPSSGAPPPS-NH 2

39

H-YAibEGTFTSDYSIYLEKIAibQQEFIQWLLAGGPSSGAPPPS-NH 2

47

H-YAibEGTFTSDYSIYLEKIAAQEFIQWLLAGGPSSGAPPPSK-NH 2

48

H-YAibEGTFTSDYSIYLEKIAAQEFINWLLAGGPSSGAPPPS-NH 2

49

H-YAibEGTFTSDYSIYLEKIAAK(OEG-OEG-yGlu-C18-

OH)EFINWLLAGGPSSGAPPPS-NH 2

50

H-YAibEGTFTSDYSIYLEKIAAKEFVNWLLAGK(OEG-OEG-yGlu-C18-

OH)PSSGAPPPS-NH 2

51

H-YAibEGTFTSDYSIYLEKIAAKEFVNWLLAGGPSSGAPPPSK(OEG-OEG-yGlu-

C18-OH)-NH 2

52

H-YAibEGTFTSDYSIYLEKIAAQEFINWLLAGK(OEG-OEG-yGlu-C18-

OH)PSSGAPPPS-NH 2

53

H-YAibEGTFTSDYSIYLEKIAAQEFINWLLAGGPSSGAPPPSK(OEG-OEG-yGlu-

C18-OH)-NH 2

54

H-YAibEGTFTSDYSIYLEKIAQK(OEG-OEG-yGlu-C18-

OH)EFVNWLLAGGPSSGAPPPS-NH 2

55

H-YAibEGTFTSDYSIYLEKIAQKEFVNWLLAGK(OEG-OEG-yGlu-C18-

OH)PSSGAPPPS-NH 2

56

H-YAibEGTFTSDYSIYLEKIAQKEFVNWLLAGGPSSGAPPPSK(OEG-OEG-yGlu-

C18-OH)-NH 2

74

H-YAibEGTFTSDYSIYLEKIAAQEFVNWLLAGGPSSGAPPPSK(OEG-OEG-yGlu-

C20-OH)-NH 2

75

H-YAibEGTFTSDYSIYLEKIAAK(OEG-OEG-yGlu-C20-

OH)EFVNWLLAGGPSSGAPPPS-NH 2

78

H-YAibEGTFTSDYSIYLEKIAAQEFVQWLLAGGPSSGAPPPS-NH 2

81

H-YAibEGTFTSDYSIYLEKIAAQEFVQWLLAGGPSSGAPPPSK(OEG-OEG-

yGlu-C20-OH)-NH 2

or a pharmaceutically acceptable salt thereof.

19 . A GLP-1 analog or a pharmaceutically acceptable salt thereof,

wherein the GLP-1 analog comprises an amino acid sequence of:

H-YAibEGTFTSDYSIYLEKIAAQEFVNWLLAGGPSSGAPPPSK (-OEG-OEG-yGlu-C 20 —OH)—NH 2 (SEQ ID NO:74);

wherein, the OEG-OEG-yGlu-C 20 —OH is