GIP agonist compounds and methods
AssigneeZealand Pharma A/S
InventorsAnne Pernille Tofteng Shelton, Pia Nørregaard, Maria Alexandrovna Deryabina, Bjarne Due Larsen, Jacob Ulrik Fog
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Estimating the term…
Abstract
The present invention relates to acylated GIP analogues which have GIP agonist activity, and their use in the treatment of metabolic disorders.
Claims21
A pharmaceutical composition formulated as a liquid suitable for administration by injection or infusion comprising a GIP analogue, or a pharmaceutically acceptable salt thereof, in admixture with a carrier, wherein the GIP analogue is represented by the general Formula I:
- (SEQ ID NO:
- 42)
- R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-X10-X11-X12-
- Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-X23-X24-
- X25-Leu-X27-X28-X29-Y1-Y2-R2 (I)
- wherein
- R1 is H—, Ac or pGlu (pyroglutamic acid, (S)-(−)-2-pyrrolidone-5-carboxylic acid);
- X2 is Aib, Ala, D-Ala, Gly, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c;
- X10 is Tyr, Leu or Ser;
- X11 is Ser or Leu;
- X12 is Lys, Ψ or Ile;
- X15 is Asp or Glu;
- X16 is Ser, Glu, Lys or Ψ;
- X17 is Ile, Lys, Gln, Arg or Ψ;
- X18 is His, Arg or Ala;
- X19 is Gln, Lys, Ala or Glu;
- X20 is Gln, Lys, Ala, His or Arg;
- X21 is Ala, Leu, Asp or Glu;
- X23 is Val or Ile;
- X24 is Asn or Glu;
- X25 is Tyr or Trp;
- X27 is Leu, Glu, Ser, Lys or Val;
- X28 is Ala, Ser or Arg;
- X29 is Aib, Gly, Ala, Gln, Thr, Ser or Lys or is absent;
- Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:
- 43), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:
- 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:
- 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:
- 46), Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln (SEQ ID NO:
- 47) or absent;
- Y2 is Ψ or is absent;
- R2 is —NH2 or —OH;
- wherein Ψ is a residue independently selected from Lys, Arg, Orn and Cys and wherein the side chain of said residue is conjugated to a lipophilic substituent;
- and wherein the GIP analogue contains one and only one residue Ψ.
A pharmaceutical composition formulated as a liquid suitable for administration by injection or infusion comprising a GIP analogue, or a pharmaceutically acceptable salt thereof, in admixture with a carrier, wherein the GIP analogue is represented by the general Formula II:
- (SEQ ID NO:
- 48)
- R1-Tyr-X2-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-X12-
- Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-X23-X24-
- X25-Leu-X27-X28-X29-Y1-Y2-R2 (II)
- wherein
- R1 is H—, Ac or pGlu;
- X2 is Aib, Ala, D-Ala, Gly;
- X12 is Lys, Ψ or Ile;
- X15 is Asp or Glu;
- X16 is Ser, Glu, Lys or Ψ;
- X17 is Ile, Lys, Gln, Arg or Ψ;
- X18 is His, Arg or Ala;
- X19 is Gln or Ala;
- X20 is Gln, Lys, Ala, His or Arg;
- X21 is Ala, Asp or Glu;
- X23 is Ile or Val;
- X24 is Asn or Glu;
- X25 is Tyr or Trp;
- X27 is Leu, Glu, Ser, Lys or Val;
- X28 is Ala, Ser or Arg;
- X29 is Aib, Gly, Ala, Gln, Thr, Ser or Lys or is absent;
- Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:
- 43), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:
- 44), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO:
- 45), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO:
- 46), Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln (SEQ ID NO:
- 47) or absent;
- Y2 is Ψ or is absent;
- R2 is —NH2 or —OH;
- wherein Ψ is a Lys residue wherein the side chain of said Lys residue is conjugated to a lipophilic substituent;
- and wherein the GIP analogue contains one and only one residue Ψ.
A pharmaceutical composition formulated as a liquid suitable for administration by injection or infusion comprising a GIP analogue, or a pharmaceutically acceptable salt thereof, in admixture with a carrier, wherein the GIP analogue is represented by the general Formula III:
- (SEQ ID NO:
- 50)
- R1-Tyr-Aib-Glu-Gly-Thr-Phe-Ile-Ser-Asp-Tyr-Ser-Ile-
- Glu-Leu-X15-X16-X17-X18-X19-X20-X21-Phe-Val-X24-
- X25-Leu-Leu-Ala-X29-Y1-Y2-R2 (III)
- wherein
- R1 is H—, Ac or pGlu;
- X15 is Asp or Glu;
- X16 is Lys or Ψ;
- X17 is Ile or Ψ;
- X18 is His or Ala
- X19 is Gln or Ala;
- X20 is Gln, Lys or Arg;
- X21 is Ala, Asp or Glu;
- X24 is Asn or Glu;
- X25 is Tyr or Trp
- X28 is Ala, Ser or Arg;
- X29 is Gln or is absent;
- Y1 is Lys-Gly, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser, Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser, Gly-Lys-Lys-Asn-Asp-Trp-Lys-His-Asn-Ile-Thr-Gln or absent;
- Y2 is Ψ or is absent;
- R2 is-NH2 or —OH;
- wherein Ψ is a residue independently selected from Lys, Arg, Orn and Cys and wherein the side chain of said residue is conjugated to a lipophilic substituent;
- and wherein the GIP analogue contains one and only one residue Ψ.
A pharmaceutical composition formulated as a liquid suitable for administration by injection or infusion comprising a GIP analogue, or a pharmaceutically acceptable salt thereof, in admixture with a carrier, wherein the GIP analogue has the following sequence;
- (SEQ ID NO:
- 51)
- Y-Aib-EGTFISDYSIELDKΨHQQDFVNWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 52)
- Y-Aib-EGTFISDYSIELDΨIHQQDFVNWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 53)
- Y-Aib-EGTFISDYSIELEKΨHQQDFVNWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 54)
- Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQGPSSGAPPPSΨ;
- (SEQ ID NO:
- 55)
- Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQΨ;
- (SEQ ID NO:
- 56)
- Y-Aib-EGTFISDYSIELDKIHQQDFVNWLLAQKGΨ;
- (SEQ ID NO:
- 57)
- Y-Aib-EGTFISDYSIELDKΨHQQDFVNYLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 59)
- Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 60)
- Y-Aib-EGTFISDYSIELEKΨAAKEFVNWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 61)
- Y-Aib-EGTFISDYSIELEKΨAQRAFVEWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 62)
- Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQGPSSGAPPPSΨ;
- (SEQ ID NO:
- 63)
- Y-Aib-EGTFISDYSIELEKIAQRAFVEWLLAQΨ;
- (SEQ ID NO:
- 64)
- Y-Aib-EGTFISDYSIELDKΨAAQDFVNWLLAGPSSGAPPPS;
- (SEQ ID NO:
- 65)
- Y-Aib-EGTFISDYSIELDKIAAQDFVNWLLAGPSSGAPPPSΨ;
- (SEQ ID NO:
- 130)
- Y-Aib-EGTFISDYSIELDKKΨAQRAFVEWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 131)
- Y-Aib-EGTFISDYSIELDKKΨAQRAFIEWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 68)
- Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAGPSSGAPPPSKΨ;
- (SEQ ID NO:
- 69)
- Y-Aib-EGTFISDYSIELDKIAQKEFIEWLLAGPSSGAPPPSKΨ;
- (SEQ ID NO:
- 70)
- Y-Aib-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKΨ;
- (SEQ ID NO:
- 71)
- Y-Aib-EGTFISDYSIELDKIAAQDFVEWLLAGPSSGAPPPSKΨ;
- (SEQ ID NO:
- 72)
- Y-Aib-EGTFISDYSIELDKIAQRAFIEWLLAQGPSSGAPPPSKΨ;
- (SEQ ID NO:
- 132)
- Y-Aib-EGTFISDYSIELDKKΨAAQAFVNWLLAGPSSGAPPPS;
- (SEQ ID NO:
- 133)
- Y-Aib-EGTFISDYSIELDKKΨAAQDFVNWLLAAGPSSGAPPPS;
- (SEQ ID NO:
- 134)
- Y-Aib-EGTFISDYSIELDKKΨAAQDFINWLLAGPSSGAPPPS;
- (SEQ ID NO:
- 135)
- Y-Aib-EGTFISDYSIELDKKΨAAQDFIEWLLAGPSSGAPPPS;
- (SEQ ID NO:
- 78)
- Y-Aib-EGTFISDYSIELDKΨIAQRAFIEWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 136)
- Y-Aib-EGTFISDYSKΨELDKIAQRAFIEWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 137)
- Y-DAla-EGTFISDYSIELDKKΨAQRAFIEWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 81)
- Y-DAla-EGTFISDYSIELDKIAAQDFIEWLLAGPSSGAPPPSKΨ;
- (SEQ ID NO:
- 138)
- Y-Aib-EGTFISDYSIELDKKΨAAQDFIEWLLAQGPSSGAPPPS;
- (SEQ ID NO:
- 139)
- Y-Aib-EGTFISDYSIELDKKΨAAQDFINWLLAQGPSSGAPPPS;
- or
- (SEQ ID NO:
- 140)
- Y-Aib-EGTFISDYSIELDKKΨAAQAFIEWLLAQGPSSGAPPPS.
Dependencies are inferred from the claim text.