GIP-GLP-1 dual agonist compounds and methods
First Claim
Patent Images
1. A GIP analogue having the general Formula I:
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R1-Tyr-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Ile-X13-Leu-X15-X16-Ψ
-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-R2
(SEQ ID NO;
56) (I)whereinR1 is H, C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
X2 is selected from Aib and D-Ala;
X10 is selected from Tyr and Leu;
X13 is selected from Ala, Tyr and Aib;
X15 is selected from Asp and Glu;
X16 is selected from Glu and Lys;
X19 is selected from Gln and Ala;
X20 is selected from Lys and Arg;
X21 is selected from Ala and Glu;
X23 is selected from Val and Ile;
X24 is selected from Asn and Glu;
X27 is selected from Leu, Glu and Val;
X28 is selected from Ala, Ser and Arg;
X29 is selected from Aib, Ala, and Gln;
X30 is selected from Lys, Gly and Y1, or is absent;
Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
57), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
58), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
59), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
60) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
61);
Ψ
is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —
Z2-Z1, wherein Z2-Z1 is;
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Abstract
The present invention relates to acylated GIP analogs which have dual GIP and GLP-1 activity, and their use in the treatment of metabolic disorders.
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Citations
19 Claims
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1. A GIP analogue having the general Formula I:
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R1-Tyr-X2-Glu-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-Ile-X13-Leu-X15-X16-Ψ
-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-R2
(SEQ ID NO;
56) (I)wherein R1 is H, C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu; X2 is selected from Aib and D-Ala; X10 is selected from Tyr and Leu; X13 is selected from Ala, Tyr and Aib; X15 is selected from Asp and Glu; X16 is selected from Glu and Lys; X19 is selected from Gln and Ala; X20 is selected from Lys and Arg; X21 is selected from Ala and Glu; X23 is selected from Val and Ile; X24 is selected from Asn and Glu; X27 is selected from Leu, Glu and Val; X28 is selected from Ala, Ser and Arg; X29 is selected from Aib, Ala, and Gln; X30 is selected from Lys, Gly and Y1, or is absent; Y1 (when present) is selected from Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
57), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
58), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
59), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
60) and Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
61);Ψ
is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a substituent having the formula —
Z2-Z1, wherein Z2-Z1 is; - View Dependent Claims (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18)
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- 2. A GIP analogue having the general Formula Ib:
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19. A GIP analog according to the following formula:
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R1—
Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-R2
(SEQ ID NO;
34);
R1—
Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-IsoGlu)-AQRAFVEWLLAQGPSSGAPPPS
(SEQ ID NO;
35)-R2;
R1—
Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQGPSSGAPPPS-R2
(SEQ ID NO;
36);
R1—
Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Peg3-Peg3)-AQRAFVEWLLAQ-R2
(SEQ ID NO;
156);
R1—
Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-IsoGlu)-AQRAFVEWLLAQ-R2
(SEQ ID NO;
157);
or
R1—
Y-Aib-EGTFTSDYSIYLDK-K([19-carboxy-nonadecanoyl]-Dapa-Peg3-Peg3)-AQRAFVEWLLAQ-R2
(SEQ ID NO;
158)wherein R1 is H, C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu; and R2 is —
NH2 or —
OH,or a pharmaceutically acceptable salt thereof.
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Specification