Glucagon-GLP-1-GIP triple agonist compounds
First Claim
Patent Images
1. A glucagon-GLP-1-GIP triple agonist compound having the general formula I:
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R1-Tyr-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R2 (SEQ ID NO;
52)
(I)whereinR1 is H—
, C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;
X2 is Aib, Gly, Ala, D-Ala, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c;
X10 is Tyr or Leu;
X12 is Lys, Ile or ψ
;
X13 is Ala, Tyr or Aib;
X15 is Asp or Glu;
X16 is Ser, Glu, Lys or ψ
;
X17 is Lys or ψ
;
X19 is Gln or Ala;
X20 is Lys, His, Arg or ψ
;
X21 is Ala, Asp or Glu;
X23 is Val or Ile;
X24 is Asn, Glu or ψ
;
X27 is Leu, Glu or Val;
X28 is Ala, Ser, Arg or ψ
;
X29 is Aib, Ala, Gln or Lys;
X30 is Lys, Gly, or is absent;
Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
53), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
54), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
55), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
56), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
57) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
58), or is absent;
ψ
is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a lipophilic substituent;
andR2 is —
NH2 or —
OH;
or a pharmaceutically acceptable salt thereof.
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Abstract
The present invention relates to compounds which have agonist activity at the glucagon, GIP and GLP-1 receptors, and to their use in the treatment of metabolic disorders.
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Citations
24 Claims
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1. A glucagon-GLP-1-GIP triple agonist compound having the general formula I:
-
R1-Tyr-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-X10-Ser-X12-X13-Leu-X15-X16-X17-Ala-X19-X20-X21-Phe-X23-X24-Trp-Leu-X27-X28-X29-X30-Y1-R2 (SEQ ID NO;
52)
(I)wherein R1 is H—
, C1-4 alkyl, acetyl, formyl, benzoyl, trifluoroacetyl or pGlu;X2 is Aib, Gly, Ala, D-Ala, Ser, N-Me-Ser, Ac3c, Ac4c or Ac5c; X10 is Tyr or Leu; X12 is Lys, Ile or ψ
;X13 is Ala, Tyr or Aib; X15 is Asp or Glu; X16 is Ser, Glu, Lys or ψ
;X17 is Lys or ψ
;X19 is Gln or Ala; X20 is Lys, His, Arg or ψ
;X21 is Ala, Asp or Glu; X23 is Val or Ile; X24 is Asn, Glu or ψ
;X27 is Leu, Glu or Val; X28 is Ala, Ser, Arg or ψ
;X29 is Aib, Ala, Gln or Lys; X30 is Lys, Gly, or is absent; Y1 is Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
53), Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
54), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
55), Lys-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
56), Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser (SEQ ID NO;
57) or Pro-Ser-Ser-Gly-Ala-Pro-Pro-Ser (SEQ ID NO;
58), or is absent;ψ
is a residue of Lys, Arg, Orn or Cys in which the side chain is conjugated to a lipophilic substituent;and R2 is —
NH2 or —
OH;or a pharmaceutically acceptable salt thereof. - View Dependent Claims (2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24)
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Specification