US 12,735,457 B2 · Compositions including multi-agonist peptides and methods of manufacture and use

Abstract

The present invention relates generally to novel multi-agonist peptides useful as agents for the treatment and prevention of metabolic diseases and disorders, for example those which can be alleviated by control of weight loss, plasma glucose and lipid levels, insulin levels, and/or insulin secretion, positive inotropic effects, reduction of catabolic effects, slowing of gastric emptying and preventing neurodegeneration. Such conditions and disorders include, but are not limited to, control of food intake, weight loss, energy metabolism, plasma glucose levels, insulin levels, and/or insulin secretion, positive inotropic effects, reduction of catabolic effects, slowing of gastric emptying, obesity, diabetes and diabetes-related conditions, liver fat-associated inflammation and injury.

A peptide or pharmaceutically acceptable salt thereof having any one of the following sequences:

(SEQ ID
Y-(d)A-E-G-T-F-I-S-D-Y-S-I-A-L-D-K-I-H-Q-
NO:
1)
Q-D-F-V-N-W-L-L-A-Q-K-G-S-G-C-N-T-A-T-C-
A-T-Q-R-L-A-N-F-L-V-H-S-S-N-N-F-G-P-I-L-
P-P-T-N-V-G-S-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-F-J-S-D-Y-S-I-A-L-D-K-I-H-Q-
NO:
2)
Q-D-F-V-N-W-L-L-A-Q-K-G-K*-G-C-N-T-A-T-C-
A-T-Q-R-L-A-N-F-L-V-H-S-S-N-N-F-G-P-I-L-
P-P-T-N-V-G-S-N-T-Y-NH2
(SEQ ID)
Y-(d)A-E-G-T-F-I-S-D-Y-S-I-A-L-D-K-I-H-Q-
NO:
3)
Q-D-F-V-N-W-L-L-A-Q-K-G-S-G-C-N-T-A-T-C-
A-T-Q-R-L-A-N-F-L-V-H-S-S-N-N-F-G-P-K*-
L-P-P-T-N-V-G-S-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-F-I-S-D-Y-S-I-A-L-D-K-I-H-Q-
NO:
4)
Q-D-F-V-N-W-L-L-A-Q-K-G-S-G-C-N-T-A-T-C-
A-T-Q-R-L-A-N-F-L-V-H-S-S-N-N-F-G-P-I-L-
P-P-T-N-V-G-K*-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-F-I-S-D-Y-S-I-A-L-D-K-I-H-Q-
NO:
5)
Q-D-F-V-N-W-L-L-A-G-G-P-S-S-C-N-T-A-T-C-
A-T-Q-R-L-A-N-F-L-V-H-S-S-N-N-F-G-P-I-L-
P-P-T-N-V-G-S-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-F-I-S-D-Y-S-I-A-L-D-K-I-H-Q-
NO:
6)
Q-D-F-V-N-W-L-L-A-Q-K-G-S-G-C-N-T-A-T-C-
V-L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-
G-S-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-F-I-S-D-Y-S-I-A-L-D-K-I-H-Q-
NO:
7)
Q-D-F-V-N-W-L-L-A-Q-K-G-K*-G-C-N-T-A-T-C-
V-L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-
G-S-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-P-I-S-D-Y-S-I-A-L-D-K-I-H-Q-
NO:
8)
Q-D-F-V-N-W-L-L-A-Q-K-G-S-G-C-N-T-A-T-C-
V-L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-
G-K*-N-T-Y-NH2
(SEQ ID
Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-I-A-
NO:
9)
Q-Q-A-P-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-
A-T-Q-R-L-A-N-F-L-V-H-S-S-N-N-F-G-P-I-L-
P-P-T-N-V-G-S-N-T-Y-NH2
(SEQ ID
Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-I-A-
NO:
10)
Q-K*-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-
C-A-T-Q-R-L-A-N-F-L-V-H-S-S-N-N-F-G-P-I-
L-P-P-T-N-V-G-S-N-T-Y-NH2
(SEQ ID
Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-I-A-
NO:
11)
Q-Q-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-
V-L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-
Q-S-N-T-Y-NH2
(SEQ ID
Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-D-K-I-A-
NO:
12)
Q-K*-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-
C-V-L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-
T-G-S-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-F-T-S-D-Y-S-I-A-L-D-K-I-A-Q-
NO:
13)
Q-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-V-
L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-G-
S-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-F-T-S-D-Y-S-I-A-L-D-K*-I-A-
NO:
14)
Q-K-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-
V-L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-
G-S-N-T-Y-NH2
(SEQ ID
Y-(d)A-E-G-T-F-T-S-D-Y-S-I-A-L-D-K-I-A-Q-
NO:
15)
Q-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-V-
L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-G-
K*-N-T-Y-NH2
(SEQ ID
(d)Y-A-E-G-T-F-T-S-D-Y-S-I-A-L-D-K-I-A-Q-
NO:
16)
Q-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-V-
L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-G-
S-N-T-Y-NH2
(SEQ ID
(d)Y-A-E-G-T-F-T-S-D-Y-S-I-A-L-D-K-I-A-Q-
NO:
17)
Q-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-V-
L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-G-
K*-N-T-Y-NH2
(SEQ 10
(d)Y-A-E-G-T-F-T-S-D-Y-S-I-A-L-D-K-I-A-Q-
NO:
18)
K*-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-V-
I-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-G-
S-N-T-Y-NH2
(SEQ ID
(d)Y-A-E-G-T-F-T-S-D-Y-S-I-Q-L-D-K-I-A-Q-
NO:
19)
Q-A-F-V-Q-W-L-L-A-G-G-P-S-C-N-T-A-T-C-V-
L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-G-
K*-N-T-Y-NH2
(SEQ ID
(d)Y-A-E-G-T-F-T-S-D-Y-S-I-Q-L-D-K-I-A-Q-
NO:
20)
Q-A-F-V-Q-W-L-L-A-G-K*-G-S-C-N-T-A-T-C-V-
L-G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-G-
S-N-T-Y-NH2
(SEQ ID
(d)Y-A-E-G-T-F-T-S-D-Y-S-I-Q-L-D-K-I-A-Q-
NO:
21)
Q-A-F-V-Q-W-L-L-A-G-S-G-C-N-T-A-T-C-V-L-
G-R-L-S-Q-E-L-H-R-L-Q-T-Y-P-R-T-N-T-G-K*-
N-T-Y-NH2
(SEQ ID
(d)Y-A-E-G-T-F-T-S-D-Y-S-I-Q-L-D-K-I-A-Q-
NO:
22)
Q-A-F-V-Q-W-L-L-A-G-S-G-C-N-T-A-T-C-A-T-
Q-R-L-A-N-F-L-V-H-S-S-N-N-F-G-P-I-L-P-P-
T-N-V-G-K*-N-T-Y-NH2
wherein K* in the above-identified sequences is Lys-γ-Glu-γ-Glu-C═O(CH2)nR3, wherein n is an integer from 12-20, and R3 is CO2H, —CO2CH3, —CO2NH2, —CO2NHCH3, —CO2N(CH3)2, —CH3, or —NH2.

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Compositions including multi-agonist peptides and methods of manufacture and use

Life of this patent

Compositions including multi-agonist peptides and methods of manufacture and use

Life of this patent

Abstract

Claims8