US2019076506A1PendingUtilityA1
Acylated glucagon analogues
Est. expiryJul 13, 2029(~3 yrs left)· nominal 20-yr term from priority
Inventors:Ditte RiberEddi MeierJens Rosengren DaugaardMarie SkovgaardJakob Lind TolborgGita Camilla Tejlgaard KampenCamilla Ærteberg Bæk
A61P 9/10A61P 5/00A61P 9/12A61P 3/10A61P 5/48A61P 9/00A61P 3/06A61P 7/12A61P 3/08A61P 3/04A61P 29/00A61P 3/00A61P 1/16C07K 14/605A61K 38/00A61K 47/54A61K 38/26
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Claims
Abstract
The invention provides materials and methods for promoting weight loss or preventing weight gain, and in the treatment of diabetes and associated metabolic disorders. In particular, the invention provides novel acylated glucagon analogue peptides effective in such methods. The peptides may mediate their effect by having increased selectivity for the GLP-1 receptor as compared to human glucagon.
Claims
exact text as granted — not AI-modified1 . A compound having the formula:
R 1 —Z—R 2
wherein R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl; R 2 is OH or NH 2 ; and Z is a peptide having the formula I
(I)
(SEQ ID NO: 4)
His-X2-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-X12-
Tyr-Leu-Asp-X16-X17-Ala-Ala-X20-X21-Phe-Val-X24-
Trp-Leu-X27-X28-Ala-X30;
wherein
X2 is selected from Aib and Ser;
X12 is selected from Lys, Arg or Leu;
X16 is selected from Arg and X;
X17 is selected from Arg and X;
X20 is selected from Arg, His and X;
X21 is selected from Asp and Glu;
X24 is selected from Ala and X;
X27 is selected from Leu and X;
X28 is selected from Arg and X;
X30 is X or is absent;
wherein at least one of X16, X17, X20, X24, X27, X28, and X30 is X;
and wherein each residue X is independently selected from the group consisting of Glu, Lys, Ser, Cys, Dbu, Dpr and Orn;
wherein the side chain of at least one residue X is conjugated to a lipophilic substituent having the formula:
(i) Z 1 , wherein Z 1 is a lipophilic moiety conjugated directly to the side chain of X; or
(ii) Z 1 Z 2 , wherein Z 1 is a lipophilic moiety, Z 2 is a spacer, and Z 1 is conjugated to the side chain of X via Z 2 ;
with the proviso that Z is not HSQGTFTSDYSKYLDS-K(Hexadecanoyl-γ-Glu)-AAHDFVEWLLRA (SEQ ID NO:5);
or a pharmaceutically acceptable salt thereof.
2 .- 30 . (canceled)
31 . A compound according to claim 1 , wherein Z has the formula:
(SEQ ID NO: 83)
HSQGTFTSDYSKYLD-K(Hexadecanoyl-γ-Glu)-
KAAHDFVEWLLRA;
(SEQ ID NO: 84)
HSQGTFTSDYSKYLDSKAAHDFVEWL-K(Hexadecanoyl-γ-
Glu)-RA;
(SEQ ID NO: 85)
HSQGTFTSDYSKYLDSKAA-K(Hexadecanoyl-γ-Glu)-
DFVEWLLRA;
(SEQ ID NO: 86)
HSQGTFTSDYSKYLDSKAAHDFVEWLL-K(Hexadecanoyl-γ-
Glu)-A;
(SEQ ID NO: 87)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-γ-Glu)-
AAHDFVEWLLRA;
(SEQ ID NO: 88)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-γ-Glu)-
AARDFVAWLLRA;
(SEQ ID NO: 89)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-γ-Glu)-
AAHDFVEWLLSA;
(SEQ ID NO: 90)
H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLL-K(Hexadecanoyl-
γ-Glu)-A;
(SEQ ID NO: 91)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-γ-Glu)-
AAHDFVEWLLKA;
(SEQ ID NO: 92)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-γ-Glu)-
AAHDFVE()WLLK()A;
(SEQ ID NO: 93)
HSQGTFTSDYSKYLDS-K(Hexadecanoyl-γ-Glu)-
AAHDFVEWLLRA;
(SEQ ID NO: 94)
H-Aib-QGTFTSDYSKYLDSKAA-K(Hexadecanoyl-γ-Glu)-
DFVAWLLRA;
(SEQ ID NO: 95)
H-Aib-QGTFTSDYSKYLDS-K(Dodecanoyl-γ-Glu)-
AAHDFVEWLLSA;
(SEQ ID NO: 96)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-[3-
aminopropanoyl])-AAHDFVEWLLSA;
(SEQ ID NO: 97)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-[8-
aminooctanoyl])-AAHDFVEWLLSA;
(SEQ ID NO: 98)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-ε-Lys)-
AAHDFVEWLLSA;
(SEQ ID NO: 99)
HSQGTFTSDYSKYLDS-K(Hexadecanoyl)-AAHDFVEWLLSA;
(SEQ ID NO: 100)
HSQGTFTSDYSKYLDS-K(Octadecanoyl-γ-Glu)-
AAHDFVEWLLSA;
(SEQ ID NO: 101)
HSQGTFTSDYSKYLDS-K([2-Butyloctanoyl]-γ-Glu)-
AAHDFVEWLLSA;
(SEQ ID NO: 102)
HSQGTFTSDYSKYLDS-K(Hexadecanoyl-[4-
Aminobutanoyl])-AAHDFVEWLLSA;
(SEQ ID NO: 103)
HSQGTFTSDYSKYLDS-K(Octadecanoyl-γ-Glu)-
AAHDFVEWLLSA;
(SEQ ID NO: 104)
HSQGTFTSDYSKYLDS-K(Hexadecanoyl-E)-AAHDFVEWLLSA;
(SEQ ID NO: 105)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl)-AAHDFVEWLLSA;
(SEQ ID NO: 106)
H-Aib-QGTFTSDYSKYLDS-K(Octadecanoyl-γ-Glu)-
AAHDFVEWLLSA;
(SEQ ID NO: 107)
H-Aib-QGTFTSDYSKYLDS-K([2-Butyloctanoyl]-γ-
Glu)-AAHDFVEWLLSA;
(SEQ ID NO: 108)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-[4-
Aminobutanoyl])-AAHDFVEWLLSA;
(SEQ ID NO: 109)
H-Aib-QGTFTSDYSKYLDS-K(Octadecanoyl-γ-Glu)-
AAHDFVEWLLSA;
or
(SEQ ID NO: 110)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-E)-
AAHDFVEWLLSA;
wherein residues marked “( )” participate in an intramolecular bond;
or a pharmaceutically acceptable salt thereof.
32 . A compound according to claim 1 , wherein Z has the formula:
(SEQ ID NO: 111)
H-Aib-QGTFTSDYS-K(Hexadecanoyl-isoGlu)-
YLDSKAAHDFVEWLLSA;
(SEQ ID NO: 112)
H-Aib-QGTFTSDYSKYLD-K(Hexadecanoyl-isoGlu)-
KAAHDFVEWLLSA;
(SEQ ID NO: 113)
H-Aib-QGTFTSDYSKYLDSKAA-K(Hexadecanoyl-isoGlu)-
DFVEWLLSA;
(SEQ ID NO: 114)
H-Aib-QGTFTSDYSKYLDSKAAHDFV-K(Hexadecanoyl-
isoGlu)-WLLSA;
(SEQ ID NO: 115)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoLys)-
AARDFVAWLLRA;
(SEQ ID NO: 116)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAKDFVEWLLSA;
(SEQ ID NO: 117)
H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLSA;
(SEQ ID NO: 118)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHEFVEWLLSA;
(SEQ ID NO: 119)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAEDFVEWLLSA;
(SEQ ID NO: 120)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLEA;
or a pharmaceutically acceptable salt thereof.
33 . A compound having the formula:
R 1 —Z—R 2
wherein R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl; R 2 is OH or NH 2 ; and Z is a peptide having the formula V
(V)
(SEQ ID NO: 12)
His-Aib-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-
Tyr-Leu-Asp-Ser-XIT-Ala-Ala-His-Asp-Phe-Val-Glu-
Trp-Leu-Leu-X28;
wherein
X17 is X
X28 is Ser or absent;
wherein X is selected from the group consisting of Glu, Lys, and Cys;
and wherein the side chain of X is conjugated to a lipophilic substituent having the formula:
(i) Z 1 , wherein Z 1 is a lipophilic moiety conjugated directly to the side chain of X; or
(ii) Z 1 Z 2 , wherein Z 1 is a lipophilic moiety, Z 2 is a spacer, and Z 1 is conjugated to the side chain of X via Z 2 .
34 . A compound according to claim 33 wherein Z has the formula:
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLS (SEQ ID NO:121);
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLL (SEQ ID NO:122);
or a pharmaceutically acceptable salt thereof.
35 . A compound having the formula:
R 1 —Z—R 2
wherein R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl; R 2 is OH or NH 2 ; and Z is a peptide having the formula VI
(VI)
(SEQ ID NO: 131)
His-Aib-Glu-Giy-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-
Tyr-Leu-Asp-Ser-XIT-Ala-Ala-His-Asp-Phe-Val-Glu-
Trp-Leu-Leu-Ser-Ala;
wherein X17 is X;
wherein X is selected from the group consisting of Glu, Lys, and Cys;
and wherein the side chain of X is conjugated to a lipophilic substituent having the formula:
(i) Z 1 , wherein Z 1 is a lipophilic moiety conjugated directly to the side chain of X; or
(ii) Z 1 Z 2 , wherein Z 1 is a lipophilic moiety, Z 2 is a spacer, and Z 1 is conjugated to the side chain of X via Z 2 ;
or a pharmaceutically acceptable salt thereof.
36 . A compound according to claim 35 wherein Z has the formula:
H-Aib-EGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-AAHDFVEWLLSA (SEQ ID NO: 123);
or a pharmaceutically acceptable salt thereof.
37 . A composition comprising a compound claim 1 , or a pharmaceutically acceptable salt thereof, in a mixture with a carrier.
38 .- 39 . (canceled)
40 . A method of diminishing weight gain or promoting weight loss in a subject, by administering a compound of claim 1 to said subject, in an amount sufficient to diminish weight gain or promote weight loss.
41 . A method of improving circulating glucose levels, glucose tolerance and/or circulating cholesterol levels, lowering circulating LDL levels, and/or increasing HDL/LDL ratio in a subject, by administering a compound of claim 1 to said subject, in an amount sufficient to improve circulating glucose levels, glucose tolerance and/or circulating cholesterol levels, lowering circulating LDL levels, and/or increasing HDL/LDL ratio.
42 . A method of treatment of a condition caused or characterized by excess body weight, and the treatment of obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, metabolic syndrome, pre-diabetes, insulin resistance, glucose intolerance, type 2 diabetes, type I diabetes, hypertension, atherogenic dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease in a subject, by administering a compound of claim 1 to said subject, in an amount sufficient to treat a condition caused or characterized by excess body weight, and to treat obesity, morbid obesity, obesity linked inflammation, obesity linked gallbladder disease, obesity induced sleep apnea, metabolic syndrome, pre-diabetes, insulin resistance, glucose intolerance, type 2 diabetes, type I diabetes, hypertension, atherogenic dyslipidemia, atherosclerosis, arteriosclerosis, coronary heart disease, peripheral artery disease, stroke or microvascular disease.
43 - 45 . (canceled)
46 . The method of claim 40 , wherein the compound is administered as part of a combination therapy with an agent for treatment of diabetes, obesity, dyslipidemia, or hypertension.
47 . The method of claim 46 wherein:
a.) the agent for treatment of diabetes is metformin, a sulfonylurea, a glinide, a DPP-IV inhibitor, a glitazone, insulin or an insulin analogue;
b.) the agent for treatment of obesity is a glucagon-like peptide receptor 1 agonist, peptide YY or analogue thereof, cannabinoid receptor 1 antagonist, lipase inhibitor, melanocortin receptor 4 agonist, or melanin concentrating hormone receptor 1 antagonist;
c.) the agent for treatment of hypertension is an angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, diuretic, beta-blocker, or calcium channel blocker and;
d.) the agent for treatment of dyslipidemia is a statin, a fibrate, a niacin, and/or a cholesterol absorption inhibitor.
48 - 50 . (canceled)Cited by (0)
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