Glucagon analogues
View Patent ↗The invention provides materials and methods for the treatment of obesity and excess weight, diabetes, and other associated metabolic disorders. In particular, the invention provides novel glucagon analog 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.
1. A compound having the formula:
R 1 —X—Z—R 2
wherein
R 1 is H, C 1-4 alkyl, acetyl, formyl, benzoyl or trifluoroacetyl;
R 2 is OH or NH 2 ;
X is a peptide which has the formula:
(SEQ ID NO: 4)
H-Aib-QGTFTSDYSKYLDEKAAKDFIEWLLSA,
(SEQ ID NO: 5)
H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLESA,
(SEQ ID NO: 6)
HSQGTFTSDYSRYLDSKAAEDFVEWLLRA,
(SEQ ID NO: 7)
HSQGTFTSDYSKYLDSKAAEDFVEWLLRA,
(SEQ ID NO: 8)
HSQGTFTSDYSKYLDSKAAHDFVEWLLS,
(SEQ ID NO: 9)
HSQGTFTSDYSKYLDSKAAHDFVEWLLR,
(SEQ ID NO: 10)
HSQGTFTSDYSKYLDEKAAHEFVEWLESA,
(SEQ ID NO: 11)
H-Aib-QGTFTSDYSKYLDEKRAKDFIEWLLS,
or
(SEQ ID NO: 12)
HSQGTFTSDYSRYLDSKAAHDFVEWLLSA,
(SEQ ID NO: 17)
H-Aib-HGTFTSDYSKYLESKAAEEFIEWLESA,
(SEQ ID NO: 18)
HSHGTFTSDYSKYLEEKAAHEFIEWLESA,
(SEQ ID NO: 19)
H-Aib-HGTFTSDYSKYLEEKAAHEFVEWLESA,
and Z is absent or is a sequence of 1-20 amino acid units independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Cys, Glu, Lys, Arg, Dbu, Dpr and Orn;
or a pharmaceutically acceptable salt thereof.
2. A compound according to claim 1 , wherein one or more of the amino acid side chains in the peptide X or Z is conjugated to a lipophilic substituent.
3. A compound according to claim 2 wherein peptide X has the formula:
(SEQ ID NO: 4)
H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-
AAKDFIEWLLSA,
(SEQ ID NO: 5)
H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLESA,
(SEQ ID NO: 6)
HSQGTFTSDYSRYLDS-K(Hexadecanoyl-isoGlu)-
AAEDFVEWLLRA,
(SEQ ID NO: 7)
HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAEDFVEWLLRA,
(SEQ ID NO: 8)
HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLS,
(SEQ ID NO: 9)
HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLR,
(SEQ ID NO: 10)
HSQGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-
AAHEFVEWLESA,
(SEQ ID NO: 11)
H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-
RAKDFIEWLLS,
(SEQ ID NO: 12)
HSQGTFTSDYSRYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLSA,
(SEQ ID NO: 17)
H-Aib-HGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-
AAEEFIEWLESA,
(SEQ ID NO: 18)
HSHGTFTSDSKYLEE-K(Hexadecanoyl-isoGlu)-
AAHEFIEWLESA,
(SEQ ID NO: 19)
H-Aib-HGTFTSDYSKYLEE-K(Hexadecanoyl-isoGlu)-
AAHEFVEWLESA,
or a pharmaceutically acceptable salt thereof.
4. A compound according to claim 3 having the formula:
(Compound 4)
(SEQ ID NO: 4)
H-H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-
AAKDFIEWLLSA-NH 2 ,
(Compound 5)
(SEQ ID NO: 5)
H-H-Aib-QGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLESA-NH 2 ,
(Compound 6)
(SEQ ID NO: 6)
H-HSQGTFTSDYSRYLDS-K(Hexadecanoyl-isoGlu)-
AAEDFVEWLLRA-NH 2 ,
(Compound 7)
(SEQ ID NO: 7)
H-HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAEDFVEWLLRA-NH 2 ,
(Compound 8)
(SEQ ID NO: 8)
H-HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLS-NH 2 ,
(Compound 9)
(SEQ ID NO: 9)
H-HSQGTFTSDYSKYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLR-OH,
(Compound 10)
(SEQ ID NO: 10)
H-HSQGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-
AAHEFVEWLESA-NH 2 ,
(Compound 11)
(SEQ ID NO: 11)
H-H-Aib-QGTFTSDYSKYLDE-K(Hexadecanoyl-isoGlu)-
RAKDFIEWLLS-OH,
(Compound 12)
(SEQ ID NO: 12)
H-HSQGTFTSDYSRYLDS-K(Hexadecanoyl-isoGlu)-
AAHDFVEWLLSA-NH 2 ,
(Compound 17)
(SEQ ID NO: 17)
H-H-Aib-HGTFTSDYSKYLES-K(Hexadecanoyl-isoGlu)-
AAEEFIEWLESA-OH,
(Compound 18)
(SEQ ID NO: 18)
H-HSHGTFTSDYSKYLEE-K(Hexadecanoyl-isoGlu)-
AAHEFIEWLESA-OH,
(Compound 19)
(SEQ ID NO: 19)
H-H-Aib-HGTFTSDYSKYLEE-K(Hexadecanoyl-isoGlu)-
AAHEFVEWLESA-NH 2 ,
or a pharmaceutically acceptable salt thereof.