US2015080295A1PendingUtilityA1
Glucagon analogues
Est. expiryDec 15, 2028(~2.4 yrs left)· nominal 20-yr term from priority
A61P 3/08A61P 3/10A61P 3/06A61P 9/12A61P 9/00A61P 9/10A61P 29/00A61P 25/00A61P 3/04A61P 3/00A61P 11/00A61P 1/16C07K 14/605A61K 38/00C12N 15/11A61K 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, metabolic syndrome and associated disorders. In particular, the invention provides novel 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 —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 I:
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-
Tyr-Leu-Asp-Ser-Lys-Ala-Ala-His-Asp-Phe-Val-Glu-
Trp-Leu-Leu-Arg-Ala
or differs from formula I at up to 4 of the following positions whereby, if different from formula I:
the residue at position 2 is selected from: Aib, D-Ser;
the residue at position 12 is selected from: Leu, Arg, Dpu, Dpr, Orn;
the residue at position 16 is selected from: Arg, His, Lys, Glu, Asp;
the residue at position 17 is selected from: Arg, Leu, Dpu, Dpr, Orn;
the residue at position 18 is selected from: Arg, Lys, His, Ser, Tyr;
the residue at position 20 is selected from: Gln, Lys, Arg, Glu, Asp;
the residue at position 21 is Glu;
the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg, Asp;
the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu;
the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu, Asp; and
the residue at position 29 is selected from: Thr, Glu, Lys;
and Z is absent or a peptide sequence of 1-20 amino acid units 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 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 I:
His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser-Lys-
Tyr-Leu-Asp-Ser-Lys-Ala-Ala-His-Asp-Phe-Val-Glu-
Trp-Leu-Leu-Arg-Ala
or differs from formula I at up to 5 of the following positions whereby, if different from formula I:
the residue at position 2 is selected from: Aib, D-Ser;
the residue at position 16 is selected from: Arg, His, Lys, Glu;
the residue at position 17 is: Arg, Leu, Dpu, Dpr, Orn;
the residue at position 20 is selected from: Gln, Lys, Arg, Glu, Asp;
the residue at position 21 is Glu;
the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg, Asp;
the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu;
the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu, Asp; and
the residue at position 29 is selected from: Thr, Glu, Lys;
and Z is absent or a peptide sequence of 1-20 amino acid units 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.
3 . A compound according to claim 1 wherein X differs from formula I at up to 4 of the following positions whereby, if different from formula I:
the residue at position 2 is selected from: Aib, D-Ser;
the residue at position 16 is selected from: Arg, His, Lys, Glu, Gly;
the residue at position 24 is selected from: Gln, Leu, Ala, Lys, Arg;
the residue at position 27 is selected from: Met, Cys, Lys, Arg, Glu;
the residue at position 28 is selected from: Asn, Ser, Lys, Glu, Ala, Leu; and
the residue at position 29 is selected from: Thr, Glu, Lys.
4 . A compound according to claim 1 wherein X comprises one or more of the following sets of residues:
17-Lys, 18-Ala;
17-Leu, 18-Ala;
17-Lys, 18-Ala, 20-His;
17-Leu, 18-Ala, 20-His;
17-Lys, 18-Ala, 24-Glu;
17-Leu, 18-Ala, 24-Glu;
17-Lys, 18-Ala, 27-Leu;
17-Leu, 18-Ala, 27-Leu;
17-Lys, 18-Ala, 29-Ala;
17-Leu, 18-Ala, 29-Ala;
17-Lys, 18-Ala, 27-Leu, 29-Ala;
17-Leu, 18-Ala, 27-Leu, 29-Ala;
17-Lys, 18-Ala, 27-Leu, 28-Arg, 29-Ala;
17-Leu, 18-Ala, 27-Leu, 28-Arg, 29-Ala;
24-Glu, 28-Arg;
24-Glu, 28-Arg, 27-Leu;
24-Glu, 28-Arg, 27-Leu, 29-Ala;
27-Leu, 28-Arg, 29-Ala;
29-Ala;
20-Arg, 24-Arg, 27-Lys, 28-Leu;
17-Arg;
18-Arg;
20-Gln;
24-Gln;
27-Met, 28-Asn, 29-Thr; or
24-Lys.
5 . A compound according to claim 2 wherein X comprises one of the following sets of residues:
20-Gln, 24-Gln, 27-Met, 28-Asn, 29-Thr; or 17-Leu, 20-Gln, 24-Gln, 28-Asn, 29-Thr.
6 . A compound according to claim 1 wherein X has a sequence selected from the group consisting of:
(SEQ ID NO: 6)
H-DSer-QGTFTSDYSKYLDSKAAHDFVEWLLRA;
(SEQ ID NO: 7)
H-Aib-QGTFTSDYSKYLDSKAAHDFVEWLLRA;
(SEQ ID NO: 5)
HSQGTFTSDYSKYLDSKAARDFVRWLKLA;
(SEQ ID NO: 12)
HSQGTFTSDYSKYLDSRAAHDFVEWLLRA;
(SEQ ID NO: 13)
HSQGTFTSDYSKYLDSKRAHDFVEWLLRA;
(SEQ ID NO: 8)
HSQGTFTSDYSKYLDSKAAQDFVEWLLRA;
(SEQ ID NO: 9)
HSQGTFTSDYSKYLDSKAAHDFVQWLLRA;
(SEQ ID NO: 10)
HSQGTFTSDYSKYLDSKAAHDFVEWLMNT;
(SEQ ID NO: 11)
HSQGTFTSDYSKYLDSKAAHDFVKWLLRA;
(SEQ ID NO: 18)
HSQGTFTSDYSKYLDSKAAKDFVEWLLRA;;
(SEQ ID NO: 19)
HSQGTFTSDYSKYLDKKAAHDFVEWLLRA;
and
(SEQ ID NO: 20)
HSQGTFTSDYSKYLDSKAAHDFVEWLLRA.
7 . A compound according to claim 2 wherein X has a sequence selected from the group consisting of:
(SEQ ID NO: 15)
HSQGTFTSDYSKYLDSKAAQDFVQWLMNT
and
(SEQ ID NO: 14)
HSQGTFTSDYSKYLDSLAAQDFVQWLLNT.
8 . A compound according to claim 1 wherein R 1 is H.
9 . A compound according to claim 1 wherein R 2 is NH 2 .
10 . A compound according to claim 1 wherein Z has no more than 25% sequence identity with the corresponding portion of the IP-1 sequence of human oxyntomodulin having the sequence Lys-Arg-Asn-Arg-Asn-Asn-Ile-Ala.
11 . A compound according to claim 1 wherein Z has a Cys as the C-terminal residue.
12 . A compound according to claim 1 wherein Z is absent.
13 . A compound according to claim 1 wherein one or more of the amino acid side chains in the compound, for example in the peptide X, is conjugated to a lipophilic substituent or a polymeric moiety.
14 . A compound according to claim 13 wherein X has the sequence:
(SEQ ID NO: 17)
HSQGTFTSDYSKYLDSK(isoGlu(Palm))AAHDFVEWLLRA.
15 . A nucleic acid encoding a compound according to claim 1 .
16 . The nucleic acid according to claim 15 , which is comprised in an expression vector.
17 . A host cell comprising a nucleic acid according to claim 15 .
18 . A pharmaceutical composition comprising a compound according to claim 1 , in admixture with pharmaceutically acceptable carrier.
19 . A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a compound according to claim 1 .
20 . A pharmaceutical composition comprising a nucleic acid according to claim 15 , in admixture with pharmaceutically acceptable carrier.
21 . A pharmaceutical composition comprising a host cell according to claim 17 , in admixture with pharmaceutically acceptable carrier.
22 . A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a nucleic acid according to claim 15 .
23 . A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a cell according to claim 17 .
24 . A compound according to claim 2 wherein R 1 is H.
25 . A compound according to claim 2 wherein R 2 is NH 2 .
26 . A compound according to claim 2 wherein one or more of the amino acid side chains in the compound, for example in the peptide X, is conjugated to a lipophilic substituent or a polymeric moiety.
27 . A nucleic acid encoding a compound according to claim 2 .
28 . A nucleic acid according to claim 27 , which is comprised in an expression vector.
29 . A host cell comprising a nucleic acid according to claim 27 .
30 . A pharmaceutical composition comprising a compound according to claim 2 , in admixture with pharmaceutically acceptable carrier.
31 . A pharmaceutical composition comprising a nucleic acid according to claim 27 , in admixture with pharmaceutically acceptable carrier.
32 . A pharmaceutical composition comprising a host cell according to claim 29 , in admixture with pharmaceutically acceptable carrier.
33 . A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a compound according to claim 2 .
34 . A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a nucleic acid according to claim 27 .
35 . A method of preventing weight gain, promoting weight loss, or for treatment of a condition caused by or associated with excess body weight or obesity including morbid obesity, obesity linked inflammation, obesity linked gallbladder disease and obesity induced sleep apnea, or for treatment of insulin resistance, glucose intolerance, type 2 diabetes, hypertension, atherogenic dyslipidimia, atherosclerois, arteriosclerosis, coronary heart disease or stroke, said method comprising administering a therapeutically effective amount of a cell according to claim 29 .Cited by (0)
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