US2009312259A1PendingUtilityA1
Long lasting glucagon-like peptide 2 (glp-2) for the treatment of gastrointestinal diseases and disorders
Assignee: CONJUCHEM BIOTECHNOLOGIES INCPriority: Feb 16, 2001Filed: Jul 19, 2009Published: Dec 17, 2009
Est. expiryFeb 16, 2021(expired)· nominal 20-yr term from priority
Inventors:Dominique P. BridonNissab BoudjellabRoger LegerMartin RobitailleKaren ThibaudeauJulie Carette
A61P 1/00A61K 47/643A61K 38/26C07K 14/605A61P 1/04A61K 38/38C07K 2319/00
63
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Claims
Abstract
This invention relates to glucagon-like peptide 2 (GLP-2) derivatives. In particular, this invention relates to GLP-2 peptide derivatives having an extended in vivo half-life, for the treatment or prevention of gastrointestinal disorders or diseases such as inflammatory bowel disease and other gastrointestinal functions, from any segment of the gastrointestinal tract, from the oesophagus to the anus.
Claims
exact text as granted — not AI-modified1 . An gastrointestinal tissue growth promoter derivative comprising
a GLP-2 peptide or an analog or fragment thereof having gastrointestinal tissue growth promoting activity, and a reactive entity coupled to the peptide,
the derivative being capable of covalently bonding in vivo with a functionality on a blood component.
2 . A derivative as claimed in claim 1 wherein the GLP-2 is of the sequence
R 1 -(Y 1 ) m -X 1 -X 2 -X 3 -X 4 -X 5 -Phe 6 -Ser 7 -Asp 8 -(P 1 )-X 14 -
Asp 15 -X 16 -X 17 -Ala 18 -X 19 -X 20 -X 21 -Phe 22 -(P 2 )-Trp 25 -
Leu 26 -X 27 -X 28 -Thr 29 -Lys 30 -P 3 -(Y 2 ) n -R 2
wherein
X 1 is His or Tyr;
X 2 is Ala, Gly, D-Ala, Pro, Ile, Nor-Val, α-aminobutyric acid, or an Ala-replacement amino acid conferring on said analog resistance to DPP-IV enzyme;
X 3 is Asp, Glu, Pro HPro; or X 2 -X 3 are X 2 ψ(CH(OH)CH 2 )X 3 ; X 2 ψ(CH 2 NH 2 )X 3 or X 2 ψ(CHCH)X 3 wherein X 2 and X 3 are as defined above;
X 4 is Gly or Ala;
X 5 is Ser or Ala;
P 1 is Glu-X 10 -Asn-Thr-Ile, Gly-X 10 -Asn-Thr-Val or Tyr-Ser-Lys-Tyr;
X 10 is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;
X 14 is Leu or Lys;
X 16 is Asn, Lys or Ala;
X 17 is Leu or Lys;
X 19 is Ala or Thr,
X 20 is Arg, Lys, His or Ala;
X 21 is Asp or Lys;
X 27 is Ile or Leu;
X 28 is Gln or His;
P 2 is Ile-Asn, Ile-Ala or Val-Gln;
P 3 is a covalent bond, or is Ile, Ile-Thr, Ile-Thr-Asp or Ile-Thr-Asn;
R 1 is NH 2 or a N-terminal blocking group;
R 2 is COOH, CONH 2 or a C-terminal blocking group;
Y 1 is one or two of Arg, Lys, and His;
Y 2 is one or two of Arg, Lys, and His; and
m and n are independently 0 or 1.
3 . A derivative as claimed in claim 2 wherein X 1 is His; X 2 is Ala or Gly, X 3 is Asp; X 4 is Gly; X 5 is Ser; P 1 is Glu-X 10 -Asn-Thr-Ile; X 10 is Met; X 16 is Asn or Lys; X 19 is Ala; X 20 is Arg; X 27 is Ile; X 28 is Gln; P 2 is Ile-Asn; P 3 is Ile-Thr-Asp and R 2 is CONH 2 .
4 . A derivative as claimed in claim 1 wherein the reactive entity is a maleimide or a maleimido-containing group.
5 . A derivative as claimed in claim 3 wherein the GLP-2 is selected from the group consisting of:
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Lys-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys-CONH 2 ;
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Lys-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Lys-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
and
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Lys-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 .
6 . A derivative as claimed in claim 1 selected from the group consisting of:
MPA-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-
Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-
Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys-MPA-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Lys(MPA)-Leu-Ala-Ala-Arg-Asp-Phe-Ile-
Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
MPA-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-
Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-
Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Lys(MPA)-Leu-Ala-Ala-Arg-Asp-Phe-Ile-
Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(MPA)-
CONH 2 ;
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Lys(AEEA-MPA)-Leu-Ala-Ala-Arg-Asp-Phe-
Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(AEEA-MPA)-
CONH 2 ;
MPA-AEEA-His-Gly-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-
Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-
Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
MPA-AEEA-His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-
Asn-Thr-Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-
Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-Asn-
Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-Lys(AEEA-MPA)-
CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Lys(AEEA-MPA)-Leu-Ala-Ala-Arg-Asp-Phe-
Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Lys(MPA)-Ala-Ala-Arg-Asp-Phe-Ile-
Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Lys(MPA)-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-Ile-
Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Lys(MPA)-Phe-Ile-
Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Lys(AEEA-MPA)-Ala-Ala-Arg-Asp-Phe-
Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Lys(AEEA-MPA)-Asp-Asn-Leu-Ala-Ala-Arg-Asp-Phe-
Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 ;
and
His-Ala-Asp-Gly-Ser-Phe-Ser-Asp-Glu-Met-Asn-Thr-
Ile-Leu-Asp-Asn-Leu-Ala-Ala-Arg-Lys(AEEA-MPA)-Phe-
Ile-Asn-Trp-Leu-Ile-Gln-Thr-Lys-Ile-Thr-Asp-CONH 2 .
7 . A derivative as claimed in claim 1 wherein the blood component comprises blood proteins.
8 . A pharmaceutical composition comprising a derivative as claimed in claim 1 in combination with a pharmaceutically acceptable carrier.
9 . A composition as claimed in claim 8 for the treatment of prevention of gastrointestinal disorders or diseases.
10 . A method for the treatment of prevention of gastrointestinal disorders or diseases in a subject comprising administering to a subject an effective amount of a derivative as claimed in claim 1 , alone or in combination with a pharmaceutically acceptable carrier.
11 . A method for the promotion of gastrointestinal tissue growth in a subject comprising administering to a subject an effective amount of a derivative as claimed in claim 1 , alone or in combination with a pharmaceutical carrier.
12 . A conjugate comprising a derivative as claimed in claim 1 covalently bonded to a blood component.
13 . A conjugate as claimed in claim 12 wherein the reactive entity is a maleimide or a maleimido-containing group and the blood component is a blood protein.
14 . A conjugate as claimed in claim 13 wherein the blood protein is serum albumin.
15 . A conjugate as claimed in claim 12 wherein the derivative is as defined in claim 6 .
16 . A method for extending the in vivo half-life of a GLP-2 peptide having gastrointestinal tissue growth promoting activity, the method comprising covalently bonding the peptide to a blood component.
17 . A method as claimed in claim 16 wherein the peptide comprises GLP-2 or an analog or fragment thereof having gastrointestinal tissue growth promoting activity.
18 . A method as claimed in claim 16 wherein the GLP-2 peptide is as defined in claim 5 .
19 . A method for the treatment of prevention of gastrointestinal disorders or diseases in a subject comprising administering to a subject an effective amount of a conjugate as claimed in claim 12 , alone or in combination with a pharmaceutical carrier.Join the waitlist — get patent alerts
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