US 2006/0234933 A1Published application

Vasoactive intestinal polypeptide pharmaceuticals

AssigneeTransition Therapeutics Inc.

InventorJohn Nestor

Life of this patent

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Abstract

Pharmaceutical compositions relating to vasoactive intestinal polypeptides and methods for the treatment of metabolic disorders, including diabetes, insulin resistance, metabolic acidosis and obesity are presented. Methods of using the vasoactive intestinal polypeptide compositions are also disclosed.

Claims25

Dependent claims

A vasoactive intestinal polypeptide selected from the group consisting of:

(a) a polypeptide corresponding to Formula (I):
Formula (I)
Acyl-His-Ser-Asp-aa1-aa2-Phe-Thr-aa3-aa4-Tyr-aa5-
Arg-aa6-Baa1-Baa2-Baa3-aa7-Ala-aa8-Baa4-Baa5-Tyr-
Leu-aa9-aa10-aa11-aa12-aa13-aa14-aa15-aa16-Haa-
(Laa-Laa-Haa-Haa)n-Laa-Lys(ε-long acyl)-X
(SEQ ID NO:
86)
wherein:
n is an integer number from 1 to 3;
each Haa is independently a hydrophilic amino acid;
each Laa is independently a lipophilic amino acid;
acyl is a C2-16 acyl chain;
long acyl is a C12-30 acyl chain;
X is OH or NHR1 where R1 is H or lower alkyl, haloalkyl, or Cys(PEG)-X, or PEG;
PEG is a functionalized polyethylene glycol chain of C10-C3000 chain;
aa1 is Gly or Ala;
aa2 is Val, Ile, or Leu;
aa3 is Asp, Arg, Gln, or Glu;
aa4 is Ser, Asn, Gln, Asp or Glu;
aa5 is Ser or Thr;
aa6 is Leu or Tyr;
Baa1 is Arg or Leu;
Baa2 is Lys, Leu, or Arg;
Baa3 is Gln, Lys or Ala;
aa7 is Met, Leu, Val or Ala;
aa8 is Ala or Val;
Baa4 is Lys, Arg or Gln;
Baa5 is Lys, Arg or Gln;
aa9 is Asn, Gln, Ala or Glu;
aa10 is Trp, Ala, or Ser;
aa11 is Ile, Val or Trp;
aa12 is Leu, Lys, Arg or Gln;
aa13 is Lys, Arg, Asn, Gln, or Gly;
aa14 is Ala, Gly, Gln, Lys or Arg;
aa15 is Lys, Arg, Leu, Ala or absent;
and
aa16 is Lys, Arg, Leu, Ala or absent.
provided that if aa15 or aa16 is absent, the next amino acid present downstream is the next amino acid in the peptide agonist sequence;
(b) a polypeptide corresponding to Formula (II):
Formula (II)
Acyl-His-Ser-Asp-aa1-aa2-Phe-Thr-aa3-aa4-Tyr-aa5-
Arg-aa6-Baa1-Baa2-Baa3-aa7-Ala-aa8-Baa4-Baa5-Tyr-
Leu-aa9-aa10-aa11-aa12-aa13-aa14-aa15-aa16-Haa-
(Laa-Laa-Haa-Haa)n-Laa-aa17-Pro-Pro-Pro-Lys(ε-
long acyl)-X (SEQ ID NO:
87)
wherein:
n is an integer number from 1 to 3;
each Haa is independently a hydrophilic amino acid;
each Laa is independently a lipophilic amino acid;
acyl is a C2-16 acyl chain;
long acyl is a C12-30 acyl chain;
X is OH or NHR1 where R1 is H or lower alkyl, haloalkyl, or Cys(PEG)-X, or PEG;
PEG is a functionalized polyethylene glycol chain of C10-C3000 chain;
aa1 is Gly or Ala;
aa2 is Val, Ile, or Leu;
aa3 is Asp, Arg, Gln, or Glu;
aa4 is Ser, Asn, Gln, Asp or Glu;
aa5 is Ser or Thr;
aa6 is Leu or Tyr;
Baa1 is Arg or Leu;
Baa2 is Lys, Leu, or Arg;
Baa3 is Gln, Lys or Ala;
aa7 is Met, Leu, Val or Ala;
aa8 is Ala or Val;
Baa4 is Lys, Arg or Gln;
Baa5 is Lys, Arg or Gln;
aa9 is Asn, Gln, Ala or Glu;
aa10 is Trp, Ala, or Ser;
aa11 is Ile, Val or Trp;
aa12 is Leu, Lys, Arg or Gln;
aa13 is Lys, Arg, Asn, Gln, or Gly;
aa14 is Ala, Gly, Gln, Lys or Arg;
aa15 is Lys, Arg, Leu, Ala or absent;
aa16 is Lys, Arg, Leu, Ala or absent;
and
aa17 is Gln, Ser, Gly, Asp, Ala, Arg, Lys, Glu, Pro, Asn, Leu, or absent,
provided that if aa15, aa16 or aa17 is absent, the next amino acid present downstream is the next amino acid in the peptide agonist sequence;
(c) a polypeptide corresponding to Formula (III):
Formula (III)
Acyl-His-Ser-Asp-aa1-aa2-Phe-Thr-aa3-aa4-Tyr-aa5-
Arg-aa6-Baa1-Baa2-Baa3-aa7-Ala-aa8-Baa4-Baa5-Tyr-
Leu-aa9-aa10-aa11-aa12-aa13-aa14-aa15-aa16-Haa-
(Laa-Laa-Haa-Haa)n-Laa-aa17-Lys(ε-long acyl)-PEG
(SEQ ID NO:
88)
wherein:
n is an integer number from 1 to 3;
each Haa is independently a hydrophilic amino acid;
each Laa is independently a lipophilic amino acid;
acyl is a C2-16 acyl chain;
long acyl is a C12-30 acyl chain;
PEG is a functionalized polyethylene glycol chain of C10-C3000 chain;
aa1 is Gly or Ala;
aa2 is Val, Ile, or Leu;
aa3 is Asp, Arg, Gln, or Glu;
aa4 is Ser, Asn, Gln, Asp or Glu;
aa5 is Ser or Thr;
aa6 is Leu or Tyr;
Baa1 is Arg or Leu;
Baa2 is Lys, Leu, or Arg;
Baa3 is Gln, Lys or Ala;
aa7 is Met, Leu, Val or Ala;
aa8 is Ala or Val;
Baa4 is Lys, Arg or Gln;
Baa5 is Lys, Arg or Gln;
aa9 is Asn, Gln, Ala or Glu;
aa10 is Trp, Ala, or Ser;
aa11 is Ile, Val or Trp;
aa12 is Leu, Lys, Arg or Gln;
aa13 is Lys, Arg, Asn, Gln, or Gly;
aa14 is Ala, Gly, Gln, Lys or Arg;
aa15 is Lys, Arg, Leu, Ala or absent;
aa16 is Lys, Arg, Leu, Ala or absent;
and
aa17 is Gln, Ser, Gly, Asp, Ala, Arg, Lys, Glu, Pro, Asn, Leu, or absent,
provided that if aa15, aa16 or aa17 is absent, the next amino acid present downstream is the next amino acid in the peptide agonist sequence;
and
(d) a polypeptide selected from SEQ ID NO:
1-SEQ ID NO:
66.

119 more elements

A vasoactive intestinal polypeptide analog comprising a sequence of Formula (IV):

Formula (IV)
Acyl-aa1-aa2-aa3-aa4-aa5-aa6-Thr-aa8-aa9-aa10-Thr-
aa12-aa13-aa14-aa15-aa16-aa17-Ala-aa19-aa20-aa21-
aa22-aa23-aa24-aa25-aa26-aa27-aa28-aa29-aa30-aa31-
aa32-aa33-aa34-aa35-aa36-aa37-aa38-aa39-aa40
wherein:
aa1 is:
any naturally occurring amino acid, dH, or is absent;
aa2 is:
any naturally occurring amino acid, dA, dS, or Aib;
aa3 is:
Asp or Glu;
aa4 is:
any naturally occurring amino acid, dA, Aib, or NMeA;
aa5 is:
any naturally occurring amino acid, dV, or Aib;
aa6 is:
any naturally occurring amino acid;
aa8 is:
Asp, Glu, Ala, Lys, Leu, Arg, or Tyr;
aa9 is:
Asn, Gln, Asp, or Glu;
aa10 is:
any naturally occurring aromatic amino acid, or Tyr (OMe);
aa12 is:
hR, Orn, Lys (isopropyl), Aib, Cit or any naturally occurring amino acid except Pro;
aa13 is:
Aib, or any naturally occurring amino acid except Pro;
aa14 is:
hR, Orn, Lys (isopropyl), Aib, Cit, or any naturally occurring amino acid except Pro;
aa15 is:
hR, Orn, Lys (isopropyl), Aib, K (Ac), Cit, or any naturally occurring amino acid except Pro;
aa16 is:
hR, Orn, Lys (isopropyl), Cit, or any naturally occurring amino acid except Pro;
aa17 is:
Nle, Aib, or any naturally occurring amino acid except Pro;
aa19 is:
any naturally occurring amino acid except Pro;
aa20 is:
hR, Orn, Lys (isopropyl), Aib, K(Ac), Cit, or any naturally occurring amino acid except Pro;
aa21 is:
hR, Orn, Aib, K(Ac), Cit, or any naturally occurring amino acid except Pro;
aa22 is:
Aib, Tyr (OMe), or any naturally occurring amino acid except Pro;
aa23 is:
Aib, or any naturally occurring amino acid except Pro;
aa24 is:
any naturally occurring amino acid except Pro;
aa25 is:
Aib, or any naturally occurring amino acid except Pro;
aa26 is:
any naturally occurring amino acid except Pro;
aa27 is:
hR, Lys (isopropyl), Orn, dK, or any naturally occurring amino acid except Pro;
aa28 is:
any naturally occurring amino acid, Aib, hR, Cit. Orn, dK, or is absent;
aa29 is:
any naturally occurring amino acid, hR, Orn, Cit, Aib or is absent;
aa30 is:
any naturally occurring amino acid, hR, Orn, Cit, Aib or is absent;
and
aa31 to aa40 are any naturally occurring amino acid or are absent;
provided that if aa1, aa28, aa29, aa30, aa31, aa32, aa33, aa34, aa35, aa36, aa37, aa38, aa39, or aa40 is absent, the next amino acid present downstream is the next amino acid in the peptide agonist sequence;
and a C-terminal sequence selected from the group consisting of:
(a)-Haa-(Laa-Laa-Haa-Haa)n-Laa-Lys(ε-
long acyl)-Z;
(SEQ ID NO:84)
(b)-Haa-(Laa-Laa-Haa-Haa-)n-Laa-aa17-Pro-Pro-Pro-
Lys(ε-long acyl)-X;
(c)-Haa-(Laa-Laa-Haa-Haa)n-Laa-Lys(ε-long acyl)
-PEG;
and
(d)-a polyproline type II helix;
wherein:
n is an integer number from 1 to 3;
each Haa is independently a hydrophilic amino acid;
each Laa is independently a lipophilic amino acid;
acyl is a C2-16 acyl chain;
long acyl is a C12-30 acyl chain;
X is OH or NHR1 where R1 is H or lower alkyl, haloalkyl, or PEG.

77 more elements

Dependencies are inferred from the claim text.

Facts

Application: 11/279,238Filed 10 Apr 2006
Priority: WO PCT/US05/362357 Oct 2005
Published: 19 Oct 2006
Term ends: Not estimatedThe source records don’t support an estimate.

Classification4 codes

A61K 38/17
Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof: from animals; from humans
C07K 14/57563
Hormones: vasoactive intestinal peptide [VIP]; Related peptides
A61K
Medicines and medical preparations
C07K
Peptides

Family

Application60/617,500Us provisional application · filed 8 Oct 2004
Application11/245,499Continuation in part · filed 7 Oct 2005
Application11/279,238Continuation in part · filed 10 Apr 2006
US 2006/0079456 A1Published application
US 7,566,691 B2Related patent
US 7,595,294 B2Related patent
US 2006/0234933 A1This patent

From the US filing history. Foreign family members aren’t listed.

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Abstract

A vasoactive intestinal polypeptide selected from the group consisting of:

(a) a polypeptide corresponding to Formula (I):
Formula (I)
Acyl-His-Ser-Asp-aa1-aa2-Phe-Thr-aa3-aa4-Tyr-aa5-
Arg-aa6-Baa1-Baa2-Baa3-aa7-Ala-aa8-Baa4-Baa5-Tyr-
Leu-aa9-aa10-aa11-aa12-aa13-aa14-aa15-aa16-Haa-
(Laa-Laa-Haa-Haa)n-Laa-Lys(ε-long acyl)-X
(SEQ ID NO:
86)
wherein:
n is an integer number from 1 to 3;
each Haa is independently a hydrophilic amino acid;
each Laa is independently a lipophilic amino acid;
acyl is a C2-16 acyl chain;
long acyl is a C12-30 acyl chain;
X is OH or NHR1 where R1 is H or lower alkyl, haloalkyl, or Cys(PEG)-X, or PEG;
PEG is a functionalized polyethylene glycol chain of C10-C3000 chain;
aa1 is Gly or Ala;
aa2 is Val, Ile, or Leu;
aa3 is Asp, Arg, Gln, or Glu;
aa4 is Ser, Asn, Gln, Asp or Glu;
aa5 is Ser or Thr;
aa6 is Leu or Tyr;
Baa1 is Arg or Leu;
Baa2 is Lys, Leu, or Arg;
Baa3 is Gln, Lys or Ala;
aa7 is Met, Leu, Val or Ala;
aa8 is Ala or Val;
Baa4 is Lys, Arg or Gln;
Baa5 is Lys, Arg or Gln;
aa9 is Asn, Gln, Ala or Glu;
aa10 is Trp, Ala, or Ser;
aa11 is Ile, Val or Trp;
aa12 is Leu, Lys, Arg or Gln;
aa13 is Lys, Arg, Asn, Gln, or Gly;
aa14 is Ala, Gly, Gln, Lys or Arg;
aa15 is Lys, Arg, Leu, Ala or absent;
and
aa16 is Lys, Arg, Leu, Ala or absent.
provided that if aa15 or aa16 is absent, the next amino acid present downstream is the next amino acid in the peptide agonist sequence;
(b) a polypeptide corresponding to Formula (II):
Formula (II)
Acyl-His-Ser-Asp-aa1-aa2-Phe-Thr-aa3-aa4-Tyr-aa5-
Arg-aa6-Baa1-Baa2-Baa3-aa7-Ala-aa8-Baa4-Baa5-Tyr-
Leu-aa9-aa10-aa11-aa12-aa13-aa14-aa15-aa16-Haa-
(Laa-Laa-Haa-Haa)n-Laa-aa17-Pro-Pro-Pro-Lys(ε-
long acyl)-X (SEQ ID NO:
87)
wherein:
n is an integer number from 1 to 3;
each Haa is independently a hydrophilic amino acid;
each Laa is independently a lipophilic amino acid;
acyl is a C2-16 acyl chain;
long acyl is a C12-30 acyl chain;
X is OH or NHR1 where R1 is H or lower alkyl, haloalkyl, or Cys(PEG)-X, or PEG;
PEG is a functionalized polyethylene glycol chain of C10-C3000 chain;
aa1 is Gly or Ala;
aa2 is Val, Ile, or Leu;
aa3 is Asp, Arg, Gln, or Glu;
aa4 is Ser, Asn, Gln, Asp or Glu;
aa5 is Ser or Thr;
aa6 is Leu or Tyr;
Baa1 is Arg or Leu;
Baa2 is Lys, Leu, or Arg;
Baa3 is Gln, Lys or Ala;
aa7 is Met, Leu, Val or Ala;
aa8 is Ala or Val;
Baa4 is Lys, Arg or Gln;
Baa5 is Lys, Arg or Gln;
aa9 is Asn, Gln, Ala or Glu;
aa10 is Trp, Ala, or Ser;
aa11 is Ile, Val or Trp;
aa12 is Leu, Lys, Arg or Gln;
aa13 is Lys, Arg, Asn, Gln, or Gly;
aa14 is Ala, Gly, Gln, Lys or Arg;
aa15 is Lys, Arg, Leu, Ala or absent;
aa16 is Lys, Arg, Leu, Ala or absent;
and
aa17 is Gln, Ser, Gly, Asp, Ala, Arg, Lys, Glu, Pro, Asn, Leu, or absent,
provided that if aa15, aa16 or aa17 is absent, the next amino acid present downstream is the next amino acid in the peptide agonist sequence;
(c) a polypeptide corresponding to Formula (III):
Formula (III)
Acyl-His-Ser-Asp-aa1-aa2-Phe-Thr-aa3-aa4-Tyr-aa5-
Arg-aa6-Baa1-Baa2-Baa3-aa7-Ala-aa8-Baa4-Baa5-Tyr-
Leu-aa9-aa10-aa11-aa12-aa13-aa14-aa15-aa16-Haa-
(Laa-Laa-Haa-Haa)n-Laa-aa17-Lys(ε-long acyl)-PEG
(SEQ ID NO:
88)
wherein:
n is an integer number from 1 to 3;
each Haa is independently a hydrophilic amino acid;
each Laa is independently a lipophilic amino acid;
acyl is a C2-16 acyl chain;
long acyl is a C12-30 acyl chain;
PEG is a functionalized polyethylene glycol chain of C10-C3000 chain;
aa1 is Gly or Ala;
aa2 is Val, Ile, or Leu;
aa3 is Asp, Arg, Gln, or Glu;
aa4 is Ser, Asn, Gln, Asp or Glu;
aa5 is Ser or Thr;
aa6 is Leu or Tyr;
Baa1 is Arg or Leu;
Baa2 is Lys, Leu, or Arg;
Baa3 is Gln, Lys or Ala;
aa7 is Met, Leu, Val or Ala;
aa8 is Ala or Val;
Baa4 is Lys, Arg or Gln;
Baa5 is Lys, Arg or Gln;
aa9 is Asn, Gln, Ala or Glu;
aa10 is Trp, Ala, or Ser;
aa11 is Ile, Val or Trp;
aa12 is Leu, Lys, Arg or Gln;
aa13 is Lys, Arg, Asn, Gln, or Gly;
aa14 is Ala, Gly, Gln, Lys or Arg;
aa15 is Lys, Arg, Leu, Ala or absent;
aa16 is Lys, Arg, Leu, Ala or absent;
and
aa17 is Gln, Ser, Gly, Asp, Ala, Arg, Lys, Glu, Pro, Asn, Leu, or absent,
provided that if aa15, aa16 or aa17 is absent, the next amino acid present downstream is the next amino acid in the peptide agonist sequence;
and
(d) a polypeptide selected from SEQ ID NO:
1-SEQ ID NO:
66.

119 more elements

Facts

Application

11/279,238Filed 10 Apr 2006

Priority

WO PCT/US05/362357 Oct 2005

Published

19 Oct 2006

Term ends

Not estimatedThe source records don’t support an estimate.

Classification4 codes

A61K 38/17
Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof: from animals; from humans
C07K 14/57563
Hormones: vasoactive intestinal peptide [VIP]; Related peptides
A61K
Medicines and medical preparations
C07K
Peptides

Family

Application60/617,500Us provisional application · filed 8 Oct 2004

Application11/245,499Continuation in part · filed 7 Oct 2005

Application11/279,238Continuation in part · filed 10 Apr 2006

US 2006/0079456 A1Published application

US 7,566,691 B2Related patent

US 7,595,294 B2Related patent

US 2006/0234933 A1This patent

From the US filing history. Foreign family members aren’t listed.