Peptide compounds analogues of the glucagon-like peptide-1...

Details Peptide compounds analogues of the glucagon-like peptide-1... Peptide compounds analogues of the glucagon-like peptide-1...

1999-03-15

2003-09-16

Low, Christopher S. F. (Department: 1653)

Chemistry: natural resins or derivatives; peptides or proteins;

Peptides of 3 to 100 amino acid residues

25 or more amino acid residues in defined sequence

C530S308000, C514S012200

Reexamination Certificate

active

06620910

ABSTRACT:

TITLE OF THE INVENTION
The present invention relates to new peptide compounds that are analogues of Glucagon-Like Peptide-1 (7-37).
BACKGROUND OF THE INVENTION
The Glucagon-Like Peptides-1 (7-37) and (7-36) NH
2
(
t
GLP-1) are peptides of intestinal origin that are heavily involved in the control of glucidic homeostasis. These peptides are the principal mediators of the “entero-insular axis” and act by bindings to specific receptors.
t
GLP-1 is predominantly active in the pancreas where it exerts a powerful stimulating effect on the secretion of insulin by &bgr; cells in a glucose-dependent manner (S. Mojsov et al., J. Clin. Invest., 1987, 79, 619; and J. J. Hoist, F.E.B.S. Letters, 1987, 211, 169). That stimulation is accompanied by stimulation of the release of somatostatin and inhibition of the release of glucagon.
In parallel with the above-mentioned effects on the pancreas,
t
GLP-1 retards gastric emptying, reduces acid secretions and stimulates the peripheral utilisation of glucose in the muscles, liver and adipocytes. (M. L. Villanueva et al., Diabetologia, 1994, 37, 1163; D. J. Drucker, Diabetes, 1998, 47, 159).
Recent studies have also demonstrated that
t
GLP-1 could have an effect on eating behaviour by inhibiting food and drink intake as a result of action on the satiety centres (M. D. Turton et al., Nature. 1996, 379, 69).
t
GLP-1 thus has many potential therapeutic applications, especially in the treatment of non-insulin-dependent type II diabetes, obesity, and type I diabetes. Like many hormonal peptides, however, it has a rather short plasma half-life—less than 2 minutes (T. J. Kieffer et al., Endocrinology, 1995, 136, 3585)—which limits its use.
DESCRIPTION OF THE PRIOR ART
The use of the natural peptide GLP
1
(7-37) for its insulinotropic properties has been described extensively, whether as the natural peptide GLP
1
(7-37) or GLP
1
(7-36) NH
2
on its own, in the form of salts, esters or amides (U.S. Pat. No. 5,616,492, WO 8706941, WO 9011 296), associated with phospholipids (WO 9318785) or associated with other hypoglycaeinic substances (WO 9318786). Analogues modified at some positions of the natural sequence have also been studied (EP 733 644, EP 708 179, EP 658 568, WO 91 11457) with the aim of devising compounds as potent as GLP
1
(7-37) that are better absorbed.
The compounds of the present invention have a novel structure derived from that of
t
GLP-1 by modifications to several residues and/or by suppression of arginine at position 36. In addition to the fact that they are new, these compounds have valuable pharmacological properties as a result of their agonist character in relation to
t
GLP-1 receptors. The modifications have the additional advantage of substantially increasing the metabolic stability of the compounds of the invention, thus giving them a duration of action superior to that of the natural peptide. Those properties make the compounds especially valuable in the treatment of pathologies in which
t
GLP-1 is involved, especially in the treatment of non-insulin-dependent type II diabetes, obesity, and type I diabetes.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to peptide compounds of the general formula (I):
Z
1
-X
1
-X
2
-X
3
-Gly-Thr-Phe-Thr-Ser-X
4
-X
5
-Ser-X
6
-X
7
-X
8
-Glu-Gly-Gln-Ala-X
9
-Lys-X
10
-X
11
-X
12
-Ala-X
13
-X
14
-Val-Lys-Gly-X
15
-Gly-Z
2
SEQ ID NO: 1  (I)
wherein:
Z
1
, substituent of the terminal amino group of the peptide of formula (I), represents a hydrogen atom, an alkyl group, a linear or branched (C
1
-C
6
)-acyl group, or an optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted arylalkylcarbonyl, optionally substituted heteroarylalkylcarbonyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkoxycarbonyl or optionally substituted alkoxycarbonyl group,
Z
2
, substituent of the terminal carbonyl group of the peptide of formula (I), represents a hydroxy group, a linear or branched (C
1
-C
6
)-alkoxy group, or an amino group optionally substituted by one or two identical or different groups selected from linear or branched (C
1
-C
6
)-alkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylcarbonyl, optionally substituted heteroarylcarbonyl, optionally substituted arylalkylcarbonyl and optionally substituted heteroarylalkylcarbonyl, or by two groups that together with the nitrogen atom form a saturated ring having from 5 to 7 ring members),
X
1
to X
14
each represents, independently of the others:
a natural or non-natural amino acid residue, having the D or L configuration, of the formula:
 wherein:
R
1
represents a hydrogen atom and R
2
represents a hydrogen atom or an alkyl, aminoalkyl (optionally substituted on the nitrogen atom by one or two alkyl, phenyl, benzyl, cycloalkyl, optionally substituted aryloxycarbonyl, optionally substituted arylalkoxycarbonyl and/or optionally substituted alkoxycarbonyl groups), thioalkyl (optionally substituted on the sulphur atom by an alkyl, phenyl, benzyl or cycloalknyl group), hydroxyalkyl (optionally substituted on the oxygen atom by an alkyl, phenyl, benzyl or cycloalkyl group), carboxyalkyl, carbamoylalkyl, guanidinoalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted fused cycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroaryl or optionally substituted heteroarylalkyl group, or an imidazolyl or imidazolylalkyl group,
or R
1
and R
2
together with the carbon atom carrying them, form a cycloalkyl or fused cycloalkyl group,
or a natural or non-natural cyclic amino acid residue, having the D or L configuration, of the formula:
 wherein A, together with the nitrogen and carbon atoms to which it is attached, forms a mono- or bi-cyclic group having from 5 to 11 ring members which is saturated, partially unsaturated or unsaturated, and is optionally substituted,
or a 3-amino-3-(2-furyl)propanoic acid residue, and
X
15
represents a bond or an arginine residue (Arg),
and addition salts thereof with a pharmaceutically acceptable acid or base.
with the proviso that:
X
15
represents a bond:
when X
1
is a residue having the L or D configuration selected from tyrosine (Tyr), arginine (Arg), phenylalanine (Phe), ornithine (Orn), methionine (Met), proline (Pro), leucine (Leu), valine (Val), isoleucine (Ile), alanine (Ala), aspartic acid (Asp), glutamic acid (Glu), asparagine (Asn), glutamine (Gln) and histidine (His),
and/or
when X
2
represents a residue having the L or D configuration selected from serine (Ser), glycine (Gly), cysteine (Cys), sarcosine (Sar), alanine (Ala), proline (Pro), valine (Val), leucine (Leu), isoleucine (Ile) and threonine (Thr),
and/or
when X
3
represents an amino acid residue having the L or D configuration selected from glutamine (Gln), aspartic acid (Asp), threonine (Thr), asparagine (Asn) and glutamic acid (Glu),
and/or
when X
5
represents a tyrosine residue (Tyr),
and/or
when X
6
represents a lysine residue (Lys),
and/or
when X
10
represents an amino acid residue selected from glutamine (Gln), alanine (Ala), threonine (Thr), serine (Ser) and glycine (Gly),
and/or
when X
13
represents an amino acid residue selected from phenylalanine (Phe), valine (Val), leucine (Leu), isoleucine (Ile), alanine (Ala) and tyrosine (Tyr),
it being understood that:
the residues X
1
to X
15
may not be so selected that the peptide obtained is identical to the natural peptide,
the term “alkyl” denotes a linear or branched chain having from 1 to 6 carbon atoms,
the term “cycloalkyl” denotes a saturated cyclic hydrocarbon group having from 3 to 8 ring members,
the expression “fused cycloalkyl” denotes a bicyclic group having from 8 to 11 ring members composed of a saturated carbon-containing rings fused with a saturated or unsaturated ring optionally comprising one or two hetero atoms selected from nitrogen, oxygen and sulphur, for example an indan, tetrahydronaphthalene or tetrahydroquinoline group,
the term “aryl” denotes a phenyl, naphthy

Affiliated with

Also associated with

Rating

Peptide compounds analogues of the glucagon-like peptide-1... does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Peptide compounds analogues of the glucagon-like peptide-1..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Peptide compounds analogues of the glucagon-like peptide-1... will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3092735