US2015196651A1PendingUtilityA1
Lipidated peptides for lowering blood glucose
Assignee: USTAV ORGANICKE CHEMIE A BIOCHEMIE AKADEMIE VED CR V V IPriority: Jan 15, 2014Filed: Jan 15, 2015Published: Jul 16, 2015
Est. expiryJan 15, 2034(~7.4 yrs left)· nominal 20-yr term from priority
A61K 38/00A61P 3/10A61K 38/22C07K 14/575A61K 47/60A61K 47/542C07K 7/08C07K 14/001A61K 47/48038A61K 47/48215
38
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Claims
Abstract
Lipidated analogs of prolactin-releasing peptides (PrRP) and their use in controlling and lowering blood glucose in mammals is disclosed. Useful compounds included lipidated analogs of PrRP20 and PrRP31. Pharmacological effects are demonstrated both in vitro and in vivo. Peripheral administration of the lipidated peptides lowers blood glucose levels. These treatments are applicable for treating impaired glucose tolerance (IGT), and glucose intolerance condition. The disclosed compounds have application in treating medical conditions including diabetes, pre-diabetes, eating disorders, and obesity.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A method of treating a subject diagnosed as having or being susceptible to one or more disorders characterised by an increased level of glucose in blood, comprising the step of administering to the subject a lipidated analog of prolactin releasing peptide (PrRP) having the formula:
(Formula 1; SEQ ID NO: 1)
J-rRPsGRt-NH 2 ,
wherein
r is isoleucine, alanine, or phenylglycine;
s is valine or phenylglycine;
t is phenylalanine, tryptophan, pyroglutamic acid or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, wherein Ar represents phenyl or naphtyl, optionally substituted by a halogen, methyl or nitro group; and
J represents a chain of 13 or 24 amino acids lipidated in one position by X, wherein X=X 1 or X 2 X 1 ;
wherein X 1 is a C8 to C18 fatty acid bound to an amino acid having at least one free amino group, SH group, or OH group, either directly by an amide bond or through X 2 ;
and wherein X 2 is a hydrophilic linker selected from the group consisting of a polyoxyethylene moiety, an arylalkyl moiety, and a saturated or unsaturated, linear or branched C3-C8 hydrocarbon chain, wherein one or more carbon atoms may be replaced by heteroatoms selected from the group comprising N, S, and O, said hydrocarbon chain carrying at least one amino group or carboxylic acid group, one of which can be substituted to form
CONH 2 ;
NH-polyoxyethylene;
COOM 1 ; wherein M 1 is alkali metal;
CN;
COOR 1 ,COR 1 ,CONHR 1 ; wherein R 1 is lower alkyl, aryl alkyl, polyoxyethylene, methylpolyoxyethylene, or aminoethylpolyoxyethylene;
(CHOH) 1 R 2 ; wherein R 2 is H or COOH and n is an integer from 2 to 10; or
(CH) n N + (R′) 3 ; wherein each R′ is independently H or C1-C4 alkyl.
2 . The method of claim 1 , wherein the lipidated analog of prolactin releasing peptide (PrRP) has the formula:
(Formula 2; SEQ ID NO: 2)
(X)kRmHnHSqEuRTPDINPAWYmoRprRPsGRt-NH 2 ,
wherein
k is serine, threonine, or diaminopropionic acid;
m is threonine, alanine, or methylalanine;
n is glutamine or arginine;
q is methionine or norleucine;
u is threonine or isoleucine;
o is glycine or serine;
p is glycine, alanine, proline or N-methylglycine;
r is isoleucine, alanine or phenylglycine;
s is valine or phenylglycine; and
t is phenylalanine, tryptophan, pyroglutamic acid, or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, where Ar represents phenyl or naphtyl, optionally substituted by a halogen, methyl or nitro group.
3 . The method of claim 2 , wherein kRmHnHSqEuRTPDINPAWYmoRp (SEQ ID NO: 35) is shortened by eliminating 1 to 11 amino acids.
4 . The method of claim 1 , wherein the lipidated analog of prolactin releasing peptide (PrRP) has the formula:
(Formula 2; SEQ ID NO: 2)
(X)kRmHnHSqEuRTPDINPAWYmoRprRPsGRt-NH 2 ,
or
(Formula 3; SEQ ID NO: 3)
(X)TPDINPAWYmoRprRPsGRt-NH 2 ,
wherein
k is serine, threonine, or diaminopropionic acid;
m is threonine, alanine, or methylalanine;
n is glutamine or arginine;
q is methionine or norleucine;
u is threonine or isoleucine;
o is glycine or serine;
p is glycine, alanine, proline, or N-methylglycine;
r is isoleucine, alanine, or phenylglycine;
s is valine or phenylglycine; and
t is phenylalanine, tryptophan, pyroglutamic acid, or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, where Ar represents phenyl or naphtyl, optionally substituted by a halogen, methyl or nitro group.
5 . The method of claim 4 , wherein the binding affinity of said lipidated analog of prolactin releasing peptide (PrRP) towards GPR10 receptor expressed in rat hypophyseal cells is not higher than 10 −6 mol.1 −1 .
6 . The method of claim 1 , wherein the lipidated analog of prolactin releasing peptide (PrRP) has the formula:
(Formula 4; SEQ ID NO: 4)
(X)SRmHnHSqEuRTPDINPAWYmoRprRPsGRt-NH 2 ,
wherein
m is threonine, alanine, or methylalanine;
n is glutamine or arginine;
q is methionine or norleucine;
u is threonine or isoleucine;
o is glycine or serine;
p is glycine, alanine, proline, or N-methylglycine;
r is isoleucine, alanine, or phenylglycine;
s is valine or phenylglycine; and
t is phenylalanine, tryptophan, pyroglutamic acid, or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, where Ar represents phenyl or naphtyl, optionally substituted by a halogen, methyl or nitro group; wherein X=X 1 or X 1 X 2 , and wherein X 1 is a C8-C18 fatty acid bound to an amino acid of formula 4, either directly by an amide bond, or through X 2 .
7 . The method according claim 1 , wherein t is selected from the group consisting of histidine, benzylhistidine, naphtylalanine, tryptophan, pyroglutamic acid, benzylcysteine, benzyl-O-glutamate, norleucine, dichlorophenylalanine, tetrachlorophynylalanine, pentafluorophenylalanine, methyl-O-phenylalanine, methyl-NH-phenylalanine, and nitrophenyalanine
8 . The method of claim 1 , wherein the lipidated analog of prolactin releasing peptide (PrRP) has the formula:
(Formula 5; SEQ ID NO: 5)
(X)TPDINPAWYmoRGrRPsGRF-NH 2 ;
(Formula 6; SEQ ID NO: 6)
(X)TPDINPAWYmoRGrRPsGR 1-Nal-NH 2 ;
or
(Formula 7; SEQ ID NO: 7)
(X)RmHnHSNleETRTPDINPAWYmoRGrRPsGR 1-Nal-NH 2 ;
wherein:
1-nal is naphtylalanine;
m is threonine, alanine, or methylalanine;
n is glutamine or arginine;
q is methionine or norleucine;
u is threonine or isoleucine;
o is glycine or serine;
p is glycine, alanine, proline, or N-methylglycine;
r is isoleucine, alanine, or phenylglycine;
s is valine or phenylglycine; and
t is phenylalanine, tryptophan, pyroglutamic acid, or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, where Ar represents phenyl or naphtyl, optionally substituted by a halogen, methyl, or nitro group.
9 . The method of claim 1 , wherein the lipidated analog of prolactin releasing peptide (PrRP) has the formula:
(Formula 10; SEQ ID NO: 10)
(X)TPDINPAWYASRGIRPVGRF-NH 2 ;
or
(Formula 8; SEQ ID NO: 8)
(X)SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH 2 .
10 . The method of claim 9 , wherein X=X 1 or X 2 X 1 , wherein X 1 is a C12 to C16 fatty acid bound to an amino acid of formula 10 or formula 8, either directly by an amide bond or through X 2 , and wherein X 2 is selected from the group consisting of β-alanine, γ-amino butyric acid, polyoxyethylene, and γ-glutamic acid.
11 . The method of claim 10 , wherein X 1 is myristic acid or palmitic acid, and wherein X 2 is γ-glutamic acid or polyexyethylene.
12 . The method of claim 11 , wherein X 1 is bound to amino acid 1, 5, or 7 of formula 10, or 1, 11, or 18 of formula 8, either directly or through X 2 .
13 . The method of claim 12 , wherein X 1 is bound to amino acid 1 or 5 of formula 10, or 1 or 11 of formula 8, either directly or through X 2 .
14 . The method of claim 1 , wherein the lipidated analog of prolactin releasing peptide (PrRP) is selected from the group consisting of:
wherein palm is palmitic acid, and wherein X 2 is γ-glutamic acid or polyoxyethylene.
15 . The method of claim 1 , wherein the lipidated analog of prolactin releasing peptide (PrRP) is selected from the group consisting of:
(SEQ ID NO: 16)
X 1 -SRAHQHSMETRTPDINPAWYTGRGIRPVGRF-NH 2 ;
(SEQ ID NO: 17)
X 1 -SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH 2 ;
(SEQ ID NO: 18)
(N-palm)-SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NHMe;
(SEQ ID NO: 19)
(N-palm)-SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NOMe;
(SEQ ID NO: 20)
(N-myr)-TPDINPAWYTGRGIRPVGRF-NH 2 ;
(SEQ ID NO: 21)
(N-myr)-TPDINPAWYASRGIRPVGRF-NH 2 ;
(SEQ ID NO: 22)
(N-oct)-TPDINPAWYASRGIRPVGRF-NH 2 ;
(SEQ ID NO: 23)
(N-dec)-TPDINPAWYASRGIRPVGRF-NH 2 ;
(SEQ ID NO: 24)
(N-dodec)-TPDINPAWYASRGIRPVGRF-NH 2 ;
(SEQ ID NO: 25)
X 1‘ -SRAHQHS Nle ETRTPDINPAWYTGRGIRPVGRF-NH 2 ;
(SEQ ID NO: 26)
X 1 -SRAHQHS Nle ETRTPDINPAWYTGRGIRPVGR 1-Nal-NH 2 ;
(SEQ ID NO: 27)
X 1 -SRAHQHS Nle ETRTPDINPAWYTGRGIRPVGR PheCl 2 -NH 2 ;
(SEQ ID NO: 28)
X 1 -SRAHQHS Nle ETRTPDINPAWYTGRGIRPVGR PheNO 2 -NH 2 ;
(SEQ ID NO: 29)
X 1 -SRAHQHS Nle ETRTPDINPAWYTGRGIRPVGR PheF 5 -NH 2 ;
(SEQ ID NO: 30)
X 1 -SRAHQHS Nle ETRTPDINPAWYTGRGIRPVGRY-NH 2 ;
(SEQ ID NO: 31)
X 1 -SRAHRHS Nle EIRTPDINPAWYASRGIRPVGRY-NH 2 ;
(SEQ ID NO: 32)
(N-myr)-Nle-ETRTPDINPAWYTGRGIRPVGRF-NH 2 ;
(SEQ ID NO: 33)
(N-myr)-QHSMETRTPDINPAWYTGRGIRPVGRF-NH 2 ;
and
(SEQ ID NO: 34)
(N-myr)-QHSMETRTPDINPAWYASRGIRPVGRF-NH 2 ;
wherein X=X 1 or X 1 ′,wherein X 1 ′ is palmitic acid, myristic acid or stearic acid; and wherein X 1 is palmitic acid or myristic acid.
16 . A lipidated analog of prolactin releasing peptide (PrRP) having the formula:
(Formula 1; SEQ ID NO: 1)
J-rRPsGRt-NH 2 ,
wherein
r is isoleucine, alanine, or phenylglycine;
s is valine or phenylglycine; and
t is phenylalanine, tryptophan, pyroglutamic acid, or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, wherein Ar represents phenyl or naphtyl, optionally substituted by a halogen, methyl or nitro group;
J represents a chain of 13 or 24 amino acids lipidated in one position by X, where X=X 1 or x 2 x 1 ;
wherein X 1 is a C8-C18 fatty acid bound to an amino acid having at least one free amino group, SH group, or OH group either directly or through X 2 ;
and wherein X 2 is a hydrophilic linker selected from the group consisting of a polyoxyethylene moiety, an arylalkyl moiety, and a saturated or unsaturated, linear or branched C3-C8 hydrocarbon chain, wherein one or more carbon atoms may be replaced by one or more heteroatoms selected from the group consisting of N, S, and O; said hydrocarbon chain carrying at least one amino group or carboxylic acid group, one of which can be substituted to form
CONH 2 ;
NH-polyoxyethylene;
COOM 1 ; wherein M 1 is alkali metal;
CN;
COOR 1 ,COR 1 ,CONHR 1 ; wherein R 1 is lower alkyl, aryl alkyl, polyoxyethylene, methylpolyoxyethylene, or aminoethylpolyoxyethylene;
(CHOH) n R 2 ; wherein R 2 is H or COOH and n is an integer from 2 to 10; or
(CH) n N + (R′) 3 ; wherein each R′ is independently H or C1-C4 alkyl, with the proviso that when X is bound to the N-terminal amino acid of formula 1, then X is X 2 X 1 .
17 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , having the formula:
(Formula 2; SEQ ID NO: 2)
(X)kRmHnHSqEuRTPDINPAWYmoRprRPsGRt-NH 2 ,
wherein
k is serine, threonine or diaminopropionic acid;
m is threonine, alanine or methylalanine;
n is glutamine or arginine;
q is methionine or norleucine;
u is threonine or isoleucine;
o is glycine or serine;
p is glycine, alanine, proline, or N-methylglycine;
r is isoleucine, alanine, or phenylglycine;
s is valine or phenylglycine;
t is phenylalanine, tryptophan, pyroglutamic acid, or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, where Ar represents phenyl or naphtyl, optionally substituted by halogen, methyl, or nitro group.
18 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 17 , wherein kRmHnHSqEuRTPDINPAWYmoRp (SEQ ID NO: 35) is shortened by eliminating 1 to 11 amino acids.
19 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , having the formula:
(Formula 2; SEQ ID NO: 2)
(X)kRmHnHSqEuRTPDINPAWYmoRprRPsGRt-NH 2 ,
or
(Formula 3; SEQ ID NO: 3)
(X)TPDINPAWYmoRprRPsGRt-NH 2 ;
wherein
k is serine, threonine, or diaminopropionic acid;
m is threonine, alanine, or methylalanine;
n is glutamine or arginine;
q is methionine or norleucine;
u is threonine or isoleucine;
o is glycine or serine;
p is glycine, alanine, proline, or N-methylglycine;
r is isoleucine, alanine, or phenylglycine;
s is valine or phenylglycine;
t is phenylalanine, tryptophan, pyroglutamic acid, or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, where Ar represents phenyl or naphtyl, optionally substituted by halogen, methyl or nitro group.
20 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , wherein the binding affinity of said lipidated analog of prolactin releasing peptide (PrRP) towards GPR10 receptor expressed in rat hypophyseal cells is not higher than 10 −6 mol.1 −1 .
21 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , having the formula:
(Formula 4; SEQ ID NO: 4)
(X)SRmHnHSqEuRTPDINPAWYmoRprRPsGRt-NH 2 ;
wherein
m is threonine, alanine, or methylalanine;
n is glutamine or arginine;
q is methionine or norleucine;
u is threonine or isoleucine;
o is glycine or serine;
p is glycine, alanine, proline, or N-methylglycine;
r is isoleucine, alanine, or phenylglycine;
s is valine or phenylglycine;
t is phenylalanine, tryptophan, pyroglutamic acid, or an amino acid with a side chain containing CH 2 —Ar or CH 2 —S—CH 2 —Ar, where Ar represents phenyl or naphtyl, optionally substituted by halogen, methyl or nitro group, and wherein X 1 is a C10-C18 fatty acid.
22 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , wherein t is selected from the group consisting of histidine, benzylhistidine, naphtylalanine, tryptophan, pyroglutamic acid, benzylcysteine, benzyl-O-glutamate, norleucine, dichlorophenylalanine, tetrachlorophynylalanine, pentafluorophenylalanine, methyl-O-phenylalanine, methyl-NH-phenylalanine and nitrophenyalanine
23 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , having the formula:
(5; SEQ ID NO: 5)
(X)TPDINPAWYmoRGrRPsGRF-NH 2 ;
(6; SEQ ID NO: 6)
(X)TPDINPAWYmoRGrRPsGR 1-Nal-NH 2 ;
or
(7; SEQ ID NO: 7)
(X)RmHnHSNleETRTPDINPAWYmoRGrRPsGR 1-Nal-NH 2 ;
wherein
1-nal is naphtylalanine;
m is threonine, alanine, or methylalanine;
n is glutamine or arginine;
o is glycine or serine;
r is isoleucine, alanine, or phenylglycine; and
s is valine or phenylglycine.
24 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , having the formula:
(Formula 10; SEQ ID NO: 10)
(X)TPDINPAWYASRGIRPVGRF-NH 2 ,
or
(Formula 8; SEQ ID NO: 8)
(X)SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH 2 ;
wherein X 1 is a C12 to C16 fatty acid bound to an amino acid of formular 8 or formula 10, either directly by an amide bond or through X 2 , and wherein X 2 is selected from the group consisting of β-alanine, γ-amino butyric acid, polyoxyethylene and γ-glutamic acid.
25 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 24 , wherein X 1 is bound to any one of amino acids 1 to 22 of formula 8, or 1 to 12 of formula 10, either directly or through X 2 , wherein said amino acid bound to X 1 is replaced by lysine.
26 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 25 , wherein X 1 is bound to amino acid 1 or 11 of formula 8, or 1 or 5 of formula 10, either directly or through X 2 , wherein said amino acid bound to X 1 is replaced by lysine.
27 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , having the formula:
(Formula 10; SEQ ID NO: 10)
(X)TPDINPAWYASRGIRPVGRF-NH 2 ;
or
(Formula 8; SEQ ID NO: 8)
(X)SRTHRHSMEIRTPDINPAWYASRGIRPVGRF-NH 2 ;
wherein X=X 1 or X 2 X 1 , wherein X 1 is myristic or palmitic acid, bound to an amino acid of formula 8 or formula 10, either directly by an amide bond or through X 2 , and wherein X 2 is γ-glutamic acid or polyoxyethylene.
28 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 27 , wherein X 1 is bound to amino acid 1, 11 or 18 of formula 8, or 1, 5 or 7 of formula 10, either directly or through X 2 .
29 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 28 , wherein X 1 is bound to amino acid 1 or 11 of formula 8, or 1 or 5 of formula 10, either directly or through X 2 .
30 . The lipidated analog of prolactin releasing peptide (PrRP) of claim 16 , selected from the group consisting of:
wherein palm is palmitic acid, and wherein X 2 is γ-glutamic acid or polyoxyethylene.
31 . A pharmaceutical composition comprising the lipidated analog of prolactin releasing peptide (PrRP) of claim 16 and a pharmaceutically acceptable carrier thereof.
32 . A method of treating or preventing elevated blood glucose levels, comprising administering the pharmaceutical composition according to claim 31 .Join the waitlist — get patent alerts
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