Glyco-modified atrial natriuretic peptide

Patent metadata

Field	Value
Publication number	US-2016017015-A1
Application number	US-201514806487-A
Country	US
Kind code	A1
Filing date	Jul 22, 2015
Priority date	Jan 23, 2013
Publication date	Jan 21, 2016
Grant date	—

Abstract

The present invention provides a modified atrial natriuretic peptide that exhibits prolonged duration in blood and maintains cGMP elevating activity. The present invention provides a modified peptide in which at least one sugar substance is linked directly through a glycosidic bond or via a linker structure to at least one hANP peptide, or a pharmaceutically acceptable salt thereof, a medicament comprising the modified peptide or the salt thereof as an active ingredient, etc.

First claim

1 . A modified peptide in which at least one sugar substance is linked directly through a glycosidic bond or via a linker structure to at least one hANP peptide, or a pharmaceutically acceptable salt thereof.

2 . The modified peptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the sugar substance is linked directly through a glycosidic bond or via a linker structure to at least one of the N terminus of the hANP peptide, the C terminus of the hANP peptide, and the side chain of at least one amino acid constituting the peptide.

3 . The modified peptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the hANP peptide is hANP(1-28), hANP(2-28), hANP(3-28), hANP(1-27), hANP(2-27), or hANP(3-27).

4 . The modified peptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the sugar substance is selected from at least one type of monosaccharide, disaccharide, trisaccharide, and glycochain of 4 or more monosaccharides bonded through glycosidic bonds, and when a plurality of sugar substances are contained in one molecule, the sugar substances may be the same as or different from each other.

5 . The modified peptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the sugar substance is a glycochain of 4 or more monosaccharides bonded through glycosidic bonds.

6 . The modified peptide according to claim 5 or a pharmaceutically acceptable salt thereof, wherein the sugar substance is a glycoprotein-derived N-linked glycochain or O-linked glycochain, or an altered glycochain thereof.

wherein Gxx is GlcNAc, Glc, or Man (hereinafter, glycochains having the above structure are referred to as “AG(9)”, “AG(9-Glc)”, and “AG(9-Man)”, respectively, according to the type of GXX), and “O/N-L” represents binding to the linker structure or the hANP peptide through an O-glycosidic bond or a N-glycosidic bond.

10 . The modified peptide according to claim 9 or a pharmaceutically acceptable salt thereof, wherein the sugar substance is a glycochain comprising a glycochain structure represented by the following formula:

wherein Gxx is GlcNAc, Glc, or Man (hereinafter, glycochains having the above structure are referred to as “SG”, “SG(Glc)”, and “SG(Man)”, respectively, according to the type of GXX), and “O/N-L” represents binding to the linker structure or the hANP peptide through an O-glycosidic bond or a N-glycosidic bond.

11 . The modified peptide according to claim 7 or a pharmaceutically acceptable salt thereof, wherein in the sugar substance, Gxx is GlcNAc.

12 . The modified peptide according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the sugar substance is SG.

13 . The modified peptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein 10 or less sugar substances are linked to one hANP peptide.

14 . The modified peptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein 1, 2, or 3 sugar substances are linked to one hANP peptide,

15 . The modified peptide according to claim 1 or a pharmaceutically acceptable salt thereof, wherein one molecule contains a divalent or higher hANP peptide.

16 . The modified peptide according to claim 3 or a pharmaceutically acceptable salt thereof, wherein the sugar substance is linked via a linker structure to the hANP peptide, and the linker structure is a chemical structure that has a linking chain of 3 or more atoms and is bonded at at least one site to the reducing end of the sugar substance through a glycosidic bond and bonded at at least one site to the hANP peptide.

17 . The modified peptide according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the sugar substance is linked to either the N terminus or the C terminus, or both, of the hANP peptide via a linker structure.

18 . The modified peptide according to claim 17 or a pharmaceutically acceptable salt thereof, wherein the linker structure is a structure having a linking chain of 15 or less atoms.

19 . The modified peptide according to claim 18 or a pharmaceutically acceptable salt thereof, wherein the modified peptide is SG-hANP(1-28) (compound 2-1), hANP(1-28)-SG (compound 2-2), SG-hANP(1-28)-SG (compound 2-7), AG(9)-hANP(1-28) (compound 2-10), SG-triazole-hANP(1-28) (compound 2-12), SG-thioacetamide-hANP(1-28) (compound 2-25), or AG(5)-hANP(1-28) (compound 2-26), or
is derived from any of these modified peptides by the replacement of the sugar substance with SG, SG(Glc), SG(Man), AG(5), AG(5-Glc), AG(5-Man), AG(7), AG(7-Glc), AG(7-Man), AG(9), AG(9-Glc), AG(9-Man), or GlcNAc and/or the replacement of the hANP peptide with hANP(1-28), hANP(2-28), hANP(3-28), hANP(1-27), hANP(2-27), or hANP(3-27).

20 . The modified peptide according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the linker structure comprises at least one structure selected from a polyoxyalkylene chain, an amino acid, and an oligopeptide chain consisting of 2 or more amino acids.

21 . The modified peptide according to claim 20 or a pharmaceutically acceptable salt thereof, wherein the polyoxyalkylene chain, the amino acid, and/or the oligopeptide chain contained in the linker structure is bonded through an amide bond to the N terminus and/or the C terminus of the hANP peptide.

22 . The modified peptide according to claim 21 or a pharmaceutically acceptable salt thereof, wherein the polyoxyalkylene chain is PEG.

23 . The modified peptide according to claim 21 or a pharmaceutically acceptable salt thereof, wherein the modified peptide is SG-PEG(3)-(SG-)Asn-hANP(1-28) (compound 2-16), AG(9)-(AG(9)-)Asn-PEG(3)-hANP(1-28) (compound 2-21), AG(7)-(AG(7)-)Asn-PEG(3)-hANP(1-28) (compound 2-22), SG-PEG(3)-hANP(1-28)-PEG(3)-SG (compound 2-24), SG-(SG-) Asn-PEG(11)-hANP(1-28) (compound 2-27), SG-(SG-)Asn-PEG(11)-PEG(11)-hANP(1-28) (compound 2-28), SG-PEG(3)-hANP(1-28) (compound 2-29), SG-PEG(11)-hANP(1-28) (compound 2-30), SG-*(SG-)Gln-Mal-PEG(3)-hANP(1-28) (compound 2-31), SG-(SG-)Gln-PEG(3)-Mal-hANP(1-28) (compound 2-32), SG-(SG-)Asn-(Ser-Gly)3-hANP(1-28) (compound 2-36), or SG-(SG-)Asn-Gly 6 -hANP(1-28) (compound 2-37), or
is derived from any of these modified peptides by the replacement of the sugar substance with SG, SG(Glc), SG(Man), AG(5), AG(5-Glc), AG(5-Man), AG(7), AG(7-Glc), AG(7-Man), AG(9), AG(9-Glc), AG(9-Man), or GlcNAc and/or the replacement of the hANP peptide with hANP(1-28), hANP(2-28), hANP(3-28), hANP(1-27), hANP(2-27), or hANP(3-27).

24 . The modified peptide according to claim 20 or a pharmaceutically acceptable salt thereof, wherein the linker structure comprises at least one amino acid having a functional group on the side chain selected from an amino acid having an amino group on the side chain, an amino acid having SH on the side chain, an amino acid having a carboxyl group on the side chain, an amino acid having a hydroxy group on the side chain, and an amino acid having phenol on the side chain and is linked at the side chain of the amino acid having a functional group on the side chain to the sugar substance or the hANP peptide.

25 . The modified peptide according to claim 24 or a pharmaceutically acceptable salt thereof, wherein the linker structure

Assignees

• Daiichi Sankyo Co Ltd

Inventors

• Iwamoto Mitsuhiro
• Yamaguchi Takahiro
• Mori Yutaka
• Saito Keiji
• Honda Takeshi
• Nagayama Takahiro

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P35/04

  specific for metastasis · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P9/00

  Drugs for disorders of the cardiovascular system · CPC title

• A61P35/00

  Antineoplastic agents · CPC title