IP Library › Patent Application 11040810
Patent Application
App. No. 11/040,810

Long lasting natriuretic peptide derivatives

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Quick Facts
Patent No.
US None
App. No.
11/040,810
Abstract

This invention relates to long lasting natriuretic peptide (NP) derivatives. The NP derivative has a NP peptide and a reactive entity coupled to the NP peptide. The reactive entity is able to covalently bond with a functionality on a blood component. In particular, this invention relates to NP derivatives having an extended in vivo half-life, and method for the treatment of cardiovascular diseases and disorders such as acute decompensated congestive heart failure (CHF) and chronic CHF.

Claims (156)

1 - 26 . (canceled)

27 . A natriuretic peptide derivative comprising a NP peptide and a reactive entity coupled to the NP peptide, the reactive entity being capable of covalently bonding with a functionality on a blood component; wherein the NP peptide has a sequence of formula:

R 1 -X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10 -Cys 11 -X 12 -X 13 -X 14 -X 15 -X 16 -Asp 17 -Arg 18 -Ile 19 -X 20 -X 21 -X 22 -Ser 23 -X 24 -Leu 25 -X 26 -Cys 27 -X 28 -X 29 -X 30 -X 31 -X 32 -X 33 -R 2

wherein

X 1 is Thr or absent;

X 2 is Ser, Thr, Ala or absent;

X 3 is Pro, Hpr, Val, or absent;

X 4 is Lys, D-Lys, Arg, D-Arg, Asn, Gln or absent;

X 5 is Met, Leu, Ile, an oxidatively stable Met-replacement amino acid, Ser, Thr or absent;

X 6 is Val, Ile, Leu, Met, Phe, Ala, D-Ala, Nle or absent;

X 7 is Gln, Asn, Arg, D-Arg, Asp, Lys, D-Lys or absent;

X 8 is Gly, Pro, Ala, D-Ala, Arg, D-Arg, Asp, Lys, D-Lys, Gln, Asn or absent;

X 9 is Ser, Thr or absent;

X 10 is Gly, Pro, Ala, D-Ala, Ser, Thr or absent;

X 12 is Phe, Tyr, Leu, Val, Ile, Ala, D-Ala, Phe with an isosteric replacement of its amide bond selected from the group consisting of N-α-methyl, methyl amino, hydroxylethyl, hydrazino, ethylene, sulfonamide and N-alkyl-β-aminopropionic acid, or a Phe-replacement amino acid conferring on said analog resistance to NEP enzyme;

X 13 is Gly, Ala, D-Ala or Pro;

X 14 is Arg, Lys, D-Lys, Asp, Gly, Ala, D-Ala or Pro;

X 15 is Lys, D-Lys, Arg, D-Arg, Asn, Gln or Asp;

X 16 is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

X 20 is Ser, Gly, Ala, D-Ala or Pro;

X 21 is Ser, Gly, Ala, D-Ala, Pro, Val, Leu, or Ile;

X 22 is Ser, Gly, Ala, D-Ala, Pro, Gln or Asn;

X 24 is Gly, Ala, D-Ala or Pro;

X 26 is Gly, Ala, D-Ala or Pro;

X 28 is Lys, D-Lys, Arg, D-Arg, Asn, Gln, His or absent;

X 29 is Val, Ile, Leu, Met, Phe, Ala, D-Ala, Nle, Ser, Thr or absent;

X 30 is Leu, Nle, Ile, Val, Met, Ala, D-Ala, Phe, Tyr or absent;

X 31 is Arg, D-Arg, Asp, Lys, D-Lys or absent;

X 32 is Arg, D-Arg, Asp, Lys, D-Lys, Tyr, Phe, Trp, Thr, Ser or absent;

X 33 is His, Asn, Gln, Lys, D-Lys, Arg, D-Arg or absent;

R 1 is NH 2 or a N-terminal blocking group;

R 2 is COOH, CONH 2 or a C-terminal blocking group;

where a peptidic bond links Arg 18 and Ile 19 and the line between Cys 11 and Cys 27 represents a direct disulfide bridge.

28 . The derivative defined in claim 27 wherein:

X 1 is Thr or absent;

X 2 is Ala or absent;

X 3 is Pro or absent;

X 4 is Arg or absent;

X 5 is Ser, Thr or absent;

X 6 is Leu, Ile, Nle, Met, Val, Ala, Phe or absent;

X 7 is Arg, D-Arg, Asp, Lys, D-Lys, Gln, Asn or absent;

X 8 is Arg, D-Arg, Asp, Lys, D-Lys, Gln, Asn or absent;

X 9 is Ser, Thr or absent;

X 10 is Ser, Thr or absent;

X 12 is Phe, Tyr, Leu, Val, Ile, Ala, D-Ala, Phe with an isosteric replacement of its amide bond selected from the group consisting of N-α-methyl, methyl amino, hydroxylethyl, hydrazino, ethylene, sulfonamide and N-alkyl-β-aminopropionic acid, or a Phe-replacement amino acid conferring on said analog resistance to NEP enzyme;

X 13 is Gly, Ala, D-Ala or Pro;

X 14 is Gly, Ala, D-Ala or Pro;

X 15 is Arg, Lys, D-Lys, or Asp;

X 16 is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

X 20 is Gly, Ala, D-Ala or Pro;

X 21 is Ala, D-Ala, Val, Leu, or Ile;

X 22 is Gln or Asn;

X 24 is Gly, Ala, D-Ala or Pro;

X 26 is Gly, Ala, D-Ala or Pro;

X 28 is Asn, Gln, His, Lys, D-Lys, Arg, D-Arg or absent;

X 29 is Ser, Thr or absent;

X 30 is Phe, Tyr, Leu, Val, Ile, Ala or absent;

X 31 is Arg, D-Arg, Asp, Lys, D-Lys or absent;

X 32 is Tyr, Phe, Trp, Thr, Ser or absent;

X 33 is absent;

R 1 is NH 2 or a N-terminal blocking group;

R 2 is COOH, CONH 2 or a C-terminal blocking group.

29 . The derivative of claim 28 wherein

X 1 is Thr or absent;

X 2 is Ala or absent;

X 3 is Pro or absent;

X 4 is Arg or absent;

X 5 is Ser or absent;

X 6 is Leu or absent;

X 7 is Arg, Asp or absent;

X 8 is Arg, Asp or absent;

X 9 is Ser or absent;

X 10 is Ser or absent;

X 12 is Phe or Phe with an isosteric replacement of its amide bond selected from the group consisting of N-α-methyl, methyl amino, hydroxylethyl, hydrazino, ethylene, sulfonamide and N-alkyl-β-aminopropionic acid;

X 13 is Gly;

X 14 is Gly;

X 15 is Arg or Asp;

X 16 is Met or Ile;

X 20 is Gly;

X 21 is Ala;

X 22 is Gln;

X 24 is Gly;

X 26 is Gly;

X 28 is Asn or absent;

X 29 is Ser or absent;

X 30 is Phe or absent;

X 31 is Arg, Asp or absent;

X 32 is Tyr or absent;

X 33 is absent;

R 1 is NH 2 or a N-terminal blocking group;

R 2 is COOH, CONH 2 or a C-terminal blocking group.

30 . The derivative of claim 29 , wherein the NP peptide is selected from the group consisting of SEQ ID NO: 1, SEQ ID NO: 8, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 15, SEQ ID NO: 17 and SEQ ID NO: 19.

31 . The derivative of claim 29 , selected from the group consisting of SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO:11, SEQ ID NO: 14, SEQ ID NO: 16, SEQ ID NO:18 and SEQ ID NO: 20.

32 . The derivative defined in claim 27 , wherein:

X 1 is absent;

X 2 is Ser, Thr or absent;

X 3 is Pro, Hpr, Val or absent;

X 4 is Lys, D-Lys, Arg, D-Arg, Asn, Gln or absent;

X 5 is Met, Leu, Ile, an oxidatively stable Met-replacement amino acid or absent;

X 6 is Val, Ile, Leu, Met, Phe, Ala, D-Ala, Nle or absent;

X 7 is Gln, Asn or absent;

X 8 is Gly, Pro, Ala, D-Ala or absent;

X 9 is Ser, Thr or absent;

X 10 is Gly, Pro, Ala, D-Ala or absent;

X 12 is Phe, Tyr, Leu, Val, Ile, Ala, D-Ala, Phe with an isosteric replacement of its amide bond selected from the group consisting of N-α-methyl, methyl amino, hydroxylethyl, hydrazino, ethylene, sulfonamide and N-alkyl-β-aminopropionic acid, or a Phe-replacement amino acid conferring on said analog resistance to NEP enzyme;

X 13 is Gly, Ala, D-Ala or Pro;

X 14 is Arg, Lys, D-Lys, or Asp;

X 15 is Lys, D-Lys, Arg, D-Arg, Asn or Gln;

X 16 is Met, Leu, Ile or an oxidatively stable Met-replacement amino acid;

X 20 is Ser, Gly, Ala, D-Ala or Pro;

X 21 is Ser, Gly, Ala, D-Ala or Pro;

X 22 is Ser, Gly, Ala, D-Ala or Pro;

X 24 is Gly, Ala, D-Ala or Pro;

X 26 is Gly, Ala, D-Ala or Pro;

X 28 is Lys, D-Lys, Arg, D-Arg, Asn, Gln or absent;

X 29 is Val, Ile, Leu, Met, Phe, Ala, D-Ala, Nle or absent;

X 30 is Leu, Nle, Ile, Val, Met, Ala, D-Ala, Phe or absent;

X 31 is Arg, D-Arg, Asp, Lys, D-Lys or absent;

X 32 is Arg, D-Arg, Asp, Lys, D-Lys or absent;

X 33 is His, Asn, Gln, Lys, D-Lys, Arg, D-Arg or absent;

R 1 is NH 2 or a N-terminal blocking group;

R 2 is COOH, CONH 2 or a C-terminal blocking group.

33 . The derivative of claim 32 wherein:

X 1 is absent;

X 2 is Ser or absent;

X 3 is Pro or absent;

X 4 is Lys or absent;

X 5 is Met, Ile or absent;

X 6 is Val or absent;

X 7 is Gln or absent;

X 8 is Gly or absent;

X 9 is Ser or absent;

X 10 is Gly or absent;

X 12 is Phe or Phe with an isosteric replacement of its amide bond selected from the group consisting of N-α-methyl, methyl amino, hydroxylethyl, hydrazino, ethylene, sulfonamide and N-alkyl-β-aminopropionic acid;

X 13 is Gly;

X 14 is Arg or Asp;

X 15 is Lys or Arg;

X 16 is Met or Ile;

X 20 is Ser;

X 21 is Ser;

X 22 is Ser;

X 24 is Gly;

X 26 is Gly;

X 28 is Lys, Arg or absent;

X 29 is Val or absent;

X 30 is Leu or absent;

X 31 is Arg, Asp or absent;

X 32 is Arg, Asp or absent;

X 33 is His or absent.

34 . The derivative of claim 33 wherein the NP peptide is selected from the group consisting of SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 28, SEQ ID NO: 31, SEQ ID NO: 34, SEQ ID NO: 37, SEQ ID NO: 39, SEQ ID NO: 42, SEQ ID NO: 45, SEQ ID NO: 48 and SEQ ID NO: 51.

35 . The derivative of claim 33 selected from the group consisting of SEQ ID NO: 24, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 44, SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56 and SEQ ID NO: 57.

36 . The derivative of claim 27 , being capable of selectively covalently bonding with a single functionality on the blood component whith a degree of selectivity of 80% or more.

37 . The derivative of claim 36 , wherein the derivative bonds the blood component in a ratio 1:1 derivative:blood component.

38 . The derivative of claim 27 , wherein the reactive entity is a maleimide or a maleimido-containing group.

39 . The derivative of claim 38 , wherein the reactive entity is MPA.

40 . A pharmaceutical composition comprising the derivative of claim 27 in combination with a pharmaceutically acceptable carrier.

Assignments (1)
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Aug 1, 2006
From: CONJUCHEM INC.
To: CONJUCHEM BIOTECHNOLOGIES INC.
Reel/Frame 018039/0669 →