Long-Acting Adrenomedullin Derivatives

Abstract

There is provided a novel adrenomedullin derivative capable of sustainably acting for a longer period than natural adrenomedullin. The invention relates to a compound represented by formula (I): A-Ln-B (I), wherein A is a modifying group selected from the group consisting of a palmitoyl group and a polyethylene glycol group, L is a divalent linking group, n is an integer of 0 or 1, and B is a peptide moiety derived from adrenomedullin or a modified form thereof with adrenomedullin activity, wherein the peptide moiety B is bound to the modifying group A or the linking group L via the N-terminal amino group of the peptide moiety B, or a salt thereof, or a hydrate thereof.

1 . A compound represented by formula (I):
   A-L n -B  (I)
   wherein   A is a modifying group selected from the group consisting of a palmitoyl group and a polyethylene glycol group,   L is a divalent linking group,   n is an integer of 0 or 1, and   B is a peptide moiety derived from adrenomedullin or a modified form thereof with adrenomedullin activity,   wherein the peptide moiety B is bound to the modifying group A or the linking group L via the N-terminal amino group of the peptide moiety B or a salt thereof, or a hydrate thereof.   
     
     
         2 . The compound according to  claim 1 , wherein the adrenomedullin or the modified form thereof with adrenomedullin activity is a peptide selected from the group consisting of:
 (i) a peptide consisting of an amino acid sequence of adrenomedullin,   (ii) a peptide that consists of an amino acid sequence of adrenomedullin and has a disulfide bond formed by two cysteine residues in the amino acid sequence,   (iii) a peptide wherein the disulfide bond in the peptide of (ii) is substituted with an ethylene group, and that has adrenomedullin activity,   (iv) a peptide wherein 1 to 15 amino acids in any of the peptides of (i) to (iii) are deleted, substituted or added, and that has adrenomedullin activity,   (v) a peptide wherein the C-terminus of any of the peptides of (i) to (iv) is amidated, and   (vi) a peptide wherein a glycine residue is added to the C-terminus of any of the peptides of (i) to (iv).   
     
     
         3 . The compound according to  claim 1 , wherein the adrenomedullin or the modified form thereof is a peptide selected from the group consisting of:
 (a) a peptide consisting of the amino acid sequence of SEQ ID NO: 1 or a peptide consisting of the amino acid sequence of SEQ ID NO: 1 and having a disulfide bond formed by the cysteine residues at positions 16 and 21;   (b) a peptide consisting of the amino acid sequence of the SEQ ID NO: 3 or a peptide consisting of the amino acid sequence of the SEQ ID NO: 3 and having a disulfide bond formed by the cysteine residues at positions 16 and 21;   (c) a peptide consisting of the amino acid sequence of SEQ ID NO: 5 or a peptide consisting of the amino acid sequence of SEQ ID NO: 5 and having a disulfide bond formed by the cysteine residues at positions 16 and 21;   (d) a peptide consisting of the amino acid sequence of SEQ ID NO: 7 or a peptide consisting of the amino acid sequence of SEQ ID NO: 7 and having a disulfide bond formed by the cysteine residues at positions 16 and 21;   (e) a peptide consisting of the amino acid sequence of SEQ ID NO: 9 or a peptide consisting of the amino acid sequence of SEQ ID NO: 9 and having a disulfide bond formed by the cysteine residues at positions 14 and 19;   (f) a peptide consisting of the amino acid sequence of SEQ ID NO: 11 or a peptide consisting of the amino acid sequence of SEQ ID NO: 11 and having a disulfide bond formed by the cysteine residues at positions 14 and 19;   (g) a peptide wherein the disulfide bond in any of the peptides of (a) to (f) is substituted with an ethylene group, and that has adrenomedullin activity;   (h) a peptide wherein 1 to 15 amino acids in any of the peptides of (a) to (g) are deleted, substituted or added, and that has adrenomedullin activity;   (i) a peptide wherein the C-terminus of any of the peptides of (a) to (h) is amidated; and   (j) a peptide wherein a glycine residue is added to the C-terminus of any of the peptides of (a) to (h).   
     
     
         4 . A method for producing the compound according to  claim 1 , comprising a linking step of linking a precursor of peptide moiety B derived from adrenomedullin or a modified form thereof, a precursor of modifying group A selected from the group consisting of a palmitoyl group and a polyethylene glycol group, and a precursor of divalent group L n  to form the compound represented by formula (I). 
     
     
         5 . A medicament comprising the compound according to  claim 1  as an active ingredient. 
     
     
         6 . The medicament according to  claim 5  for use in the prevention or treatment of a cardiovascular disease, an inflammatory disease, or a peripheral vascular disease. 
     
     
         7 . An agent for preventing or treating a cardiovascular disease, an inflammatory disease, or a peripheral vascular disease, wherein the agent comprises the compound according to  claim 1  as an active ingredient.