Antagonists of the bradykinin B1 receptor

Abstract

The present invention relates to a method of treating, preventing, or ameliorating a disease or condition associated with or mediated by B1 activity that involves administering a composition of matter containing bradykinin B1 receptor antagonist peptides conjugated to a multivalent vehicle, including peptides conjugated to multivalent PEG. The method can be used therapeutically or prophylactically against diseases or conditions, such as inflammation or pain, linked to the bradykinin B1 receptor.

1 . A method of treating, preventing, or ameliorating a disease or condition associated with or mediated by B1 activity comprising administering to a human or animal subject a therapeutically effective amount of a composition of matter of the formula:
 F′—R z , or a physiologically acceptable salt thereof, wherein:   F′ is a multivalent vehicle;   R is independently in each instance —(X 1 )—(Y 1 ) n  wherein R is covalently bound to F′;   X 1  and Y 1  are independently in each instance peptides of the formula -L 1 -P 1  and -L 2 -P 2 , respectively;   L 1  and L 2  are independently in each instance absent or linkers;   n is 0 to 3;   Z is 2 to 8; and   P 1  and P 2  are independently in each instance peptide antagonists of the bradykinin B1 receptor.   
     
     
         2 . The method of  claim 1 , wherein P 1  and P 2  are independently in each instance peptide antagonists selected from peptides defined by the formula:
   NH 2 - a   0   a   1   a   2   a   3   a   4   a   5   a   6   a   7   a   8   a   9   a   10   a   11   a   12   a   13   a   14 -COOH   
       wherein:
 a 0  is a basic or neutral aromatic, aliphatic, heterocyclic, or alicyclic amino acid, a basic di-peptide, or absent; 
 a 1 , a 2 , a 3 , and a 4  are independently in each instance basic or neutral aromatic, aliphatic, heterocyclic, or alicyclic amino acids; 
 a 6  is Ser; 
 a 5 , a 7 , and a 8  are independently in each instance aromatic, aliphatic, heterocyclic, or alicyclic amino acids, provided that at least one of a 5 , a 7 , and a 8  is selected from Chg, Cpg, Igla, Iglb, Niga and Nigb of the D- or L-configuration; and 
 a 9 , a 10 , a 11 , a 12 , a 13 , and a 14  are independently in each instance a natural amino acid or absent. 
 
     
     
         3 . The method of  claim 1 , wherein F′ is a multivalent polyethylene glycol (PEG). 
     
     
         4 . The method of  claim 1 , wherein P 1  and P 2  are independently in each instance peptide antagonists of the bradykinin B1 receptor selected from the peptides shown in SEQ ID NOS: 5-26, 43-60, and derivatives thereof. 
     
     
         5 . The method according to  claim 1 , wherein the disease or condition is selected from the group consisting of inflammation, inflammatory pain, acute pain, dental pain, back pain, lower back pain, pain from trauma, surgical pain, inflammatory bowel disorders, asthma, and allergic rhinitis. 
     
     
         6 . The method of  claim 2  wherein:
 a 0  is a basic amino acid or basic di-peptide or absent;   a 1  is a basic amino acid or basic di-peptide;   a 2  is Pro;   a 3  is Hyp;   a 4  is Gly;   a 5  is an Indanyl amino acid;   a 6  is Ser;   a 7  is a D-Indanyl amino acid;   a 8  is Cpg; and   a 9 , a 10 , a 11 , a 12 , a 13 , and a 14  are independently in each instance a natural amino acid or absent.   
     
     
         7 . The method of  claim 2  wherein:
 a 0  is an amino acid selected from Arg, D-Arg, Orn, D-Orn, Lys, and D-Lys, or a di-peptide consisting of two amino acids independently selected from Arg, D-Arg, Orn, D-Orn, Lys, and D-Lys;   a 1  is Arg;   a 2  is Pro;   a 3  is Hyp;   a 4  is Gly;   a 5  is Cpg;   a 6  is Ser;   a 7  is DTic; and   a 8  is Cpg.   
     
     
         8 . The method of  claim 2  wherein:
 a 0  is Lys-Lys;   a 1  is Arg;   a 2  is Pro;   a 3  is Hyp;   a 4  is Gly;   a 5  is Iglb;   a 6  is Ser;   a 7  is DIglb; and   a 8  is Oic.   
     
     
         9 . The method of  claim 2  wherein:
 a 0  is DArg;   a 1  is Arg;   a 2  is Pro;   a 3  is Hyp;   a 4  is Gly;   a 5  is Igl;   a 6  is Ser;   a 7  is DIgl; and   a 8  is Oic.   
     
     
         10 . The method of  claim 2  wherein:
 a 0  is absent or a basic amino acid or a basic di-peptide;   a 1  is Arg;   a 2  is Pro;   a 3  is Pro;   a 4  is Gly;   a 5  is Me-Phe;   a 6  is Ser;   a 7  is D-β-Nal; and   a 8  is Ile.   
     
     
         11 . The method of  claim 2  wherein:
 a 0  is a basic amino acid, a basic di-peptide, or absent;   a 1  is a basic amino acid;   a 2  is Pro;   a 3  is Hyp;   a 4  is Gly;   a 5  is an Indanyl amino acid;   a 6  is Ser;   a 7  is a D-Indanyl amino acid; and   a 8  is Cpg.   
     
     
         12 . The method of  claim 2  wherein:
 a 0  is D-Arg, or a dipeptide selected from Lys-Lys, DLys-Lys, and DOrn-Lys;   a 1  is Arg;   a 2  is Pro;   a 3  is Hyp;   a 4  is Gly;   a 5  is Iglb;   a 6  is Ser;   a 7  is DIglb; and   a 8  is Oic.   
     
     
         13 . The method of  claim 2  wherein:
 a 0  is DArg or a Lys-Lys di-peptide;   a 1  is Arg;   a 2  is Pro;   a 3  is Hyp;   a 4  is Gly;   a 5  is Igl;   a 6  is Ser;   a 7  is DIgl; and   a 8  is Oic.   
     
     
         14 . The method of  claim 2  wherein:
 a 0  is an amino acid selected from Arg, D-Arg, Orn, D-Orn, Lys, and D-Lys, or a dipeptide consisting of two amino acids independently selected from Arg, D-Arg, Orn, D-Orn, Lys, and D-Lys;   a 1  is Arg;   a 2  is Pro;   a 3  is Pro;   a 4  is Gly;   a 5  is Me-Phe;   a 6  is Ser;   a 7  is D-β-Nal; and   a 8  is Ile.   
     
     
         15 . The method of  claim 1 , wherein L 1  and L 2  are independently absent or a peptidyl linker having from 1 to 9 amino acid residues. 
     
     
         16 . The method of  claim 15 , wherein the peptidyl linker has an amino acid sequence selected from SEQ ID NO:61 to SEQ ID NO:65, inclusive. 
     
     
         17 . The method of  claim 3  wherein n is 0 and Z is 2-8. 
     
     
         18 . The method of  claim 3  wherein Z is 4. 
     
     
         19 . The method of  claim 3 , wherein said PEG has a combined molecular mass of about 1000 Daltons to 100,000 Daltons.