US2005272652A1PendingUtilityA1

Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity

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Individually held — no corporate assignee on recordPriority: Mar 29, 1999Filed: Mar 25, 2005Published: Dec 8, 2005
Est. expiryMar 29, 2019(expired)· nominal 20-yr term from priority
Inventors:Victor GaultFinbarr Paul Mary O'HarteNigel IrwinPatrick HarriottPeter Raymond Flatt
A61K 38/00Y10T29/4935C07K 14/575
52
PatentIndex Score
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Claims

Abstract

The present invention provides peptide analogues which are antagonists of gastric inhibitory peptide (GIP). The peptides, based on GIP 1-42 include substitutions and/or modifications which have enhanced resistance to degradation by the enzyme dipeptidyl peptidase IV (DPP IV). The invention also provides a process of N terminally modifying GIP and the use of the peptide analogues for treatment of diabetes.

Claims

exact text as granted — not AI-modified
1 . A peptide analogue of GIP(1-42) (SEQ ID NO: 1), comprising at least 12 amino acid residues from the N-terminal end of GIP(3-42).  
     
     
         2 . A peptide analogue of GIP(1-42) (SEQ ID NO:1), comprising at least 12 amino acid residues from the N-terminal end of GIP(1-42) and having an amino acid substitution at Glu 3 .  
     
     
         3 . The peptide analogue of  claim 2 , wherein the amino acid substituted at Glu 3  is selected from the group consisting of: proline, hydroxyproline, lysine, tyrosine, phenylalanine and tryptophan.  
     
     
         4 . The peptide analogue of  claim 3 , wherein proline is substituted for Glu 3 .  
     
     
         5 . The peptide analogue of  claim 2 , further comprising modification by fatty acid addition at an epsilon amino group of at least one lysine residue.  
     
     
         6 . The peptide analogue of  claim 5 , wherein the modification is the linking of a C-16 palmitate group to the epsilon amino group of a lysine residue.  
     
     
         7 . The peptide analogue of  claim 6 , wherein the lysine residue is Lys 16 .  
     
     
         8 . The peptide analogue of  claim 6 , wherein the lysine residue is Lys 37 .  
     
     
         9 . A peptide analogue of GIP(1-42) (SEQ ID NO:1), comprising at least 12 amino acid residues from the N-terminal end of GIP(1-42), and having an amino acid modification at amino acid residues 1, 2 or 3.  
     
     
         10 . The peptide analogue of  claim 9 , wherein the N-terminal amino acid residue is acetylated.  
     
     
         11 . The peptide analogue of  claim 10 , further comprising modification by fatty acid addition at an epsilon amino group of at least one lysine residue.  
     
     
         12 . The peptide analogue of  claim 11 , wherein the modification is the linking of a C-16 palmitate group to the epsilon amino group of a lysine residue.  
     
     
         13 . The peptide analogue of  claim 12 , wherein the lysine residue is Lys 16 .  
     
     
         14 . The peptide analogue of  claim 12 , wherein the lysine residue is Lys 37 .  
     
     
         15 . A pharmaceutical composition comprising the peptide analogue of  claim 2 .  
     
     
         16 . The pharmaceutical composition of  claim 15 , further comprising a pharmaceutically acceptable carrier.  
     
     
         17 . The pharmaceutical composition of  claim 15 , wherein the peptide analogue is in the form of a pharmaceutically acceptable salt.  
     
     
         18 . The pharmaceutical composition of  claim 15 , wherein the peptide analogue is in the form of a pharmaceutically acceptable acid addition salt.  
     
     
         19 . A method of treating insulin resistance, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of the composition of  claim 15 .  
     
     
         20 . A method of treating obesity, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of the composition of  claim 15 .  
     
     
         21 . A method of treating type 2 diabetes, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of the composition of  claim 15 .  
     
     
         22 . A peptide analogue of GIP(1-42) (SEQ ID NO: 1), wherein the analogue comprises: 
 a base peptide consisting of one of the following: GIP(1-12), GIP(1-13), GIP(1-14), GIP(1-15), GIP(1-16), GIP(1-17), GIP(1-18), GIP(1-19), GIP(1-20), GIP(1-21), GIP(1-22), GIP(1-23), GIP(1-24), GIP(1-25), GIP(1-26), GIP(1-27), GIP(1-28), GIP(1-29), GIP(1-30), GIP(1-31), GIP(1-32), GIP(1-33), GIP(1-34), GIP(1-35), GIP(1-36), GIP(1-37), GIP(1-38), GIP(1-39), GIP(1-40), GIP(1-41) and GIP(1-42);    which possesses one or more of the following modifications:    an amino acid substitution at one or more of the residues;    an amino acid substitution of lysine for one or more or the residues;    an amino acid substitution at Glu 3 ;    a modification by fatty acid addition at an epsilon amino group of at least one lysine residue; and    a modification by N-terminal acetylation.    
     
     
         23 . The peptide analogue of  claim 22 , wherein the analogue has a proline substituted for Glu 3 .  
     
     
         24 . The peptide analogue of claims  22 , further comprising modification by fatty acid addition at an epsilon amino group of at least one lysine residue.  
     
     
         25 . The peptide analogue of  claim 24 , wherein the modification is the linking of a C-16 palmitate group to the epsilon amino group of a lysine residue.  
     
     
         26 . The peptide analogue of  claim 25 , wherein the lysine residue is Lys 16 .  
     
     
         27 . The peptide analogue of  claim 25 , wherein the lysine residue is Lys 37 .  
     
     
         28 . A pharmaceutical composition comprising the peptide analogue of  claim 22 .  
     
     
         29 . The pharmaceutical composition of  claim 28 , further comprising a pharmaceutically acceptable carrier.  
     
     
         30 . The pharmaceutical composition of  claim 28 , wherein the peptide analogue is in the form of a pharmaceutically acceptable salt.  
     
     
         31 . The pharmaceutical composition of  claim 28 , wherein the peptide analogue is in the form of a pharmaceutically acceptable acid addition salt.  
     
     
         32 . A method of treating insulin resistance, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of the composition of  claim 28 .  
     
     
         33 . A method of treating obesity, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of the composition of  claim 28 .  
     
     
         34 . A method of treating type 2 diabetes, the method comprising administering to a mammal in need of such treatment a therapeutically effective amount of the composition of  claim 28 .  
     
     
         35 . A peptide analogue of GIP(1-42) (SEQ ID NO:1), comprising at least 12 amino acid residues from the N-terminal end of GIP(3-42), wherein the peptide analogue is resistant to degradation by enzyme DPP IV when compared to naturally-occurring GIP.  
     
     
         36 . A peptide analogue of GIP(1-42) (SEQ ID NO:1), comprising at least 12 amino acid residues from the N-terminal end of GIP(1-42) and having an amino acid substitution at Glu 3 , wherein the peptide analogue is resistant to degradation by enzyme DPP IV when compared to naturally-occurring GIP.  
     
     
         37 . A peptide analogue of GIP(1-42) (SEQ ID NO:1), comprising at least 12 amino acid residues from the N-terminal end of GIP(3-42), wherein the peptide analogue modulates insulin secretion.  
     
     
         38 . A peptide analogue of GIP(1-42) (SEQ ID NO:1), comprising at least 12 amino acid residues from the N-terminal end of GIP(1-42) and having an amino acid substitution at Glu 3 , wherein the peptide analogue modulates insulin secretion.

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