US2003166514A1PendingUtilityA1

Cyclic peptides that bind to urokinase-type plasminogen activator receptor

49
Priority: Nov 12, 1996Filed: Jan 22, 2003Published: Sep 4, 2003
Est. expiryNov 12, 2016(expired)· nominal 20-yr term from priority
Inventors:Terence R. JonesDavid N. HaneyJanos Varga
A61P 35/04A61P 35/00A61P 29/00A61P 27/02C12Y 304/21073A61P 19/02C12N 9/6462C07K 7/54A61K 38/00
49
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Claims

Abstract

Cyclic peptide compounds having 11 amino acids joined by a linking unit L, such that the linear dimension between the C α carbon of the first amino acid and the C α carbon of eleventh amino acid is between about 4 and 12 Ångstrom units; are useful for inhibiting the binding of uPA to the uPAR receptor.: Methods for using the cyclic peptide compounds, and compositions containing them, for inhibiting the growth or metastasis of cancerous tumors are also disclosed.

Claims

exact text as granted — not AI-modified
We claim:  
     
         1 . A cyclic peptide compound of Formula 1 or Formula 2 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein, in Formula 1, all of X 1  through X 11  represent L-series amino acids and, in Formula 2, all of X 1  through X 11  represent D-series amino acids; 
 X 1  is Val, Pro, or Ala;  
 X 2  is Ser or Ala;  
 X 3  is Asn or Gln;  
 X 4  is Lys or His;  
 X 5  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalamine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;  
 X 6  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;  
 X 7  is Ser or Ala;  
 X 8  is Asn or Ala;  
 X 9  is Ile, Leu, or Val;  
 X 10  is His or Ala;  
 X 11  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine; and  
 L is a linking unit, such that when X 1  and X 11  are linked, the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 4 and 12 Ångstrom units;  
 with the proviso that, when said compound is of Formula 1, L does not comprise two cysteine units linked by a disulfide bond.  
 
     
     
         2 . The compound of  claim 1  wherein the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 5 and 10 Ångstrom units.  
     
     
         3 . The compound of  claim 1  wherein the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 6 and 8 Ångstrom units.  
     
     
         4 . The compound of  claim 1  wherein said compound is of Formula 1, and all of X 1  through X 11  represent L-series natural amino acids.  
     
     
         5 . The compound of  claim 4  wherein L is selected from the group consisting of:  
       —CO—CH 2 —CH 2 —CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH 2 —CH 2 —CH 2 —CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH(NH 2 )—CH 2 —S—CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —S—CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —S—CH 2 —CH 2 —CH(COOH)—NH—, —CO—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH(COOH)—NH—; —CO—CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH 2 —S—CH 2 —CH 2 —CH(COOH)—NH—; and —CO—CH 2 -meta-phenylene—CH 2 —NH—.  
     
     
         6 . The compound of  claim 1  wherein said compound is of Formula 2, and wherein all of X 1  through X 11  represent D-series non-natural amino acids.  
     
     
         7 . The compound of  claim 6  wherein L is selected from the group consisting of:  
       —NH—CH(COOH)—CH 2 —S—CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —S—CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH 2 —CH 2 —CH 2 —S—CH 2 —CH(NH 2 )—CO—; —NH—CH 2 —CH 2 —CH 2 —S—CH 2 —CH 2 —CO—; —NH—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —S—CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —S—CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —S—CH 2 —CO—; and —NH—CH 2 -meta-phenylene-CH 2 —CO—.  
     
     
         8 . The compound of  claim 1  wherein said compound exhibits an IC 50  value of less than about 10 −5  molar, i.e., less than about 10 μM.  
     
     
         9 . The compound of  claim 1  wherein said compound exhibits an IC 50  value less than about 10 −6  molar.  
     
     
         10 . The compound of  claim 1  wherein said compound exhibits an IC 50  value in the range of 10 −7  molar.  
     
     
         11 . A method for inhibiting the binding of uPA to uPAR, said method comprising the step of contacting living cells with a cyclic peptide compound of Formula 1 or Formula 2 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein, in Formula 1, all of X 1  through X 11  represent L-series amino acids and, in Formula 2, all of X 1  through X 11  represent D-series amino acids; 
 X 1  is Val, Pro, or Ala;  
 X 2  is Ser or Ala;  
 X 3  is Asn or Gln;  
 X 4  is Lys or His;  
 X 5  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;  
 X 6  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;  
 X 7  is Ser or Ala;  
 X 8  is Asn or Ala;  
 X 9  is Ile, Leu, or Val;  
 X 10  is His or Ala;  
 X 11  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine; and  
 L is a linking unit, such that when X 1  and X 11  are linked, the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 4 and 12 Ångstrom units;  
 with the proviso that, when said compound is of Formula 1, L does not comprise two cysteine units linked by a disulfide bond.  
 
     
     
         12 . The method of  claim 11  wherein the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 5 and 10 Ångstrom units.  
     
     
         13 . The method of  claim 11  wherein the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 6 and 8 Ångstrom units.  
     
     
         14 . The method of  claim 11  wherein said compound is of Formula 1, and all of X 1  through X 11  represent L-series natural amino acids.  
     
     
         15 . The method of  claim 14  wherein L is selected from the group consisting of:  
       —CO—CH 2 —CH 2 —CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH 2 —CH 2 —CH 2 —CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH(NH 2 )—CH 2 —S—CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —S—CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —S—CH 2 —CH 2 —CH(COOH)—NH—, —CO—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH(COOH)—NH—; —CO—CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH 2 —S—CH 2 —CH 2 —CH(COOH)—NH—; and —CO—CH 2 -meta-phenylene—CH 2 —NH—.  
     
     
         16 . The method of  claim 11  wherein said compound is of Formula 2, and wherein all of X 1  through X 11  represent D-series non-natural amino acids.  
     
     
         17 . The method of  claim 16  wherein L is selected from the group consisting of:  
       —NH—CH(COOH)—CH 2 —S—CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —S—CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH 2 —CH 2 —CH 2 —S—CH 2 —CH(NH 2 )—CO—; —NH—CH 2 —CH 2 —CH 2 —S—CH 2 —CH 2 —CO—; —NH—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —S—CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —S—CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —S—CH 2 —CO—; and —NH—CH 2 -meta-phenylene-CH 2 —CO—.  
     
     
         18 . The method of  claim 11  wherein said compound exhibits an IC 50  value of less than about 10 −5  molar.  
     
     
         19 . The method of  claim 11  wherein said compound exhibits an IC 50  value of less than about 10 −6  molar.  
     
     
         20 . The method of  claim 11  wherein said compound exhibits an IC 50  value of less than about 10 −7  molar.  
     
     
         21 . The method of  claim 11  wherein said method has the effect of inhibiting the growth or metastasis of cancerous tumors.  
     
     
         22 . A pharmaceutical composition comprising (a) the cyclic peptide compound of Formula 1 or Formula 2 
       
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
       
       wherein, in Formula 1, all of X 1  through X 11  represent L-series amino acids and, in Formula 2, all of X 1  through X 11  represent D-series amino acids; 
 X 1  is Val, Pro, or Ala;  
 X 2  is Ser or Ala;  
 X 3  is Asn or Gln;  
 X 4  is Lys or His;  
 X 5  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;  
 X 6  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-(2-thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine;  
 X 7  is Ser or Ala;  
 X 8  is Asn or Ala;  
 X 9  is Ile, Leu, or Val;  
 X 10  is His or Ala;  
 X 11  is Tyr, Trp, Phe, substituted Phe, di-substituted Phe, homophenylalanine, β-(3-pyridyl)alanine, β-( 2 -thienyl)alanine, β-(1-naphthyl)alanine, or β-(2-naphthyl)alanine; and  
 L is a linking unit, such that when X 1  and X 11  are linked, the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 4 and 12 Ångstrom units;  
 with the proviso that, when said compound is of Formula 1, L does not comprise two cysteine units linked by a disulfide bond; and  
 (b) a pharmaceutically acceptable carrier.  
 
     
     
         23 . The composition of  claim 22  wherein the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 5 and 10 Ångstrom units.  
     
     
         24 . The composition of  claim 22  wherein the linear dimension between the C α  carbon of amino acid X 1  and the C α  carbon of amino acid X 11  is between about 6 and 8 Ångstrom units.  
     
     
         25 . The composition of  claim 22  wherein said compound is of Formula 1, and all of X 1  through X 11  represent L-series natural amino acids.  
     
     
         26 . The composition of  claim 25  wherein L is selected from the group consisting of:  
       —CO—CH 2 —CH 2 —CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH 2 —CH 2 —CH 2 —CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH(NH 2 )—CH 2 —S—CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —S—CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —NH—; —CO—CH 2 —CH 2 —S—CH 2 —CH 2 —CH(COOH)—NH—, —CO—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH(COOH)—NH—; —CO—CH 2 —S—CH 2 —CH(COOH)—NH—; —CO—CH 2 —S—CH 2 —CH 2 —CH(COOH)—NH—; and —CO—CH 2 -meta-phenylene—CH 2 —NH—.  
     
     
         27 . The composition of  claim 22  wherein said compound is of Formula 2, and wherein all of X 1  through X 11  represent D-series non-natural amino acids.  
     
     
         28 . The composition of  claim 27  wherein L is selected from the group consisting of:  
       —NH—CH(COOH)—CH 2 —S—CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —S—CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH 2 —CH 2 —CH 2 —S—CH 2 —CH(NH 2 )—CO—; —NH—CH 2 —CH 2 —CH 2 —S—CH 2 —CH 2 —CO—; —NH—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —S—CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —CH 2 —CH 2 —CH 2 —CO—; —NH—CH(COOH)—CH 2 —S—CH 2 —CO—; —NH—CH(COOH)—CH 2 —CH 2 —S—CH 2 —CO—; and —NH—CH 2 -meta-phenylene-CH 2 —CO—.  
     
     
         29 . The composition of  claim 22  wherein said compound exhibits an IC 50  value of less than about 10 −5  molar.  
     
     
         30 . The composition of  claim 22  wherein said compound exhibits an IC 50  value of less than about 10 −4  molar.  
     
     
         31 . The composition of  claim 22  wherein said compound exhibits an IC 50  value of less than about 10 −7  molar.  
     
     
         32 . The composition of  claim 22  wherein said composition is in a form suitable for injection.

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