US2005059584A1PendingUtilityA1

Novel chemokine mimetics synthesis and their use

53
Priority: Aug 16, 2002Filed: Aug 16, 2002Published: Mar 17, 2005
Est. expiryAug 16, 2022(expired)· nominal 20-yr term from priority
Inventors:Ahmed MerzoukAbdelkrim HabiDonald WongHassan Salari
C07K 14/521A61K 38/12A61K 38/16A61K 38/19
53
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Claims

Abstract

The present invention is concerned with chemokine derived analogs, including SDF-1 and/or SDF-1/MIP1α hybrid analogs, that are useful for the treatment of a variety of diseases and disorders, and as an adjunct to the treatment of a variety of diseases and disorders. A therapeutically effective amount of the chemokine analog may be administered to a patient in need of such treatment.

Claims

exact text as granted — not AI-modified
1 ) A compound comprising a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:818, inclusive.  
     
     
         2 ) The compound of  claim 1 , wherein the R group is a PEG (polyethyleneglycol) moiety (MW=500 to 20000).  
     
     
         3 ) The compound of  claim 1 , wherein the R group is an alkylcarbonyl or an arylcarbonyl.  
     
     
         4 ) A method for treating disease or disorder comprising administering to a patient in need of such a treatment a therapeutically effective amount of a chemokine analog having a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:818, inclusive, in a pharmaceutically acceptable carrier, 
 wherein, in the above sequences:    R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, PEG (polyethyleneglycol) and any other modifying group;    Xaa 3  is selected from the group consisting of L-Pro, D-Pro, P*, Btd and any L- or D-natural and non-natural amino acid;    Xaa 4  is selected from the group consisting of P*, Btd and any L- or D-natural amino acid and any non-natural amino acid;    P* is:                          where Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Btd* is:                          Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy; Xaa 1  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid;    Xaa 2  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid; and    the linker is a bifunctional group covalently attached to the N-terminal and C-terminal portions of the analog having the structure: H 2 N-Z A -COOH wherein Z A  is selected from the group consisting of: (1) alkyl, alkenyl, aralkyl, alkynyl; (2) —(CH 2 ) n — wherein n is an integer n=9 to 14; (3) any combination of 4 natural amino acids or non-natural amino acids; and (4) —(Gly) 4 -(SEQ ID NO: 868).    
     
     
         5 ) The method of  claim 4 , wherein said disease or disorder is selected from the group consisting of autoimmune diseases, chronic inflammation, cancer, cardiovascular disease, or infectious disease.  
     
     
         6 ) The method of  claim 4 , wherein said administration increases the hemocrit, assists in mobilizing stem cells, assists in vaccine production, or assists in gene therapy.  
     
     
         7 ) The methods of  claims 4  to  6  wherein said method further comprises a chemokine analog composition comprising a drug delivery vehicle.  
     
     
         8 ) A method of producing a composition comprising a chemokine analog having a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:818, inclusive, wherein, in the above sequences: 
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, PEG(polyethyleneglycol) and any other modifying group;    Xaa 3  is selected from the group consisting of L-Pro, D-Pro, P*, Btd and any L- or D-natural and non-natural amino acid;    Xaa 4  is selected from the group consisting of P*, Btd and any L- or D-natural amino acid and any non-natural amino acid;    P* is:                          where Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Btd* is:                          Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Xaa 1  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid;    Xaa 2  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid; and    the linker is a bifunctional group covalently attached to the N-terminal and C-terminal portions of the analog having the structure: H 2 N-Z A -COOH wherein Z A  is selected from the group consisting of: (1) alkyl, alkenyl, aralkyl, alkynyl; (2) —(CH 2 ) n — wherein n is an integer n=9 to 14; (3) any combination of 4 natural amino acids or non-natural amino acids; and (4) -(Gly) 4 -(SEQ ID NO: 868).    
     
     
         9 ) The method of  claim 8  wherein said composition further comprises a drug delivery vehicle.  
     
     
         10 ) A method for modulating the activity of a chemokine receptor comprising the steps of contacting said chemokine receptor with a compound comprising a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:818, inclusive, wherein, in the above sequences: 
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, PEG (polyethyleneglycol) and any other modifying group;    Xaa 3  is selected from the group consisting of L-Pro, D-Pro, P*, Btd and any L- or D-natural and non-natural amino acid;    Xaa 4  is selected from the group consisting of P*, Btd and any L- or D-natural amino acid and any non-natural amino acid;    P* is:                          where Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Btd* is:                          Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Xaa 1  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid;    Xaa 2  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid; and    the linker is a bifunctional group covalently attached to the N-terminal and C-terminal portions of the analog having the structure: H 2 N-Z A -COOH wherein Z A  is selected from the group consisting of: (1) alkyl, alkenyl, aralkyl, alkynyl; (2) —(CH 2 ) n — wherein n is an integer n=9 to 14; (3) any combination of 4 natural amino acids or non-natural amino acids; and (4) -(Gly) 4 -(SEQ ID NO: 868).    
     
     
         11 ) A chemokine analog which comprises a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:800, and SEQ ID NO:810 to SEQ ID NO:818, inclusive, except for the structures represented by SEQ ID NO:820, SEQ ID NO:82 1, SEQ ID NO:822, SEQ ID NO:823, SEQ ID NO:824, and SEQ ID NO:825, wherein, in the above sequences: 
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, PEG (polyethyleneglycol) and any other modifying group;    Xaa 3  is selected from the group consisting of L-Pro, D-Pro, P*, Btd and any L- or D-natural and non-natural amino acid;    Xaa 4  is selected from the group consisting of P*, Btd and any L- or D-natural amino acid and any non-natural amino acid;    P* is:                          where Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Btd* is:                          Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Xaa 1  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid;    Xaa 2  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid; and    the linker is a bifunctional group covalently attached to the N-terminal and C-terminal portions of the analog having the structure: H 2 N-Z A -COOH wherein Z A  is selected from the group consisting of: (1) alkyl, alkenyl, aralkyl, alkynyl; (2) —(CH 2 ) n — wherein n is an integer n=9 to 14; (3) any combination of 4 natural amino acids or non-natural amino acids; and (4) -(Gly) 4 -(SEQ ID NO: 868).    
     
     
         12 ) The chemokine analog of claims  1 ,  2 ,  3 , or  11 , wherein the cysteine at position 9 is replaced by alanine, and cysteine at position 11 is replaced by phenylalanine.  
     
     
         13 ) The compound of  claim 1  wherein said compound has a structure represented by AcHN-Lys-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[11 aminoundecanoic acid]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:812), wherein the underlined residues are cyclized.  
     
     
         14 ) The method of  claim 4  wherein said chemokine analog has a structure represented by AcHN-Lys-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[11 aminoundecanoic acid]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:812), wherein the underlined residues are cyclized.  
     
     
         15 ) The compound of  claim 1  wherein said compound has a structure represented by H 2 N-[desNH 2 Lys]-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:813), wherein the underlined residues are cyclized.  
     
     
         16 ) The method of  claim 4  wherein said chemokine analog has a structure represented by H 2 N-[desNH 2 Lys]-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:813), wherein the underlined residues are cyclized.  
     
     
         17 ) The compound of  claim 1  wherein said compound has a structure represented by H 2 N-Lys-[D-Pro]-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Its-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:814), wherein the underlined residues are cyclized.  
     
     
         18 ) The method of  claim 4  wherein said chemokine analog has a structure represented by H 2 N-Lys-[D-Pro]-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:814), wherein the underlined residues are cyclized.  
     
     
         19 ) The compound of  claim 1  wherein said compound has a structure represented by H 2 N-Lys-Pro-Val-Ser-[D-Pro]-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:815), wherein the underlined residues are cyclized.  
     
     
         20 ) The method of  claim 4  wherein said chemokine analog has a structure represented by H 2 N-Lys-Pro-Val-Ser-[D-Pro]-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:815), wherein the underlined residues are cyclized.  
     
     
         21 ) The compound of  claim 1  wherein said compound has a structure represented by H 2 N -Lys-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[11 aminoundecanoic acid]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:816), wherein the underlined residues are cyclized.  
     
     
         22 ) The method of  claim 4  wherein said chemokine analog has a structure represented by H 2 N-Lys-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[11 aminoundecanoic acid]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:8 16), wherein the underlined residues are cyclized.  
     
     
         23 ) The compound of  claim 1  wherein said compound has a structure represented by AcHN-Lys-Pro-Leu-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NE 2  (SEQ ID NO:817) wherein the underlined residues are cyclized.  
     
     
         24 ) The method of  claim 4  wherein said chemokine analog has a structure represented by AcHN-Lys-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Cys-Pro-Cys-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Las-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:817) wherein the underlined residues are cyclized.  
     
     
         25 ) The compound of  claim 1  wherein said compound has a structure represented by AcHN-Lys-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Ala-Pro-Phe-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:818).  
     
     
         26 ) The method of  claim 4  wherein said chemokine analog has a structure represented by AcHN-Lys-Pro-Val-Ser-Leu-Ser-Tyr-Arg-Ala-Pro-Phe-Arg-Phe-Phe-[Gly-Gly-Gly-Gly]-Leu-Lys-Trp-Ile-Gln-Glu-Tyr-Leu-Glu-Lys-Ala-Leu-Asn-NH 2  (SEQ ID NO:818).  
     
     
         27 ) The compound of  claim 1  wherein said compound has a structure represented by SEQ ID NO:810.  
     
     
         28 ) The method of  claim 4  wherein said chemokine analog has a structure represented by SEQ ID NO:810.  
     
     
         29 ) A method for mobilizing intracellular calcium in a patient comprising administering to a patient in need of such a treatment an effective amount of a chemokine analog having a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:818, inclusive, in a pharmaceutically acceptable carrier, wherein, in the above sequences: 
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, PEG (polyethyleneglycol) and any other modifying group;    Xaa 3  is selected from the group consisting of L-Pro, D-Pro, P*, Btd and any L- or D-natural and non-natural amino acid;    Xaa 4  is selected from the group consisting of P*, Btd and any L- or D-natural amino acid and any non-natural amino acid;    P* is:                          where Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Btd* is:                          Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Xaa 1  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid;    Xaa 2  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid; and    the linker is a bifunctional group covalently attached to the N-terminal and C-terminal portions of the analog having the structure: H 2 N-Z A -COOH wherein Z A  is selected from the group consisting of: (1) alkyl, alkenyl, aralkyl, alkynyl; (2) —(CH 2 ) n — wherein n is an integer n=9 to 14; (3) any combination of 4 natural amino acids or non-natural amino acids; and (4) -(Gly) 4 -(SEQ ID NO: 868).    
     
     
         30 ) A method for protecting hematopoietic cells in a patient undergoing treatment with a cytotoxic agent comprising administering to a patient in need of such a treatment an effective amount of a chemokine analog having a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:818, inclusive, in a pharmaceutically acceptable carrier, wherein, in the above sequences: 
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, PEG (polyethyleneglycol) and any other modifying group;    Xaa 3  is selected from the group consisting of L-Pro, D-Pro, P*, Btd and any L- or D-natural and non-natural amino acid;    Xaa 4  is selected from the group consisting of P*, Btd and any L- or D-natural amino acid and any non-natural amino acid;    P* is:                          where Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Btd* is:                          Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Xaa 1  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid;    Xaa 2  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid; and    the linker is a bifunctional group covalently attached to the N-terminal and C-terminal portions of the analog having the structure: H 2 N-Z A -COOH wherein Z A  is selected from the group consisting of: (1) alkyl, alkenyl, aralkyl, alkynyl; (2) —(CH 2 ) n — wherein n is an integer n=9 to 14; (3) any combination of 4 natural amino acids or non-natural amino acids; and (4) -(Gly) 4 -(SEQ ID NO: 868).    
     
     
         31 ) The method of  claim 30  wherein the survival of white blood cells is increased.  
     
     
         32 ) The method of  claim 30  wherein the survival of leukocytes is increased.  
     
     
         33 ) A method for maintaining cells capable of division in a quiescent state cells in a patient undergoing treatment with a cytotoxic agent comprising administering to a patient in need of such a treatment an effective amount of a chemokine analog having a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:818, inclusive, in a pharmaceutically acceptable carrier, wherein, in the above sequences: 
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, PEG (polyethyleneglycol) and any other modifying group;    Xaa 3  is selected from the group consisting of L-Pro, D-Pro, P*, Btd and any L- or D-natural and non-natural amino acid;    Xaa 4  is selected from the group consisting of P*, Btd and any L- or D-natural amino acid and any non-natural amino acid;    P* is:                          where Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Btd* is:                          Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Xaa 1  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid;    Xaa 2  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid; and    the linker is a bifunctional group covalently attached to the N-terminal and C-terminal portions of the analog having the structure: H 2 N-Z A -COOH wherein Z A  is selected from the group consisting of: (1) alkyl, alkenyl, aralkyl, alkynyl; (2) —(CH 2 ) n — wherein n is an integer n=9 to 14; (3) any combination of 4 natural amino acids or non-natural amino acids; and (4) -(Gly) 4 -(SEQ ID NO: 868).    
     
     
         34 ) A method for mobilizing leukocytes in a patient comprising administering to a patient in need of such a treatment an effective amount of a chemokine analog having a structure selected from the group consisting of SEQ ID NO:9 to SEQ ID NO:818, inclusive, in a pharmaceutically acceptable carrier, wherein, in the above sequences: 
 R is selected from the group consisting of hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, PEG (polyethyleneglycol) and any other modifying group;    Xaa 3  is selected from the group consisting of L-Pro, D-Pro, P*, Btd and any L- or D-natural and non-natural amino acid;    Xaa 4  is selected from the group consisting of P*, Btd and any L- or D-natural amino acid and any non-natural amino acid;    P* is:                          where Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Btd* is:                          Z is hydrogen, alkyl, alkenyl, alkynyl, alkylcarbonyl, arylcarbonyl, aryl, or aryl-hydroxy;    Xaa 1  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid;    Xaa 2  is selected from the group consisting of any L- or D-natural amino acid and any non-natural amino acid; and    the linker is a bifunctional group covalently attached to the N-terminal and C-terminal portions of the analog having the structure: H 2 N-Z A -COOH wherein Z A  is selected from the group consisting of: (1) alkyl, alkenyl, aralkyl, alkynyl; (2) —(CH 2 ) n — wherein n is an integer n=9 to 14; (3) any combination of 4 natural amino acids or non-natural amino acids; and (4) -(Gly) 4 -(SEQ ID NO: 868).    
     
     
         35 ) The method of  claim 34  wherein said leukocytes are neutrophils.

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