Cyclic peptide cxcr4 antagonists

Abstract

Provided are lactam-cyclized peptide CXCR4 antagonists useful in the treatment of cancers, rheumatoid arthritis, pulmonary fibrosis, and HIV infection.

1 - 14 . (canceled) 
     
     
         15 . A lactam-cyclized peptide of formula I: 
       
         
           
                 
               
                   (I) 
                 
                 
               
                   (SEQ ID NO: 1) 
                 
                 
               
                   R 1 -cyclo[X 1 -Tyr-X 3 -DArg-2Nal-Gly-X 7 ]-X 8 -X 9 -X 10 -R 2   
                 
             
                
               
            
             
                
               
            
             
                
               
            
           
         
       
       or a pharmaceutically acceptable salt thereof,
 wherein: 
 X 1  is selected from the group consisting of ( D/L )Agl, Ala, β-Ala,  D Ala, 5-aminovaleryl, 4-AMB, 4-AMPA, Asp, Dab, Dap, Dap(Ac), Glu, Gly, Leu, Lys, Lys(Ac), 2Nal, Phe,  D Phe, and succinyl, or is absent,
 wherein when X 1  is ( D/L )Agl, Dab, or Dap and the α-amino group of X 1  is not a constituent of the lactam amide bond, said α-amino group is substituted with R 1  which is selected from the group consisting of Ac and n-hexanoyl; 
 wherein when X 1  is Asp or Glu and the α-amino group of X 1  is not a constituent of the lactam amide bond, said α-amino group is substituted with R 1  which is selected from the group consisting of Ac and Bz; and 
 wherein when X 1  is Ala, β-Ala,  D Ala, 5-aminovaleryl, 4-AMB, 4-AMPA, Dap(Ac), Gly, Leu, Lys, Lys(Ac), 2Nal, Phe,  D Phe or succinyl, R 1  is absent; 
 
 X 3  is selected from the group consisting of Arg, Lys, Lys(iPr), and Lys(Me 2 ); 
 X 7  is selected from the group consisting of ( D/L )Agl, Asp, Dab, Dap,  D Dap, Glu,  D Glu, Lys, and Orn; 
 X 8  is selected from the group consisting of β-Ala, Arg,  D Arg, Gly, Lys, Lys(iPr), and Orn, or is absent; 
 X 9  is selected from the group consisting of Gly, 2Nal,  D 2Nal, and  D Phe, or is absent; 
 X 10  is 2Nal, or is absent,
 wherein when X 8  is absent, X 9  and X 10  are each absent, and when X 9  is absent, X 10  is absent; and 
 
 R 2  is selected from the group consisting of NH 2  and NHEt, 
 and further wherein:
 said lactam is formed by an amide bond between the side chain amino group of X 1  and the side chain carboxyl group of X 7 , and X 1  and X 7  are, respectively, a pair selected from the group consisting of ( D/L )Agl/Glu, Dab/Glu, and Dap/Glu, and R 1  is Ac or n-hexanoyl; or 
 said lactam is formed by an amide bond between the side chain carboxyl group of X 1  and the side chain amino group of X 7 , and X 1  and X 7  are, respectively, a pair selected from the group consisting of Asp/( D/L )Agl, Asp/Dab, Asp/Dap, Glu/( D/L )Agl, Glu/Dab, Glu/Dap, Glu/ D Dap, and Glu/Lys, and R 1  is Ac or Bz, or wherein X 1  and X 7  are, respectively, a pair selected from the group consisting of succinyl/( D/L )Agl, succinyl/Dab, succinyl/Dap, succinyl/Lys, and succinyl/Orn, and R 1  is absent; or 
 said lactam is formed by an amide bond between the α-amino group of X 1  and the side chain carboxyl group of X 7 , and X 1  and X 7  are, respectively, a pair selected from the group consisting of Ala/Glu, Ala/ D Glu,  D Ala/Glu,  D Ala/ D Glu, Dap(Ac)/Glu, Gly/Asp, Gly/Glu, Gly/ D Glu, Leu/Glu, Leu/ D Glu, Lys/ D Glu, Lys(Ac)/Glu, 2Nal/Glu, Phe/Glu, Phe/ D Glu,  D Phe/Glu, and  D Phe/ D Glu, and R 1  is absent; or 
 said lactam is formed by an amide bond between a non-α, non-side-chain amino group of X 1  and the side chain carboxyl group of X 7 , and X 1  and X 7  are, respectively, a pair selected from the group consisting of β-Ala/Asp, β-Ala/Glu, 5-amino-valeryl/Asp, 5-aminovaleryl/Glu, 4-AMB/Glu, 4-AMPA/Asp, and 4-AMPA/Glu, and R 1  is absent; or 
 said lactam is formed by an amide bond between the α-amino group of Tyr at X 2  and the side chain carboxyl group of X 7 , and X 7  is selected from the group consisting of Asp, Glu, and  D Glu, and R 1  and X 1  are each absent. 
 
 
     
     
         16 . The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 15 , wherein:
 said lactam is formed by an amide bond between the side chain amino group of X 1  and the side chain carboxyl group of X 7 ;   R 1  is selected from the group consisting of Ac and n-hexanoyl;   X 1  is selected from the group consisting of ( D/L )Agl, Dab, and Dap;   X 3  is selected from the group consisting of Arg and Lys(iPr);   X 7  is Glu;   X 8  is Arg;   X 9  is absent;   X 10  is absent; and   R 2  is NH 2 .   
     
     
         17 . The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 15 , wherein:
 said lactam is formed by an amide bond between the side chain carboxyl group of X 1  and the side chain amino group of X 7 ;   R 1  is selected from the group consisting of Ac and Bz;   X 1  is selected from the group consisting of Asp and Glu;   X 3  is selected from the group consisting of Arg and Lys(Me 2 );   X 7  is selected from the group consisting of ( D/L )Agl, Dab, Dap,  D Dap, and Lys;   X 8  is Arg;   X 9  is absent;   X 10  is absent; and   R 2  is NH 2 .   
     
     
         18 . The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 15 , wherein:
 said lactam is formed by an amide bond between the side chain carboxyl group of X 1  and the side chain amino group of X 7 ;   R 1  is absent;   X 1  is succinyl;   X 3  is Arg;   X 7  is selected from the group consisting of ( D/L )Agl, Dab, Dap, Lys, and Orn;   X 8  is Arg;   X 9  is absent;   X 10  is absent; and   R 2  is NH 2 .   
     
     
         19 . The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 15 , wherein:
 said lactam is formed by an amide bond between the α-amino group of X 1  and the side chain carboxyl group of X 7 ;   R 1  is absent;   X 1  is selected from the group consisting of Ala,  D Ala, Gly, Dap(Ac), Leu, Lys, Lys(Ac), 2Nal, Phe, and  D Phe;   X 3  is selected from the group consisting of Arg, Lys, Lys(iPr), and Lys(Me 2 );   X 7  is selected from the group consisting of Asp, Glu, and  D Glu;   X 8  is selected from the group consisting of β-Ala, Arg, Gly, Lys, Lys(iPr), and Orn, or is absent;   X 9  is selected from the group consisting of Gly, 2Nal,  D 2Nal, and  D Phe, or is absent;   X 10  is 2Nal, or is absent;   wherein when X 8  is absent, X 9  and X 10  are each absent; and   R 2  is selected from the group consisting of NH 2  and NHEt.   
     
     
         20 . The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 15 , wherein:
 said lactam is formed by an amide bond between a non-α, non-side-chain amino group of X 1  and the side chain carboxyl group of X 7 ;   R 1  is absent;   X 1  is selected from the group consisting of β-Ala, 4-AMB, 5-aminovaleryl, and 4-AMPA;   X 3  is Arg;   X 7  is selected from the group consisting of Asp and Glu;   X 8  is selected from the group consisting of Arg and  D Arg;   X 9  is absent;   X 10  is absent; and   R 2  is NH 2 .   
     
     
         21 . The lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 15 , wherein:
 said lactam is formed by an amide bond between the α-amino group of X 2  and the side chain carboxyl group of X 7 ;   R 1  is absent;   X 1  is absent;   X 3  is Arg;   X 7  is selected from the group consisting of Asp, Glu, and  D Glu;   X 8  is Arg;   X 9  is absent;   X 10  is absent; and   R 2  is NH 2 .   
     
     
         22 . A pharmaceutical composition, comprising a lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 15 , and a pharmaceutically acceptable carrier, diluent, or excipient. 
     
     
         23 . A method of treating rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer selected from the group consisting of breast cancer, pancreatic cancer, melanoma, prostate cancer, kidney cancer, neuroblastoma, non-Hodgkin's lymphoma, lung cancer, ovarian cancer, colorectal cancer, multiple myeloma, glioblastoma multiforme, and chronic lymphocytic leukemia, comprising administering to a patient in need thereof an effective amount of a lactam-cyclized peptide or pharmaceutically acceptable salt thereof of  claim 15 .