Rgd-containing cyclic peptides

Abstract

The present invention is drawn to cyclic RGD peptides linked via a disulfide bond, where the terminal cysteines are preferably in the D configuration. These peptides target αvβ3 integrin on tumor cells and neovasculatures and function as targeting agents for tumor diagnostic imaging and therapy. Compared with the commonly used RGD ligands, compounds of the present invention have improved targeting efficacy and lower nonspecific binding to normal organs. Moreover, the compounds of the present invention can be functionalized to conjugate imaging payload without decreasing binding strength.

What is claimed is: 
     
         1 . A compound of formula I:
   X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8   (I)
   wherein   X 1 , X 2 , X 6 , X 7  and X 8  are each independently an amino acid, wherein at least one of X 1 , X 2 , X 6 , X 7  and X 8  is a D-amino acid;   X 3  is a basic amino acid;   X 4  is Gly; and   X 5  is an acidic amino acid;   wherein the compounds of formula I are peptides cyclized via a disulfide or a diselenium bond between amino acids X 1  and X 8 .   
     
     
         2 . The compound of  claim 1 , wherein
 X 3  is selected from the group consisting of Lys, Arg, HoArg, Agp, Agb, Dab, Dap and Orn, and stereoisomers thereof; and   X 5  is selected from the group consisting of Asp, Glu, Aad and Bec, and stereoisomers thereof.   
     
     
         3 . The compound of  claim 1 , wherein
 X 3  is selected from the group consisting of Lys, Arg, HoArg, Agp, and Orn, and stereoisomers thereof; and   X 5  is selected from the group consisting of Asp, Glu, Aad and Bec, and stereoisomers thereof.   
     
     
         4 . The compound of  claim 1 , wherein
 X 3  is Arg; and   X 5  is Asp.   
     
     
         5 . The compound of  claim 4 , wherein X 3  and X 5  are each in the L-configuration. 
     
     
         6 . The compound of  claim 1 , wherein X 1  and X 8  are each independently selected from the group consisting of Cys, Pen, Sec and HoCys, and stereoisomers thereof. 
     
     
         7 . The compound of  claim 6 , wherein X 1  and X 8  are each a D-amino acid. 
     
     
         8 . The compound of  claim 6 , wherein X 1  and X 8  are independently selected from the group consisting of DCys and DPen. 
     
     
         9 . The compound of  claim 1 , having the formula II: 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is selected from the group consisting of H, C 1-6  alkyl, —C(O)R 1a , and L-A; 
         R 1a  is selected from the group consisting of C 1-6  alkyl, C 1-6  heteroalkyl, C 1-6  alkyl-NH 2 , C 1-6  alkyl-C(O)N(H)—C 1-6  heteroalkyl, cycloalkyl, C 1-6  alkyl-cycloalkyl, heterocycloalkyl, C 1-6  alkyl-heterocycloalkyl, aryl, C 1-6  alkyl-aryl, heteroaryl, and C 1-6  alkyl-heteroaryl, wherein the cycloalkyl, heterocycloalkyl, heteroaryl and aryl groups are optionally substituted with a member selected from the group consisting of halogen, —NO 2 , —OH, —CN, C 1-6  alkyl, C 1-6  alkoxy, C 1-6  haloalkyl and C 1-6  haloalkoxy; 
         R 2  is selected from the group consisting of H, C 1-6  alkyl and L-A; 
         L is a linker; and 
         A is an active agent. 
       
     
     
         10 . The compound of  claim 9 , wherein
 R 1  and R 2  are each independently selected from the group consisting of H, C 1-6  alkyl and L-A;   L is a linker; and   A is an active agent.   
     
     
         11 . The compound of  claim 9 , wherein
 X 2  is selected from the group consisting of Gly, Ala, Sar and β-alanine, and stereoisomers thereof;   X 6  is selected from the group consisting of Val, Leu, Ile, Met, Phe, Asn, Glu, Gln, His, Lys, Arg, Asp, Gly, Ala, Ser, Thr, Tyr, Trp, Pro, Aad, Bec, Bmc, Bmp, Phe(4COOH), Hyp, HoSer, Tha, Ahch, Actp, Akch, Tyr(diI), Trp, Thz, 2Thi, 3Thi, Cit, HoCit, Aib, Nglu, and Fua, and stereoisomers thereof; and   X 7  is selected from the group consisting of Val, Leu, Ile, Met, Phe, Asn, Glu, Gln, His, Lys, Arg, Asp, Gly, Ala, Ser, Thr, Tyr, Trp, Pro, Bmp, HoSer, Nglu, HoCit, Bec, Aad, Hyp, Ahch, Phe(4COOH), Akch, Aecc, Abu, Phe(3,4-diOMe), Cpa, 2-Thi, Thz, Phg, Phe(4-NO 2 ), Nle, (NMe)Phe, Aic, Chg, Bta, Bpa, Nal2, Nal1, Tic, Ppca, Cha, Bipa, Deg, Dpg, Acpc, Bmc, Cit, Sar, Tha, Pra, Actp, Aib, Agl, Acbc, Fua, Nva, Thi, Trp, Bug, Ach, (NMe)Val, Cpeg, (CαMe)Phe, Tyr(diI), Phe(2-Cl), Bua, HoPhe, HoLeu, Sta, Ing, Phe(4-CF 3 ), Oic, Dpa, Phe(4-t-Bu), HoCha and Phe(3,4-diCl), and stereoisomers thereof.   
     
     
         12 . The compound of  claim 9 , wherein X 2 , X 6  and X 7  are each a D-amino acid. 
     
     
         13 . The compound of  claim 9 , having formula IIa: 
       
         
           
           
               
               
           
         
       
     
     
         14 . The compound of  claim 13 , wherein
 X 6  is selected from the group consisting of DSer, DAsp, Ahch, Bmp, DGlu, Nglu and DCit; and   X 7  is selected from the group consisting of DPhe, DGlu, DSer, DBug, DBta, DVal, DAgl, DPra, D(NMe)Val, D(CαMe)Val, DAbu, DIng, DIle, Actp, DTha, DAsp, Ppca and DNal1.   
     
     
         15 . The compound of  claim 13 , wherein
 X 6  is selected from the group consisting of DAsp and DSer; and   X 7  is selected from the group consisting of DGlu, DPhe, DSer, DVal, DBug and DBta.   
     
     
         16 . The compound of  claim 1 , wherein the compound is selected from the group consisting of cGRGDsfc, cGRGDdfc, cGRGDsec, cGRGDdsc, cGRGDd-DBug-c, cGRGDd-DBta-c, cGRGDdvc, CGRGDdvc, cGRGDdvC, CGRGDdvC, DPen-GRGDdv-DPen, DPen-GRGDdvc, cGRGDdv-DPen, Ac-cGRGDdvc, (β-alanine)-cGRGDdvc, (Ebes)-cGRGDdvc, caRGDdvc, c-Sar-RGDdvc, c-β-alanine-RGDdvc, cG-HoArg-GDdvc, cG-Agp-GDdvc, cG-Agp-GEdvc, cG-Agp-G-Aad-dvc, cGRGDd-DAgl-c, cGRGDd-DPra-c, cGRGDd-DBug-c, cGRGDd-D(NMe)Val-c, cGRGDd-D(CαMe)Val-c, cGRGDd-DAbu-c, CGRGDd-DIng-c, c-Sar-RGD-Ahch-ic, c-Sar-RGD-Ahch-DBug-c, cGRGDd-DAgl-C, C-Sar-RGDd-DPra-C, C-Sar-RGDd-Actp-C, c-Sar-RGDd-DPra-C, c-Sar-RGDd-Actp-C, CGRGDd-DTha-C, cGRGDd-DPra-C, cGRGDd-Actp-C, c-Sar-RGD-Ahch-iC, c-Sar-RGD-Ahch-DBug-C, C-Sar-RGD-Bmp-dC, CGRGDe-Ppca-c, cGRGD-Nglu-Ppca-c, cGRGDd-DNal1-c, and cGRGDd-DBta-c. 
     
     
         17 . The compound of  claim 1 , wherein the compound is selected from the group consisting of cGRGDsfc, cGRGDdfc, cGRGDsec, cGRGDdsc, cGRGDdvc, cGRGDd-DBug-c and cGRGDd-DBta-c. 
     
     
         18 . The compound of  claim 9 , wherein the linker L is selected from the group consisting of β-alanine, 2,2′-ethylenedioxy bis(ethylamine) monosuccinamide (Ebes), and bis(Ebes)-Lys. 
     
     
         19 . The compound of  claim 9 , having the formula: 
       
         
           
           
               
               
           
         
         wherein R 2  is L-A. 
       
     
     
         20 . The compound of  claim 19 , wherein
 X 6  is DAsp;   X 7  is DVal; and   R 2  is Ebes-Ebes-Lys-biotin.   
     
     
         21 . The compound of  claim 9 , having formula IIc: 
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 21 , selected from the group consisting of acetyl-cGRGDdvc, 3-amino propanoyl-cGRGDdvc, (Ebes)-cGRGDdvc, isobutyryl-cGRGDdvc, valeryl-cGRGDdvc, cyclohexyl acetyl-cGRGDdvc, 3-phenyl-propionyl-cGRGDdvc, p-chlorophenyl acetyl-cGRGDdvc, 4-nitrobezoyl-cGRGDdvc, 3,5-dihydroxy-beznoyl-cGRGDdvc, 4-(trifluoromethyl)benzoyl-cGRGDdvc, 2-methylthiazole-4-carbonyl-cGRGDdvc, nicotinyl-cGRGDdvc, 2-naphthoyl-cGRGDdvc, and biphenyl-4-carbonyl-cGRGDdvc. 
     
     
         23 . A pharmaceutical composition comprising a compound of  claim 1  and a pharmaceutically acceptable excipient. 
     
     
         24 . A method of inhibiting αvβ3 integrin, the method comprising contacting the αvβ3 integrin with an amount of a compound of  claim 1  sufficient to inhibit the activity of the αvβ3 integrin. 
     
     
         25 . The method of  claim 24 , wherein the contacting is conducted in an in vitro assay. 
     
     
         26 . The method of  claim 24 , wherein the contacting is conducted in in vivo.