Rgd-containing cyclic peptides

Patent metadata

Field	Value
Publication number	US-2016017000-A1
Application number	US-201514755041-A
Country	US
Kind code	A1
Filing date	Jun 30, 2015
Priority date	Dec 21, 2009
Publication date	Jan 21, 2016
Grant date	—

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.

First claim

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.

Assignees

• Univ California

Inventors

• Lam Kit S
• Wang Yan
• Xiao Wenwu

Classifications

• C07K14/78 Primary

  Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG] · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• C07K7/54 Primary

  with at least one abnormal peptide link in the ring · CPC title

• C07K7/64

  Cyclic peptides containing only normal peptide links · CPC title