Transporters comprising spaced arginine moieties

• US 20030032593A1
• Filed: 02/14/2002
• Published: 02/13/2003
• Est. Priority Date: 02/16/2001
• Status: Active Grant

• Current Assignee: Kai Pharmaceuticals, Inc. (Amgen Inc.), Board of Trustees of the Leland Stanford Junior University (Stanford Management Co.)
• Original Assignee: Cellgate, Inc. (Tbg Diagnostics Limited)
• Inventors: VanDeusen, Christopher J., Wender, Paul A., Rothbard, Jonathan B., Kreider, Erik L., Wright, Lee
• Granted Patent: US 7,585,834 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 47/64 Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent peptidic linkers A61K47/65
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Abstract

The present invention provides compositions and methods for enhancing transport of biologically active compounds across biological membranes and across and into animal epithelial or endothelial tissues. The composition includes a biologically active agent and a transport moiety. The transport moiety includes a structure selected from the group consisting of (ZYZ)_nZ, (ZY)_nZ, (ZYY)_nZ and (ZYYY)_nZ. Subunit “Z” is L-arginine or D-arginine, and subunit “Y” is an amino acid that does not comprise an amidino or guanidino moiety. Subscript “n” is an integer ranging from 2 to 10. The method for enhancing transport involves the administration of the aforementioned composition.

Claims

1. A composition comprising a biologically active compound and a transport moiety, wherein the transport moiety comprises a structure selected from the group consisting of (ZYZ)_nZ, (ZY)_nZ, (ZYY)_nZ and (ZYYY)_nZ, wherein each Z is L-arginine or D-arginine, and each Y is independently an amino acid that does not comprise an amidino or guanidino moiety, and wherein n is an integer of from 2 to 10.

2. The composition according to claim 1, wherein each Y is independently selected from the group consisting of alanine, cysteine, aspartic acid, glutamic acid, phenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, proline, glutamine, serine, threonine, valine, tryptophan, hydroxyproline, tyrosine, γ

-amino butyric acid, β

-alanine, sarcosine and ε

-amino caproic acid.

3. The composition according to claim 1, wherein the transport moiety comprises the structure (ZYZ)_nZ, and wherein n is an integer ranging from 2 to 5.

4. The composition according to claim 1, wherein the transport moiety comprises the structure (ZY)_nZ, and wherein n is an integer ranging from 4 to 10.

5. The composition according to claim 1, wherein the transport moiety comprises the structure (ZYY)_nZ, and wherein n is an integer ranging from 4 to 10.

6. The composition according to claim 1, wherein the transport moiety comprises the structure (ZYYY)_nZ, and wherein n is an integer ranging from 4 to 10.

7. The composition according to claim 1, wherein the transport moiety is attached to the biologically active compound by a linking moiety to form a conjugate.

8. The composition according to claim 1, wherein Y is a gene-encoded amino acid.

9. The composition according to claim 1, wherein Y is an amino acid other than a gene-encoded amino acid.

10. The composition according to claim 3, wherein each Y is independently selected from the group consisting of glycine, γ

-amino butyric acid, β

-alanine and ε

-amino caproic acid, and n is 3 or 4.

11. The composition according to claim 4, wherein each Y is independently selected from the group consisting of glycine, γ

-amino butyric acid, β

-alanine and ε

-amino caproic acid, and n is 6, 7 or 8.

12. The composition according to claim 5, wherein each Y is independently selected from the group consisting of glycine, γ

-amino butyric acid, β

-alanine and ε

-amino caproic acid, and n is 6, 7 or 8.

13. The composition according to claim 6, wherein each Y is independently selected from the group consisting of glycine, γ

-amino butyric acid, β

-alanine and ε

-amino caproic acid, and n is 6, 7 or 8

14. The composition according to claim 7, wherein the conjugate has the following structure:

15. The composition according to claim 14, wherein each of X and Y is independently selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

OC(O)NH—

, —

S—

S—

, —

C(S)O—

, —

C(S)NH—

, —

NHC(O)NH—

, —

SO₂NH—

, —

SONH—

, phosphate, phosphonate and phosphinate.

16. The composition according to claim 14, wherein each of X and Y is independently selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

OC(O)NH— and

—

NHC(O)NH—

.

17. The composition according to claim 7, wherein the conjugate has the following structure:

18. The composition according to claim 17, wherein each of X and Y is independently selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

OC(O)NH—

, —

S—

S—

, —

C(S)O—

, —

C(S)NH—

, —

NHC(O)NH—

, —

SO₂NH—

, —

SONH—

, phosphate, phosphonate and phosphinate.

19. The composition according to claim 17, wherein each of X and Y is independently selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

OC(O)NH— and

—

NHC(O)NH—

.

20. The composition according to claim 7, wherein the conjugate has the following structure:

21. The composition according to claim 20, wherein each of X and Y is independently selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

OC(O)NH—

, —

S—

S—

, —

C(S)O—

, —

C(S)NH—

, —

NHC(O)NH—

, —

SO₂NH—

, —

SONH—

, phosphate, phosphonate and phosphinate.

22. The composition according to claim 20, wherein each of X and Y is independently selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

OC(O)NH— and

—

NHC(O)NH—

.

23. The composition according to claim 7, wherein the conjugate has the following structure:

24. The composition according to claim 23, wherein each of X and Y is independently selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

OC(O)NH—

, —

S—

S—

, —

C(S)O—

, —

C(S)NH—

, —

NHC(O)NH—

, —

SO₂NH—

, —

SONH—

, phosphate, phosphonate and phosphinate.

25. The composition according to claim 23, wherein each of X and Y is independently selected from the group consisting of —

C(O)O—

, —

C(O)NH—

, —

OC(O)NH— and

—

NHC(O)NH—

.

26. The composition according to claim 12, wherein A is N, R² is benzyl, k, m and n are 1, and X is —

C(O)O—

.

27. The composition according to claim 13, wherein R⁴ is S, R⁵ is NHR⁶, R⁶ is hydrogen, methyl, allyl, butyl or phenyl, k and m are 1 and X is —

C(O)O—

.

28. The composition according to claim 14, wherein R⁵ is NHR⁶, R⁶ is hydrogen, methyl, allyl, butyl or phenyl, k is 2 and X is —

C(O)O—

.

29. The composition according to claim 15, wherein Ar is an unsubstituted aryl group, R⁴ is S, R⁵ is NHR⁶, R⁶ is hydrogen, methyl, allyl, butyl or phenyl, k and m are 1 and X is —

C(O)O—

.

31. The method according to claim 20, wherein the biologically active compound is attached to the transport moiety by a linking moiety to form a conjugate.

32. The method of claim 21, wherein the conjugate has the following structure:

33. The method of claim 21, wherein the conjugate has the following structure:

34. The method of claim 21, wherein the conjugate has the following structure:

35. The method of claim 21, wherein the conjugate is of the following structure:

30. A method for increasing the transport of a biologically active compound across a biological membrane comprising:

administering a composition comprising a biologically active compound and a transport moiety, wherein the transport compound comprises a structure selected from the group consisting of (ZYZ)_nZ, (ZY)_nZ, (ZYY)_nZ and (ZYYY)_nZ, wherein Z is L-arginine or D-arginine, and wherein Y is an amino acid that does not comprise an amidino or guanidino moiety, and wherein n is an integer ranging from 2 to 10,

wherein transport of the biologically active compound across the biological membrane is increased relative to transport of the biologically active compound in the absence of said transport moiety.