Cyclic peptides that bind to urokinase-type plasminogen activator receptor

• US 20030166514A1
• Filed: 01/22/2003
• Published: 09/04/2003
• Est. Priority Date: 11/12/1996
• Status: Abandoned Application

• Current Assignee: David N. Haney, Janos Varga, Terence R. Jones
• Original Assignee: David N. Haney, Janos Varga, Terence R. Jones
• Inventors: Haney, David N., Jones, Terence R., Varga, Janos
• Application Number:
  US10/349,543
• Publication Number:
  US 20030166514A1
• Time in Patent Office: Days
• US Class Current: 514/9
• CPC Class Codes: A61K 38/00 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 Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 35/04 specific for metastasis
• CPC Class Codes: C07K 7/54 with at least one abnormal peptide link in the ring
• CPC Class Codes: C12N 9/6462 u-Plasminogen activator (3.4.21.73), i.e. urokinase
• CPC Class Codes: C12Y 304/21073 u-Plasminogen activator (3.4.21.73), i.e. urokinase

Abstract

Cyclic peptide compounds having 11 amino acids joined by a linking unit L, such that the linear dimension between the C^α carbon of the first amino acid and the C^α carbon of eleventh amino acid is between about 4 and 12 Ångstrom units; are useful for inhibiting the binding of uPA to the uPAR receptor.: Methods for using the cyclic peptide compounds, and compositions containing them, for inhibiting the growth or metastasis of cancerous tumors are also disclosed.

Claims

1. A cyclic peptide compound of Formula 1 or Formula 2

2. The compound of claim 1 wherein the linear dimension between the C^α

carbon of amino acid X¹ and the C^α

carbon of amino acid X¹¹ is between about 5 and 10 Å

ngstrom units.

3. The compound of claim 1 wherein the linear dimension between the C^α

carbon of amino acid X¹ and the C^α

carbon of amino acid X¹¹ is between about 6 and 8 Å

ngstrom units.

4. The compound of claim 1 wherein said compound is of Formula 1, and all of X¹ through X¹¹ represent L-series natural amino acids.

5. The compound of claim 4 wherein L is selected from the group consisting of:

—

CO—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH(NH₂)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CH(COOH)—

NH—

, —

CO—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

S—

CH₂—

CH₂—

CH(COOH)—

NH—

; and

—

CO—

CH₂-meta-phenylene—

CH₂—

NH—

.

6. The compound of claim 1 wherein said compound is of Formula 2, and wherein all of X¹ through X¹¹ represent D-series non-natural amino acids.

7. The compound of claim 6 wherein L is selected from the group consisting of:

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(NH₂)—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

S—

CH₂—

CO—

; and

—

NH—

CH₂-meta-phenylene-CH₂—

CO—

.

8. The compound of claim 1 wherein said compound exhibits an IC₅₀ value of less than about 10⁻

5 molar, i.e., less than about 10 μ

M.

9. The compound of claim 1 wherein said compound exhibits an IC₅₀ value less than about 10⁻

6 molar.

10. The compound of claim 1 wherein said compound exhibits an IC₅₀ value in the range of 10⁻

7 molar.

11. A method for inhibiting the binding of uPA to uPAR, said method comprising the step of contacting living cells with a cyclic peptide compound of Formula 1 or Formula 2

12. The method of claim 11 wherein the linear dimension between the C^α

carbon of amino acid X¹ and the C^α

carbon of amino acid X¹¹ is between about 5 and 10 Å

ngstrom units.

13. The method of claim 11 wherein the linear dimension between the C^α

carbon of amino acid X¹ and the C^α

carbon of amino acid X¹¹ is between about 6 and 8 Å

ngstrom units.

14. The method of claim 11 wherein said compound is of Formula 1, and all of X¹ through X¹¹ represent L-series natural amino acids.

15. The method of claim 14 wherein L is selected from the group consisting of:

—

CO—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH(NH₂)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CH(COOH)—

NH—

, —

CO—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

S—

CH₂—

CH₂—

CH(COOH)—

NH—

; and

—

CO—

CH₂-meta-phenylene—

CH₂—

NH—

.

16. The method of claim 11 wherein said compound is of Formula 2, and wherein all of X¹ through X¹¹ represent D-series non-natural amino acids.

17. The method of claim 16 wherein L is selected from the group consisting of:

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(NH₂)—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

S—

CH₂—

CO—

; and

—

NH—

CH₂-meta-phenylene-CH₂—

CO—

.

18. The method of claim 11 wherein said compound exhibits an IC₅₀ value of less than about 10⁻

5 molar.

19. The method of claim 11 wherein said compound exhibits an IC₅₀ value of less than about 10⁻

6 molar.

20. The method of claim 11 wherein said compound exhibits an IC₅₀ value of less than about 10⁻

7 molar.

21. The method of claim 11 wherein said method has the effect of inhibiting the growth or metastasis of cancerous tumors.

22. A pharmaceutical composition comprising (a) the cyclic peptide compound of Formula 1 or Formula 2

23. The composition of claim 22 wherein the linear dimension between the C^α

carbon of amino acid X¹ and the C^α

carbon of amino acid X¹¹ is between about 5 and 10 Å

ngstrom units.

24. The composition of claim 22 wherein the linear dimension between the C^α

carbon of amino acid X¹ and the C^α

carbon of amino acid X¹¹ is between about 6 and 8 Å

ngstrom units.

25. The composition of claim 22 wherein said compound is of Formula 1, and all of X¹ through X¹¹ represent L-series natural amino acids.

26. The composition of claim 25 wherein L is selected from the group consisting of:

—

CO—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH(NH₂)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

NH—

;

—

CO—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CH(COOH)—

NH—

, —

CO—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

S—

CH₂—

CH(COOH)—

NH—

;

—

CO—

CH₂—

S—

CH₂—

CH₂—

CH(COOH)—

NH—

; and

—

CO—

CH₂-meta-phenylene—

CH₂—

NH—

.

27. The composition of claim 22 wherein said compound is of Formula 2, and wherein all of X¹ through X¹¹ represent D-series non-natural amino acids.

28. The composition of claim 27 wherein L is selected from the group consisting of:

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH(NH₂)—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CO—

;

—

NH—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

S—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

CH₂—

CH₂—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

S—

CH₂—

CO—

;

—

NH—

CH(COOH)—

CH₂—

CH₂—

S—

CH₂—

CO—

; and

—

NH—

CH₂-meta-phenylene-CH₂—

CO—

.

29. The composition of claim 22 wherein said compound exhibits an IC₅₀ value of less than about 10⁻

5 molar.

30. The composition of claim 22 wherein said compound exhibits an IC₅₀ value of less than about 10⁻

4 molar.

31. The composition of claim 22 wherein said compound exhibits an IC₅₀ value of less than about 10⁻

7 molar.

32. The composition of claim 22 wherein said composition is in a form suitable for injection.