CXCR4 antagonists and methods of use

1. A method of treating a subject suffering from a clinical condition associated with overexpression, activation and/or upregulation of CXCR4, said method comprising administering to a subject in need of such a treatment a therapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

a is 0 or 1;

AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine;

AA 2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;

Ar 1 is an optionally substituted aryl;

X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);

X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-Dab, D-Orn, D-Lys, D-Dap(iPr), D-Dab(iPr), D-Orn(iPr), D-Lys(iPr), or absent;

X 3 is Gly or absent;

X 4 is Phe, 2Nal, 1Nal, a D-isomer thereof, or absent;

X 5 is Gly or absent;

R 2 is —OR 4 or —NHR 5 ;

R 4 is H or alkyl; and

R 5 is H, alkyl, optionally substituted aryl, optionally substituted aralkyl.

2. The method of claim 1 , wherein said clinical condition comprises rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer.

3. The method of claim 2 , wherein said cancer is 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.

4. The method according to claim 1 , wherein said compound is of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

a is an integer 0 or 1;

m and n are independently 1 or 2;

R 1 is H or NHR 3 , wherein R 3 is H, alkyl, acyl, optionally substituted aryl, optionally substituted aralkyl, —C(═O)—Ar a , wherein Ar a is optionally substituted aryl; and

Ar 1 , X 1 , X 2 , X 3 , X 4 , X 5 and R 2 are those defined in claim 1 .

5. The method according to claim 1 , wherein a=1 and Ar 1 is an optionally substituted phenyl.

6. The method according to claim 4 , wherein m=1 and n=1.

7. The method according to claim 4 , wherein m=1 and n=2.

8. The method according to claim 4 , wherein m=2 and n=1.

9. The method according to claim 1 , wherein X 2 is a (D)-isomer or absent.

10. The method according to claim 1 , wherein X 4 absent.

11. The method according to claim 4 , wherein R 1 is H and m=1.

12. The method according to claim 4 , wherein R 1 is Ac—NH and m=2.

13. The method according to claim 4 , wherein R 2 is —NH(Et), and X 4 and X 5 are absent.

14. The method according to claim 1 selected from the group consisting of from SEQ ID NO:4 to SEQ ID NO:28.

15. The method according to claim 4 , wherein m=1, n=1 and R 1 is NHR 3 .

16. The method according to claim 4 , wherein m=1, n=2, and R 1 is NHR 3 .

17. The method according to claim 4 , wherein m=2, n=1, and R 1 is NHR 3 .

18. A method of treating a patient suffering from rheumatoid arthritis, pulmonary fibrosis, HIV infection, or a cancer, said method comprising administering to said patient a therapeutically effective amount of a compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein

a is 0 or 1;

AA 1 along with the sulfur atom that is attached thereto is 3-mercaptopropionic acid, optionally substituted cysteine, or optionally substituted homocysteine;

AA 2 along with the sulfur atom that is attached thereto is cysteine or homocysteine;

Ar 1 is an optionally substituted aryl;

X 1 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), or Lys(iPr);

X 2 is Arg, Dap, Dab, Orn, Lys, Dap(iPr), Dab(iPr), Orn(iPr), Lys(iPr), D-Arg, D-Dap, D-Dab, D-Orn, D-Lys, D-Dap(iPr), D-Dab(iPr), D-Orn(iPr), D-Lys(iPr), or absent;

X 3 is Gly or absent;

X 4 is Phe, 2Nal, 1Nal, a D-isomer thereof, or absent;

X 5 is Gly or absent;

R 2 is —OR 4 or —NHR 5 ;

R 4 is H or alkyl; and

R 5 is H, alkyl, optionally substituted aryl, optionally substituted aralkyl.

19. The method according to claim 18 , wherein said patient suffers from 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.

20. The method according to claim 18 , wherein said compound is of the formula:

or a pharmaceutically acceptable salt thereof, wherein:

a is an integer 0 or 1;

m and n are independently 1 or 2;

R 1 is H or NHR 3 , wherein R 3 is H, alkyl, acyl, optionally substituted aryl, optionally substituted aralkyl, —C(═O)—Ar a , wherein Ar a is optionally substituted aryl; and

Ar 1 , X 1 , X 2 , X 3 , X 4 , X 5 and R 2 are those defined in claim 18 .