CXCR4 antagonists and methods of use
The present invention provides compounds that are antagonists of CXCR4 and methods for using the same for treatment of a clinical condition associated with CXCR4 activation. In particular, compounds of the invention include cyclic peptides. Compounds of the invention can be used to treat a variety of clinical conditions, including but not limited to, cancers, pulmonary fibrosis, HIV infection, rheumatoid arthritis, and other immune disorders. In addition, compounds of the invention can also be used in stem cell therapy. In one particular embodiment, compounds of the invention are cyclic peptides 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), a D-isomer thereof, or absent; X 3 is Gly or absent; X 4 is Phe, 2Nal, 1Nal, 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.
1. 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 compound according to claim 1 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 .
3. The compound according to claim 1 , wherein the pharmaceutically acceptable salt is an acetate salt, a hydrochloric acid salt or a triflouroacetate salt.
4. The compound according to claim 2 , wherein a=1 and Ar 1 is an optionally substituted phenyl.
5. The compound according to claim 2 , wherein m=1 and n=1.
6. The compound according to claim 2 , wherein m=1 and n=2.
7. The compound according to claim 2 , wherein m=2 and n=1.
8. The compound according to claim 1 , wherein X 2 is a (D)-isomer or absent.
9. The compound according to claim 1 , wherein X 4 is a (D)-isomer or absent.
10. The compound according to claim 2 , wherein R 1 is H and m=1.
11. The compound according to claim 2 , wherein R 1 is Ac—NH and m=2.
12. The compound according to claim 2 , wherein R 2 is —NH(Et), and X 4 and X 5 are absent.
13. The compound according to claim 1 selected from the group consisting of from SEQ ID NO:4 to SEQ ID NO:28.
14. The compound according to claim 2 , wherein m=1, n=1 and R 1 is NHR 3 , wherein R 3 is as defined in claim 2 .
15. The compound according to claim 2 , wherein m=1, n=2, and R 1 is NHR 3 , wherein R 3 is as defined in claim 2 .
16. The compound according to claim 2 , wherein m=2, n=1, and R 1 is NHR 3 , wherein R 3 is as defined in claim 2 .
17. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.
18. The pharmaceutical composition of claim 17 , wherein said pharmaceutically acceptable excipient comprises a pharmaceutically acceptable carrier, a diluent, an excipient, a binder, a flavoring agent, or a combination thereof.