CD4-mimetic inhibitors of HIV-1 entry and methods of use thereof
Described herein are small-molecule mimics of CD4, which both enter the Phe43 cavity and target Asp368 of gp120, the HIV-1 envelope protein. Also described herein are methods of using these compounds to inhibit the transmission or progression of HIV infection. These compounds exhibit antiviral potency greater than that of a known antiviral, NBD-556, with 100% breadth against clade B and C viruses. Importantly, the compounds do not activate HIV infection of CD4-negative, CCR5-positive cells, in contrast to NBD-556.
1. A compound of Formula VII
or a pharmaceutically acceptable salt or solvate thereof,
wherein
R 1 is
R 2 is —H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, optionally substituted alkoxy, optionally substituted amino, or halo;
R 3 is —H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, optionally substituted alkoxy, optionally substituted amino, or halo;
R 4 is —H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, optionally substituted alkoxy, optionally substituted amino, or halo;
R 5 is —H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, hydroxy, optionally substituted alkoxy, optionally substituted amino, or halo; and
n is 0, 1, 2, 3, 4, or 5.
2. The compound of claim 1 , wherein n is 1 or 2.
3. The compound of claim 1 , which is a compound of Formula IV
or a pharmaceutically acceptable salt or solvate thereof,
wherein m is 1.
4. The compound of claim 1 , which is a compound of Formula V
or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.
5. The compound of claim 1 , which is a compound of Formula VI
or a pharmaceutically acceptable salt or solvate thereof, wherein m is 1.
6. The compound of claim 1 , which is
or a pharmaceutically acceptable salt thereof.
7. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
8. A method of activating HIV exterior envelope glycoprotein gp120, inhibiting transmission of HIV to a cell, or inhibiting the progression of HIV infection in a cell comprising the step of:
contacting HIV with an effective amount of a compound of claim 1 , thereby activating HIV exterior envelope glycoprotein gp120, inhibiting transmission of HIV to said cell, or inhibiting progression of HIV in said cell.
9. The method of claim 8 , wherein the method is a method of inhibiting transmission of HIV to a cell or inhibiting the progression of HIV infection in a cell, further comprising the step of:
contacting HIV with an effective amount of an exogenous ligand mimicking the chemokine receptor expressed on said cell.
10. The compound of claim 1 , wherein R 1 is
one of R 2 , R 3 , R 4 , and R 5 is halo; three of R 2 , R 3 , R 4 , and R 5 are —H; and n is 1.
11. The compound of claim 1 , wherein R 1 is
one of R 2 and R 3 is halo; one of R 2 and R 3 is —H; R 4 is —H; R 5 is —H; and n is 1.
12. The compound of claim 1 , wherein R 1 is
R 2 is —H; R 3 is halo; R 4 is —H; R 5 is —H; and n is 1.
13. The compound of claim 1 , wherein R 1 is
one of R 2 , R 3 , R 4 , and R 5 is —Cl or —Br; three of R 2 , R 3 , R 4 , and R 5 are —H; and n is 1.
14. The compound of claim 1 , wherein R 1 is
one of R 2 and R 3 is —Cl or —Br; one of R 2 and R 3 is —H; R 4 is —H; R 5 is —H; and n is 1.
15. The compound of claim 1 , wherein R 1 is
R 2 is —H; R 3 is —Cl or —Br; R 4 is —H; R 5 is —H; and n is 1.
16. The compound of claim 1 , wherein R 1 is
R 2 is —H; R 3 is substituted alkyl; R 4 is —H; R 5 is —H; and n is 1.
17. The compound of claim 1 , wherein R 1 is
R 2 is —H; R 3 is substituted methyl; R 4 is —H; R 5 is —H; and n is 1.
18. A pharmaceutical composition comprising a compound that is
or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.
19. The method of claim 8 , wherein the compound is
20. A method of treating HIV in a patient comprising administering to the patient a compound of claim 1 .
21. The method of claim 20 , wherein the compound is