CD4-mimetic inhibitors of HIV-1 entry and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9403763-B2
Application number	US-201214365389-A
Country	US
Kind code	B2
Filing date	Dec 14, 2012
Priority date	Dec 14, 2011
Publication date	Aug 2, 2016
Grant date	Aug 2, 2016

Abstract

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.

First claim

We claim:

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

Assignees

• Dana Farber Cancer Inst Inc
• Univ Pennsylvania
• Us Health
• Bryn Mawr College
• Univ Johns Hopkins
• Univ Columbia

Inventors

• Sodroski Joseph
• Lalonde Judith M
• Smith Iii Amos B
• Kwong Peter D
• Kwon Young Do
• Jones David M
• Sun Alexander W
• Courter Joel R
• Soeta Takahiro
• Kobayashi Toyoharu
• Princiotto Amy M
• Wu Xueling
• Mascola John R
• Schon Arne
• Freire Ernesto
• Madani Navid
• Le-Khac Matthew
• Hendrickson Wayne A
• Park Jongwoo

Classifications

• C07D235/02

  condensed with carbocyclic rings or ring systems · CPC title

• A61K31/167

  having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol · CPC title

• C07C279/16 Primary

  having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings · CPC title

• C07D207/335

  Radicals substituted by nitrogen atoms not forming part of a nitro radical · CPC title

• C07C237/22

  having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated (peptides C07K) · CPC title