Inhibitors of HIV-1 entry and methods of use thereof

Patent metadata

Field	Value
Publication number	US-9975848-B2
Application number	US-201515503207-A
Country	US
Kind code	B2
Filing date	Aug 13, 2015
Priority date	Aug 13, 2014
Publication date	May 22, 2018
Grant date	May 22, 2018

Abstract

The disclosure provides compositions and methods for sensitizing primary HIV-1, including transmitted/founder viruses, to neutralization by monoclonal antibodies, e.g., those directed against CD4-induced (CD4i) epitopes and the V3 region. In certain embodiments, the disclosure relates to the use of small molecules as microbicides to inhibit HIV-1 infection directly and to sensitize primary HIV-1 to neutralization by readily elicited antibodies.

First claim

We claim:

1. A compound of Formula I

or a salt or solvate thereof,
wherein,
R 1 is

wherein n is 1;
R 2A is H, optionally substituted alkylaminoalkyl, optionally substituted cycloalkylaminoalkyl, or

R 3A is H, optionally substituted alkylaminoalkyl, optionally substituted cycloalkylaminoalkyl, or

R 4A is H, optionally substituted alkylaminoalkyl, optionally substituted cycloalkylaminoalkyl, or

R 5A is H, optionally substituted alkylaminoalkyl, optionally substituted cycloalkylaminoalkyl, or

wherein R 6 is H, C 1-6 alkyl, or C 3-8 cycloalkyl;
provided at least one of R 2a , R 3A , R 4A , or R 5A is optionally substituted alkylaminoalkyl, optionally substituted cycloalkylaminoalkyl, or

2. The compound of claim 1 , wherein R 3A is H.

3. The compound of claim 1 , wherein R 3A is methylaminoalkyl, ethylaminoalkyl, or propylaminoalkyl.

4. The compound of claim 1 , wherein R 3A is alkylamino-CH 2 —.

5. The compound of claim 1 , wherein R 3A is CH 3 —NH—CH 2 — or (CH 3 ) 2 CH—NH—CH 2 —.

6. The compound of claim 1 , wherein R 3A is cyclopropylaminoalkyl, cyclobutylaminoalkyl, cyclopentylaminoalkyl, or cyclohexylaminoalkyl.

7. The compound of claim 1 , wherein R 3A is cyclopropylamino-CH 2 —, cyclobutylamino-CH 2 —, cyclopentylamino-CH 2 —, or cyclohexylamino-CH 2 —.

8. The compound of claim 1 , wherein R 3A is

9. The compound of claim 1 , wherein R 6 is H, methyl, ethyl, isopropyl, or cyclopropyl.

10. The compound of claim 1 , wherein R 2A , R 4A , and R 5A are H.

11. The compound of claim 1 , wherein R 4A is H.

12. The compound of claim 1 , wherein R 4A is methylaminoalkyl, ethylaminoalkyl, or propylaminoalkyl.

13. The compound of claim 1 , wherein R 4A is optionally substituted alkylamino-CH 2 —.

14. The compound of claim 13 , wherein R 4A is CH 3 —NH—CH 2 —, (CH 3 ) 2 CH—NH—CH 2 —, CH 3 —N(CH 2 -phenyl)-CH 2 —, CH 3 —N(—CH 2 CH 2 -phenyl)-CH 2 — or CH 3 —N(CH 2 COOH)—CH 2 —.

15. The compound of claim 1 , wherein R 4A is cyclopropylaminoalkyl, cyclobutylaminoalkyl, cyclopentylaminoalkyl, or cyclohexylaminoalkyl.

16. The compound of claim 1 , wherein R 4A is cyclopropylamino-CH 2 —, cyclobutylamino-CH 2 —, cyclopentylamino-CH 2 —, or cyclohexylamino-CH 2 —.

17. The compound of claim 1 , wherein R 4A is

18. The compound of claim 17 , wherein R 6 is H, methyl, ethyl, isopropyl, or cyclopropyl.

19. The compound of claim 1 , wherein R 2A , R 3A , and R 5A are H.

20. The compound of claim 1 , wherein the compound is

21. The compound of claim 1 , wherein the compound is a single stereoisomer.

22. The compound of claim 1 , wherein the compound is the (R,R) stereoisomer.

23. A complex comprising (i) a compound of claim 1 , (ii) gp120 in a functional conformational state, and (iii) optionally, an antibody.

24. The compound of claim 1 , wherein the compound is:

or a salt thereof.

25. The compound of claim 24 , wherein the compound is:

26. The compound of claim 24 , wherein the compound is a salt of the compound that is:

27. The compound of claim 24 , that is:

Assignees

• Univ Pennsylvania
• Dana Farber Cancer Inst Inc
• Bryn Mawr College

Inventors

• Smith Iii Amos B
• Sodroski Joseph
• Madani Navid
• Melillo Bruno
• Lalonde Judith M
• Princiotto Amy M

Classifications

• C12N2740/16122

  New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes · CPC title

• C12N7/00

  Viruses; Bacteriophages; Compositions thereof; Preparation or purification thereof (preparing medicinal viral antigen or antibody compositions, e.g. virus vaccines, A61K39/00) · CPC title

• C07K14/005

  from viruses · CPC title

• A61K39/42

  viral · CPC title

• A61K31/167

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