Inhibitors of viral entry into mammalian cells
The present invention is related to the development of compounds and methods for inhibiting viral infection in a mammal. A pseudotype virus was developed for use in a high throughput assay for identifying nonpeptidic small molecule inhibitors that prevent viral entry into a host cell.
1. A method of inhibiting influenza virus infection in a mammal comprising administering an effective amount of at least one compound having the structure comprising Formula I:
wherein:
Ar 1 and Ar 2 are independently an aryl or heteroaryl moiety which may be unsubstituted or substituted by up to 5 substituents selected from the group consisting of halo, amino, amidino, guanidino, alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, alkylamino, acylamino, amido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, and alkylsulfonyl;
R 1 is an alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl moiety that may be unsubstituted or additionally substituted by any of the following substituents selected from the group consisting of cycloalkyl, heterocycloalkyl, aryl, heteroaryl, hydroxy, alkoxy, aryloxy, heteroaryloxy, acyl, carboxy, alkoxycarbonyl, aryloxycarbonyl, amino, alkylamino, acylamino, amido, sulfonamido, mercapto, alkylthio, arylthio, hydroxamate, thioacyl, alkylsulfonyl, and aminosulfonyl;
R 2 and R 3 are independently selected from the group consisting of hydrogen, an alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, hydroxy, alkoxy, amino, alkylamino, and acylamino moiety;
R 4 is selected from the group consisting of hydrogen, a monovalent alkyl, haloalkyl, alkenyl, alkynyl, cycloalkyl, and heterocycloalkyl moiety;
and wherein
R 2 and R 3 may be joined to form carbocyclic or heterocyclic rings; and
where R 2 and R 3 are different, the enantiomer may be of either the (R)- or (S)-configuration, or a racemic compound;
and a pharmaceutically acceptable carrier or excipient.
2. The method according to claim 1 , wherein said compound if effective to inhibit influenza virus entry into a host cell.
3. The method according to claim 1 , wherein said pharmaceutically acceptable carrier or excipient is selected from binding agents, fillers, lubricants, disintegrants, wetting agents, suspending agents, emulsifying agents, non-aqueous vehicles, and preservatives.
4. The method according to claim 1 , wherein said influenza is avian influenza.
5. The method according to claim 4 , wherein said avian influenza is the H5N1 subtype.
6. The method according to claim 1 , wherein said mammal is a human.
7. The method according to claim 1 , wherein said compound is administered via a route selected from intradermally, transdermally, intramuscularly, intraperitoneally, intravenously, or orally.
8. The method according to claim 7 , wherein said compound is administered orally.
9. The method of claim 8 , wherein said oral administration is selected from the group consisting of a tablet, gelatin capsule, microcapsule, and liquid formula.
10. The method according to claim 1 , wherein said compound is selected from the group consisting of:
11. The method according to claim 1 , wherein said compound is selected from the group consisting of: