Compounds that modulate negative-sense, single-stranded RNA virus replication and uses thereof
The present invention relates to compounds that modulate the replication of negative-sense, single-stranded RNA viruses, such as influenza virus, and the use of such compounds. The invention relates to methods for increasing the titer of negative-sense, single-stranded RNA viruses, such as influenza virus, in substrates for virus propagation (e.g., tissue culture). The invention also relates to the use of compounds that decrease virus replication as antiviral agents. The invention further relates to methods for identifying compounds that modulate the replication of negative-sense, single-stranded RNA viruses, in particular, influenza virus.
1. A method of inhibiting replication of a negative-sense, single-stranded RNA virus in an animal subject, or preventing, treating or managing an influenza virus infection comprising administering to an animal subject in need thereof an effective amount of a compound with the formula
or a pharmaceutically acceptable salt, hydrate, solvate, prodrug or stereoisomer thereof, wherein:
R 1 and R 2 are at each occurrence independently a C 1 -C 8 alkyl group; or
R 1 and R 2 , together with the nitrogen atom R 1 and R 2 are bound to, form a 3 to 8 membered saturated heterocyclic ring.
2. The method of claim 1 , wherein the compound is 2-(5-(2,3-dimethyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-ylthio)-1-(pyrrolidin-1-yl)ethanone (“A3”); 2-(5-(2,3-dimethyl-1H-indol-5-yl-1,3,4-oxadiazol-2-ylthio-N,N-diethylacetamide (“A3-2”); 2-(5-(2,3-dimethyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-ylthio)-1-(indolin-1-yl)ethanone (“A3-3”); 2-(5-(2,3-dimethyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-ylthio)-N,N-diisopropylacetamide (“A3-4”); 2-(5-(2,3-dimethyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-ylthio)-1-morpholinoethanone (“A3-5”); or 1-(azepan-1-yl)-2-(5-(2,3-dimethyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-ylthio)ethanone (“A3-6”).
3. The method of claim 2 , wherein the compound is 2-(5-(2,3-dimethyl-1H-indol-5-yl)-1,3,4-oxadiazol-2-ylthio)-1-(pyrrolidin-1-yl)ethanone (“A3”).
4. The method of claim 1 , wherein the negative-sense, single-stranded RNA virus is a paramyxovirus or orthomyxovirus.
5. The method of claim 1 , wherein the negative-sense, single-stranded RNA virus is influenza virus, NDV, VSV, or Sendai virus.
6. The method of claim 1 , wherein the animal subject is a human subject.