Aminopiperidines as novel anti influenza agents

Influenza A viruses belong to the orthomyxoviridae family with a negative sense
segmented RNA genome which can cause seasonal or pandemic flu with high morbidity
and significant mortality Vaccination is the most prevalent prophylactic means for
controlling influenza infections However an effective vaccine usually takes at least
months to develop for the circulating strains Furthermore vaccination has limited
effectiveness in treatment of immunocompromised patients and its effectiveness is also
limited during a pandemic The current therapeutic options for flu infections are all based
on the NA inhibitors NAIs while the influenza M ion channel blockers amantadine
and rimantadine are not recommended anymore since all the circulating influenza
strains are resistant to them However the rapid emergence of the NAI resistant strains
of influenza A viruses strongly suggest that NAIs alone may not be sufficient as an
effective means of the anti flu therapies and thus new treatment options targeting the
other viral host factors are urgently needed This application defines a plan to develop
potent small molecule inhibitors which block entry of influenza A viruses We have
identified compounds that inhibit entry of infectious influenza A viruses IC values
M These hit compounds exhibit selectivity for H N and H N entry The overall
objective of this Phase I application is to develop these inhibitors as potential anti flu
therapeutics This application will focus on the following three specific aims
Synthesize structurally diverse analogs of the anti flu CBS hit series based on
structure activity relationships SARs to improve potency and selectivity Validate
the lead inhibitor candidates in the infectious assay and investigate the mechanism of
action MOA of the inhibitors Select flu inhibitors with in vitro ADME properties
suitable for i v and oral dosing Project Narrative
This project is to discover and develop small molecule entry inhibitors for influenza viral
infection The proposed research will help to develop potential antiviral therapeutics